Non-antigen-specific tolerance-based clinical trials for type 1 diabetes.
1. Introduction
Type 1 diabetes, formerly termed insulin-dependent diabetes mellitus (IDDM), is a chronic organ-specific autoimmune disorder thought to be caused by proinflammatory autoreactive CD4+ and CD8+ T cells, which mediate progressive and selective damage of insulin-producing pancreatic beta-cells (Atkinson & Eisenbarth, 2001). The reduction of beta-cell mass leads to a lack of insulin and thereby loss of blood glucose control (Boettler &von Herrath, 2010).
The worldwide prevalence of T1D was estimated to be 171 million cases among the adult population (Wild et al., 2004). Its annual incidence varies widely from one country to another (from less than 1 per 100,000 inhabitants in Asia to approximately up to 25/100,000 population/year in North America, more than 30 per 100,000 in Scandinavia and up to 41/100,000 population/year in Europe). It is in steady increase across the globe, especially among children aged less than five years (Kajanderet al., 2000, Vija et al., 2009).
According to the European Diabetes (EURODIAB) study group, the prevalence of T1D in Europe will increase significantly in children younger than 15 years of age to reach 160,000 cases in 2020 (Patterson et al., 2009). These data will result in an increasing number of patients with longstanding diabetes and with a risk of serious complications (Kessler, 2010). These include heart diseases and strokes, high blood pressure, renal failure and ketoacidosis (DKA) (Boettler &von Herrath, 2010).
To date, it has not been possible to prevent the autoimmune response to beta-cells in human, due probably to its unknown aetiology, although it is known that development of T1D is genetically controlled and thought to be initiated in susceptible individuals by environmental factors such as virus infections (Luo et al., 2010, Mukherjee & DiLorenzo, 2010, von Herrath, 2009).
It is now evident that targeted destruction may go undetected for many years, but antibodies to various beta-cell antigens can be easily demonstrable in the sera of patients at risk before clinical onset (Achenbach et al., 2005). Additionally, some endogenous insulin secretion is generally present at the onset of clinical diabetes (Scheen, 2004), during which time, immunotherapeutic intervention may be effective (Staeva-Vieira et al., 2007).
This chapter emphasizes the principal immunological risk markers of T1D and especially the role of cell-mediated immune response leading to pancreatic beta-cells destruction, as well as the most promising immunotherapeutic approaches for prevention and treatment of the disease.
2. Autoimmunity of the type 1 diabetes
The autoimmune nature of T1D is initially affirmed by several arguments that are primarily indirect, including the association with other autoimmune diseases (Barker, 2006), such as the autoimmune thyroid disease (Hashimoto thyroiditis or Graves disease) (Criswell et al., 2005, Levin et al., 2004), Addison disease (Barkeret al., 2005), myasthenia or Biermer’s anemia, and the detection of various autoantibodies (Seyfert-Margolis et al., 2006) and islet lymphocytes infiltrates (Bach, 1979).
2.1. Humoral markers of type 1 diabetes
Although T1D is primarily mediated by mononuclear cells (Carel et al., 1999), diagnosis means of the preclinical period are primarily markers of humoral immune response that are represented, for instance, by antibodies to beta-cell antigens, including glutamic acid decarboxylase 65, insulin, insulinoma-associated protein 2 islet tyrosine phosphatase, islet cell cytoplasm and more recently zinc transporter 8 (Luo et al., 2010) (Fig. 1). Studies of twins or in subjects with a family history of autoimmune diabetes have shown that these markers, when associated in the same subject, confer very high risk of developing diabetes within 5 years (Verge et al., 1996). The predictive value increases from less than 5% in the absence of antibodies to more than 90% when antibodies to GAD, tyrosine phosphatase IA-2 and insulin are present (Bingley et al., 1999, Verge et al., 1996). Additionally, taken in aggregate, the use of the level of autoantibody can provide additional predictive information for the persistence of autoantibodies and development of T1D (Barker et al., 2004). Moreover, among metabolic risk markers, the loss of first phase insulin response to intravenous glucose has the same prediction value with multiple positive antibodies when it is associated with one of these autoantibodies (Krischer et al., 2003). Furthermore, the predictive value of having multiple autoantibodies can increase significantly by the presence of a high-risk genotype, with a positive predictive value of 67% in multiple antibody–positive DR3/4 individuals, versus 20% in those without DR3/4 (Yamamotoet al., 1998). While, high sensitivity and specificity are required for detection of prediabetes in the general population where the prevalence is of the order of 0.3% even when genetic susceptibility markers are also included (Hermann et al., 2004).
2.1.1. Islet cell autoantibodies
These are markers with best predictive value (Bonifacio & Christie, 1997), because of their high sensitivity to the pancreatic insulite (Kulmala et al., 1998) and their high specificity for T1D (Gorsuchet al., 1981).
Islet cell autoantibodies (ICAs) have been the first disease-specific autoantibodies to be described in patients with T1D (Bottazzo et al., 1974). They appear until ten years before the clinical onset of diabetes (Rileyet al., 1990). ICA corresponds to a compounding of different specificities antibodies, because they can be fixed on all cellular types of antigenic structures present in the islet cell cytoplasm (Atkinson & Maclaren, 1993).
High ICA levels could be a marker of strong autoimmune reaction and accelerated depletion of beta-cell function (Zamaklaret al., 2002). In prediabetic subjects, a higher ICA titer is associated with a higher risk for T1D development (Mire-Sluis et al., 2000). In newly diagnosed type 1 diabetic patients, ICAs are present in 80%, and ICA reactivity often waned after diagnosis, with no more than 5% to 10% of patients remaining ICA positive after 10
years (Gilliamet al., 2004). Thefrequency of the positive ICA is 80% to 100%(Schatzet al., 1994) of revelation for a 25 years old T1D or less (Elfvinget al., 2003). It decreases remotely by the primo-decompensation, reaching approximately 3% in related subjects aged of less than 20 years (Schatzet al., 1994).
ICAs are highlighted by indirect immunofluorescence (Borg et al., 2002a, Elfvinget al., 2003, Perez-Bravo et al., 2001) on sera incubated with human blood group O pancreas (Takahashi et al., 1995, Thivolet & Carel, 1996). They can be also detected by complementary-fixing antibody (Knip et al., 1994, Montanaet al., 1991), since they mainly belong to the IgG1 subclass antibodies (Bottazzoet al., 1980). The increase in ICAs may indicate the presence of other autoantibodies, corresponding to more IgG1subclasses (Dozio et al., 1994). Association with other autoantibodies increases the test specificity, with a decrease in sensitivity however (Thivolet & Carel, 1996). ICA levels that exceed 80 JDF (Juvenile Diabetes Foundation) units at the time of diagnosis despite better beta-cell function are associated with short clinical remission (Zamaklaret al., 2002), and include 53% of disease development risk in five years following their revelation (Dozio et al., 1994). Nevertheless, the high levels of ICA found in the family relatives do not necessarily lead to T1D development (Bingley, 1996). Likewise, the low rates of these antibodies lessen the disease risk (Bonifacioet al., 1990).
2.1.2. Insulin autoantibodies
It would be important to recall that protective alleles of insulin gene
Insulin autoantibodies (IAAs) are of weak prevalence at the time of diagnosis (Breidertet al., 1998). Their levels are increased especially in prediabetics (Palmer et al., 1983), but also in newly diagnosed type 1 diabetic subjects. Additionally, IAAs could be confused with insulin antibodies (IAs) produced following injection of exogenous insulin; therefore, we cannot assess the real level of IAAs in treated patients (Gilliamet al., 2004).
On the other hand, various studies have shown that the elevated IAA frequency and levels are observed mainly in young children (Landin-Olsson et al., 1992) and HLA DR4 subjects (Achenbachet al., 2004, Savola et al., 1998 ,Ziegler et al., 1991). Moreover, IAAs could be detected in all children who develop diabetes when they are associated with multiple autoantibodies. Furthermore, these antibodies confer high risk in T1D relatives (Ziegler et al., 1989), essentially in combination with other autoimmune markers (Bingleyet al. 1999, Thivoletet al., 2002, Winnocket al., 2001). However, the actual frequency of positivity varies considerably from one study to another, according to the IAA assay, age at diagnosis, as well as the populations studied (Gilliamet al., 2004).
Interestingly, IAAs do not necessarily reflect beta-cell destruction. Indeed, they have been reported to occur in other autoimmune diseases, such as Hashimoto thyroiditis, Addison disease, chronic hepatitis, pernicious anemia, systemic lupus erythematosis, and rheumatoid arthritis (Di Mario et al., 1990).
IAAs can be detected by two assay methods, a fluid-phase radioimmunoassay (RIA) and a solid-phase enzyme-linked immunosorbent assay (ELISA); however, it has been shown that IAAs measured by RIA were more closely linked to T1D development than those measured by ELISA (Murayamaet al., 2006, Schlosseret al., 2004, Schneideret al., 1976, Wilkin et al., 1988).
2.1.3. Glutamic acid decarboxylase autoantibodies
Of note, a 64kDa islet cell protein was initially isolated by precipitation with autoantibodies present in sera of patients with T1D (Baekkeskov et al., 1982). After laborious searches, this protein was identified as glutamic acid decarboxylase (GAD) (Baekkeskov et al., 1990); the enzyme that synthesizes the gamma-aminobutyric acid neurotransmitter in neurons and pancreatic beta-cells (Dirkx et al., 1995). At that time, GAD autoantibodies had been demonstrated to have a common identity in patients with stiff-man syndrome (SMS) and T1D (Baekkeskov et al., 1990; Solimena et al., 1988). During the same period, GAD complementary deoxyribonucleic acid (GAD cDNA) cloning demonstrate that there are two different genes of GAD, designated GAD1 and GAD2 (Bu et al., 1992, Erlander et al., 1991, Karlsen et al., 1991), located on chromosome 2q31.1 and chromosome 10p11.23, respectively (Bennett et al., 2005). GAD1 mRNA has been reported to be translated into GAD67, which is not detected in human islets (Karlsen et al., 1991), but is predominantly found in mouse islets (Petersen et al., 1993, Velloso et al., 1994). The mRNA for GAD2 gene encodes the GAD65kDa isoform that is expressed in human pancreatic islets and brain (Gilliam et al., 2004).
GAD65 autoantibodies (GAD65A) are revealed in 70% to 80% of cases among prediabetic subjects and newly diagnosed patients (Kulmala et al., 1998). They are considered as a good retrospective marker of the autoimmune progression, because of their persistence in the sera of patients with T1D for many years following diagnosis (Borg et al., 2002b). Whereas, these antibodies have a low positive predictive value for beta-cell failure (47%) compared to ICAs (74%) (Borg et al., 2001) and can be revealed in patients with neurological disorders, including those with gamma-aminobutyric acid (GABA)-ergic alterations (Piquer et al., 2005, Solimena et al., 1990). Similarly, they can be present in patients who have other autoimmune diseases (Davenport et al., 1998, Nemni et al., 1994, Tree et al., 2000) as well as in patients with type 2 diabetes (Hagopian et al., 1993, Tuomi et al., 1993). Consequently, they don’t seem to be specific to pancreatic beta-cells destruction (Wie et al., 2004, Costa et al., 2002).
GADAsare usually detected by radioligand-binding assay, which is reported to have higher sensitivity, specificity, and reproducibility than other methods using ELISA, enzymatic immunoprecipitation, and immunofluorescence assays (Damanhouriet al., 2005, Knowleset al., 2002, Kobayashiet al., 2003).
2.1.4. Anti-tyrosin phosphatase autoantibodies
These antibodies are directed against two digestion fragments (Jun & Yoon, 1994; Maugendre et al., 1997) resulting from trypsin hydrolysis of transmembrane protein expressed in islets and the brain, and are present in two related forms with distinct molecular weights, 40kDa and 37kDa (Bonifacio et al., 1995a, Li et al., 1997, Yamada et al., 1997).
Of note, the 40kDa antigen is the receptor tyrosine phosphatase-like protein IA-2 associated with the insulin secretory granules of pancreatic beta-cells (Trajkovski et al., 2004), also called islet cell autoantigen 512 (ICA512)/IA-2 (Bonifacioet al., 1995b, Payton et al., 1995). The 37kDa antigen is a tryptic fragment related protein tyrosine phosphatase, designated IA-2
It has been shown that antibodies to the two antigens have similar sensitivity; however, epitope mapping studies have suggested that antibodies to IA-2 (IA-2A, insulinoma-associated protein 2 islet tyrosine phosphatase) appear to be more important for the pathogenesis of T1D than those to IA-2
IA-2As can be evaluated by radioligand-binding assay and ELISA (Bonifacioet al., 2001; Chen et al., 2005a, Kotani et al., 2002); whereas, RIAs performed much better than ELISAs, as was found for GAD65A assays (Verge et al., 1998).
2.1.5. Zinc transporter 8 autoantibodies
The human beta-cell-specific zinc transporter Slc30A8 (ZnT8) is a member of the large cation efflux family of which at least seven are expressed in islets (Chimienti et al., 2004).It has been recently defined as a major target of humoral autoimmunity in human T1D based on a bioinformatics analysis (Dang et al., 2011, Wenzlau et al., 2009). Autoantibodies to ZnT8 (ZnT8A) have been therefore detected in high prevalence in newly diagnosed type 1 diabetic patients (Yang et al., 2010) and obviously overlap with GADA, IA2A, and IAA (Wenzlau et al., 2007).
Of note, ZnT8 autoimmunity could be an independent marker of T1D,given that ZnT8As can be present in antibody-negative individuals andin type 2 diabetes, and in patients with other autoimmune disorders (Wenzlau et al., 2008).
Antibodies to ZnT8 can be measured by radioimmunoprecipitation assay using 35S labelled methionine
2.2. Immunological anomalies of type 1 diabetes and cellular autoimmunity
In reality, our understanding of the exact cellular immune mechanisms that lead to the development of T1D is limited, and it is possible that the potential target autoantigens may be less well defined and more diverse, probably because of the epitopes diversification.
The immune reaction against beta-cells is due primarily to a deficit in the establishment ofcentral thymic tolerance and the activation of potentially dangerous autoreactive T cells and B cells that recognize isletantigens. Additionally, aggression of the beta-cells may be initiated by other cells and components of the innate immune system. In fact, it has been observed that the immune cells peripheral infiltration of the Langerhans islets, a process termed perished-insulitis, begins initially with the monocytes/macrophages and dendritic cells (DCs) (Rothe et al., 2001, Yoon et al., 2005, Yoon et al., 2001). Upon exposure to antigens, islet-resident antigen presenting cells, likely DCs, undergo maturation, leading to the expression of cell surface markers that are subsequently required for T cell activation in the pancreatic lymph nodes (panLN). CD4+ T cells and macrophages home to islets and release pro-inflammatory cytokines and other death signals that acutely trigger necrotic and pro-apoptotic pathways (Fig.2).
2.2.1. T cells and B cells
Although both humoral and cell-mediated immune mechanisms are active during T1D, CD4+ and CD8+ T cells recognizing islet autoantigens are the main actors of beta-cells death (DiLorenzoet al., 2007, Gianani&Eisenbarth, 2005, Tomaet al., 2005). B cells may play a role in inducing inflammation and presentation of self-antigen to diabetogenic CD4+ T cells (Silveira et al., 2007).
It has been repeatedly observed that the pancreatic islets of diabetic patients prior to and at diagnosis are infiltrated by T lymphocytes of both CD4 and CD8 subsets (Hanninenet al., 1992, Imagawa et al., 2001, Kentet al., 2005). Additionally, their circulating number among type 1 diabetic patients is higher than those of B cells (Martin et al., 2001). Moreover, the disease can be transferred to NOD-
2.2.2. CD4+ and CD8+ T cells and ways of beta-cells destruction
The precise role of each of these cells in pancreatic islets destruction remains unclear and controversial. Therefore, two main pathways may be involved in triggering the disease, both of which are activated following recognition of beta-cell autoantigens.
According to the indirect way, the critical role in T1D development could be attributed to autoreactive CD4 T cells, as exemplified by the observation that the major histocompatibility complex class II (MHC II) genes are the main candidate genes to which a key role can be assigned in the autoimmune process according to their strong association with the disease (Aribi, 2008, Concannonet al., 2009). These cells can initiate beta-cells destruction and lead to tissue cell damage (Peterson & Haskins, 1996), through the secretion of cytokines with toxic effects (Amrani et al., 2000), then recruit T CD8+ lymphocytes (McGregoret al., 2004).
According to the direct way, autoreactive T CD8+ lymphocytes (Anderson et al., 1999) could initiate beta-cells destruction, as shown in transgenic TCR (NOD/AI4αβ Tg) NOD mice, that T1D autoimmunity beginning can be achieved in total absence of CD4+ T cells and requires only CD8+ T cells (Graser et al., 2000). Additionally, disease development is reduced only when adult NOD mice are injected with anti-class I MHC molecules or anti-CD8 mAb molecules (Wang et al., 1996). Moreover, β2-microglobulin-deficient (β2m–/–) and anti-CD8 mAb-treated NOD mice, yet deficient in CD8+ T cells develop neither insulitis nor T1D (Yang et al., 2004).
However, direct evidence for these observations is compelling only in animal models in which adoptive transfer experiments are feasible ethically (Di Lorenzo et al., 2007). Additionally, several differences can be revealed between men and animal models of T1D. For example, in men, immunohistological studies of type 1 diabetic pancreatic-biopsy showed a strong number of islet-infiltrated CD8+ cytotoxic T cells compared to that of islet-infiltrated CD4+ T helper cells (Itoh et al., 1993). In contrast, in NOD mice, pancreatic islets are infiltrated predominantly by CD4 + T cells compared to CD8+ T cells(Kida et al., 1998).
2.2.3. Regulatory T cells/effectors T cells imbalance
The primary function of Treg cells is the maintenance of self-tolerance in order to prevent the development of autoimmune diseases (Sakaguchi et al., 1995). They also have the ability to control a runaway immune response by different feedback mechanisms, involving the production of anti-inflammatory cytokines, direct cell-cell contact or modulating the activation state of antigen-presenting cells (AgPCs) (Corvaisier-Chiron & Beauvillaina, 2010). Normal tolerance to self-antigens is an active process that has a central component and a peripheral component. Central tolerance implies induction of tolerance in developing lymphocyte when they encounter self-antigens that are present in high concentration in the thymus or bone marrow; while peripheral tolerance is maintained by mechanisms of self-reactive T cells elimination by clonal deletion, anergy or ignorance(Wallace et al., 2007). AmongthesethreemechanismsonlythedeletionisinducedbyTreg cells(Corvaisier-Chiron & Beauvillaina, 2010).
Different subpopulations of Treg cells have been identified: natural Treg (nTreg) cells that drived from the thymus and migrate to peripheral tissues, and peripherally induced Treg (iTreg) (Corvaisier-Chiron & Beauvillaina, 2010). nTreg cells represent 2-4% of circulating lymphocytes in humans (Wahlberg et al., 2005) and are characterized by the expression of CD4, CD25high, CD127low molecules and high levels of the transcription factor FoxP3 (forkhead box P3) (Corvaisier-Chiron & Beauvillaina, 2010, Wahlberg et al., 2005). They also express surface CTLA-4 (cytotoxic T lymphocyte-associated antigen 4) and GITR (TNF receptor family glucocorticoidinduced-related gene) involved in membrane mechanisms of Treg suppression (Corvaisier-Chiron & Beauvillaina, 2010).
Except pathological conditions, there is a balance between regulatory T cells and effector T cells. Some genetic and environmental factors might cause deregulation of this balance in favor of self-reactive lymphocytes that may induce or predispose to the development of autoimmune diseases, including T1D (Brusko et al., 2008).
In NOD mice and diabetic patients and in several organ-specific animal models of autoimmunity as well as in humans (Furtado et al., 2001, Kriegel et al., 2004;Kukreja et al., 2002), it has been demonstrated that number and/or function of peripheral regulatory cells affecting both nTreg cells (CD4+CD25+Foxp3+) (Fontenotet al., 2003, Horiet al., 2003, Khattrial., 2003) and natural killer (NK) T cells (Duarte et al., 2004, Hong et al., 2001) are decreased; while self-reactive peripheral T cells number is increased (Berzins et al., 2003). Additionally, decreased contacts between effectors and nT-reg cells seem to belong to additional events leading to autoreactive T cells activation and proliferation (Lindley et al., 2005, Maloy & Powrie, 2001, Piccirillo et al., 2005).
On the other hand, various studies showed that T1D in both humans and NOD mice could be due to the weak secretion of IL-4 resulting from a deficiency in NK T cells (Lehuen et al., 1998, Wilson et al., 1999) and that diabetes can be prevented in mice by transfer of NK T cell–enriched CD4–CD8– double negative cells (Baxter et al., 1997, Falcone et al., 1999, Lehuen et al., 1998) or of thymic-derived nT-reg cells (Chen et al., 2005b, Lindley et al., 2005, Luo et al., 2007).
2.2.4. Regulatory T cells/Th17 cells imbalance
Th17 cells represent a subtype of T cells that can be generated in the presence of IL-23 even from cells deficient in transcription factors required for Th1 (T-bet) or Th2 (GATA-3) cells development (Harrington et al., 2005, Park et al., 2005). However, IL-23 would not be a factor for Th17 cells differentiation but rather intervene in their survival and proliferation. In fact, naive T cells do not express receptors for IL-23 and do not differentiate into Th17 cells only in the presence of IL-23 (Mangan et al., 2006). Additionally, Th17 cells express a specific transcription factor, RORC2 (retinoic acid receptor-related orphan receptor C2, known as RORγt in mice), which is crucial for the generation of Th17 cells, especially via the transcriptional induction of the gene encoding IL-17 and the expression of IL-23 receptor (Ivanov et al., 2006). To acquire a full differentiation of such cells, RORC2 acts in cooperation with other transcription factors, including RORα, STAT3, IRF-4 and Runx1 (Miossec et al., 2009).
The discovery of factors involved in the differentiation of Th17 and Treg cells suggests the existence of Treg/Th17 balance, controlled by IL-6 (Kimura et al., 2011). More recently, increased Th17 immune responses or imbalance of nTreg cells and IL-17 producing Th17 have been found to be associated to the onset of the disease in both humans and NOD mice or Diabetes-prone BioBreeding (DP-BB) rats (Honkanenet al., 2010, Shi et al., 2009, van den Brandt et al., 2010). While, these observations should be confirmed further.
2.2.5. Th1/Th2 imbalance
Different factors, including physical, psychological, and chemical stress (Ernerudh et al., 2004) can produce imbalance in the proportions of CD4+ Th1 cell and CD4+ Th2 cell subsets (Eizirik et al., 2001, Rabinovitch et al., 1994, Thorvaldson et al., 2005). Several studies have shown that the autoimmune aggression leading to T1D involves Th1 cells (Kida et al., 1999, Sharif et al., 2002,Yoon & Jun, 2005). However, Th2 cells seem to be associated with protection against beta-cells destruction (Cameron et al., 1997, Ko et al., 2001, Suarez-Pinzon & Rabinovitch, 2001).
In NOD mouse model, T1D can be transferred among animals through the injection of Th1 cells (Kukreja et al., 2002). T1D-sex relationship has been linked to the type of produced cytokines. Lymphocytes infiltrating female mice pancreatic islets produce high levels of Th1 cytokine mRNA and low levels of Th2 cytokine mRNA. On the other hand, male mice are more resistant to T1D because they produce more Th2 cytokine mRNA and less cytokine Th1 mRNA (Azar et al., 1999, Fox &Danska, 1997). Likewise, young NOD mice spleenocytes expressing CD62L and CD25, i.e. CD4+CD45RBlow (memory/activated cells) which are involved in dominant protection against T1D development, show an overproduction of Th2 cytokines, yet tend towards an overproduction of Th1 cytokines right before diabetes onset (Shimada et al., 1996). Besides, female NOD mice have more spleenocytes CD45RBlow CD4+ and more spleenocytes CD4+CD25+ activated helper cells than do male NOD mice have (Azar et al., 1999). Moreover, it is possible to prevent T1D in NOD mice with a single injection of insulin or GAD peptide (Han et al., 2005), because it causes a reduction in levels of Th1 cytokines and an increase in the ones of Th2 cytokines (Muir et al., 1995, Sai et al., 1996).
2.2.6. Innate immunity
It has been recently observed that innate immunity may play a critical role in the development of T1D. This observation has been supported by works showing that infusions of alpha-1 antitrypsin, a serine protease inhibitor that protects tissues from enzymes produced from inflammatory cells, were found to reverse new-onset diabetes in NOD mice (Koulmandaet al., 2008). Many effects have been described, including reduced insulitis, enhanced beta-cell regeneration, and improvement in peripheral insulin sensitivity (Luo et al., 2010).
Thanks to many experiments conducted in animal models, it has been shown that toll-like receptors (TLRs), as part of the innate immune system, may have an important role in T1D development (Filippi & von Herrath, 2010). For example, injection of low dose of TLR-3 stimulus poly I:C has been shown to prevent diabetes in the disease-prone Biobreeding rat model (Sobel et al., 1998). Inaddition, TLR deficiency has been associated with decreased number of some Treg. Indeed, T cells with a regulatory phenotype can express TLR-2, TLR-4, TLR-5, TLR-7 and TLR-8 (Caramalho et al., 2003; Sutmuller et al., 2006), and the proliferation of Treg cells has been observed especially following the administration of TLR-2 ligands to TLR-2-deficient mice (Sutmuller et al., 2006). Moreover, it has been suggested that protection against T1D in NOD mice through infection with Lymphocytic Choriomeningitis Virus (LCMV) is dependent on the emergence of Tregs and TLR-2 (Boettler & von Herrath, 2011).
2.2.7. Macrophages
Macrophages play a significant role in the oxidative stress (Ishii et al., 1999, Rozenberg et al., 2003), innate immunity (Bedoui et al., 2005, Lawrence et al., 2005) and inflammation (Ishii et al., 1999;Lawrence et al., 2005). Macrophages and other AgPCs in the panLN(Pearl-Yafe et al., 2007) initiate T cell sensitization, and concomitantly activate regulatory mechanisms (Kaminitz et al., 2007). The central role of macrophagesin the cellular immune response (Durum et al., 1985) and in the development and activation of beta-cell-cytotoxic T cells during T1D (Yoon & Jun, 2001) has been previously proven in BioBreeding (BB) rats where a macrophage insulitis preceding lymphocyte insulitis could be prevented by a silica intraperitoneal injection (Albina et al., 1991). However, macrophages are also able to exert a suppressor effect on lymphocyte proliferation (Albina et al., 1991, Taylor et al., 1998, Zhang & McMurray, 1998). This effect is exerted on T and B cells alike and is mediated by several ways involving especially prostaglandins and nitric oxide as metabolic mediators (Albina et al., 1991, Ding et al., 1988, Jiang et al., 1992).
A mechanism by which macrophages intervene preferentially in Th1 and Th2 clones differentiation has been suggested. Hence, macrophages can interact with Th cells and induce polarization toward the Th1 or Th2 cell subset depending on the oxidation level of their glutathione content. With low levels of oxidized glutathione, they induce a polarization toward Th1 phenotype, whereas high levelsofoxidized glutathioneleadtoTh2 differentiation (Murata et al., 2002).Additionally, some IL-12 antigenic stimulations induce Th1 cells activation (Hsieh et al., 1993). Th2 cells activation goes through the action of IL-4 and IL-10, which can also be produced by activated macrophages in the presence of immune complexes (Fiorentino et al., 1991).
2.2.8. Dendritic cells
DCs play an important role in initiating the immune response and antigen presentation, as well as in maintaining peripheral self-tolerance (Steinman et al., 2003). There are mostly immature DCs (iDCs), which have poor antigen presentation functions (de Vrieset al., 2003), may be involved in immunoregulatory functions in autoimmune processes (Dorman et al., 1997). These functions depend largely on co-stimulation during the maturation process. Thus, tolerogenic DCs are iDCs with reduced allostimulatory capacities and lowexpressionlevelsof costimulatorymolecules, like CD40, CD80andCD86 molecules. However, the transition tothemature state, followingexposure to pathogens,leads to increased antigen presentation and expression of T cell co-stimulatory molecules and T cell responses (Steinman &Banchereau, 2007).
Nevertheless, theacquisitionof ahigh degreeofmaturityandexpressionof adhesion molecules, especiallyCD86molecule, allowstheDCsto provokethe activationofCD4+CD25+ regulatory T cells capable of inhibiting autoimmune disease (Yamazaki et al., 2003). ItisthereforequitepossiblethattheDCs involvedin triggeringtheautoimmune processleadingtoT1D(Clare-Salzler et al., 1992, Feutren et al., 1986, Mathis et al., 2001),aremature cells withalargecapacityforantigen presentation, butwithouteffectonregulatory T cells.
Additionally, ithas been shownthatDCs are the initiators of the islet infiltration in NOD mice (DiLorenzo et al., 2007).Such cells isolatedfrom the panLN could prevent diabetes development when transferred adoptively to young recipients (Bekris et al., 2005), while those from other sites could not,suggestingthat the activationofautoreactiveT cellsoccurs at this site and that their suppression would be due to deletion or regulation mechanisms (Belz et al., 2002, Hugues et al., 2002).
2.2.9. Adhesion and costimulation molecules and cell signaling
T-cell-receptor (TCR)-mediated recognition of pancreatic autoantigens is a central step in the diabetes pathogenesis (Bach, 2002). Interaction between TCR and pancreatic peptides aberrantly complexed with class II MHC molecules on pancreatic beta-cells (Foulis, 1996) or expressed on the AgPCs in panLN is required for the activation of Th1 lymphocytes. Similarly, TCR interaction with autoantigen peptides presented by class I MHC molecules on pancreatic beta-cells is essential for the activation of cytotoxic CD8+ autoreactive T lymphocytes in pancreatic islet. Activated Th1 cells induce positive signals involving IL-2, TNF-β and IFN-γ cytokines to increase the activation of islet-infiltrated macrophage and cytotoxic CD8+ cells.
Beta-cells aggression can be mediated by proinflammatory cytokine-mediated cell killing (IL-1 (Aribi et al., 2007, Sparre et al., 2005), TNF-α (Christenet al., 2001; Lee et al., 2005), TNF-β, IFN-γ, IL-18 (Nakanishi et al., 2001, Szeszko et al., 2006), IL-12 (Giulietti et al., 2004, Holtz et al., 2001), IL-6 (Kristiansen & Mandrup-Poulsen, 2005; Targher et al., 2001), and IL-8 (Erbağci et al., 2001, Lo et al., 2004), etc.), granzymes (GRZ) and perforin (PRF1), FasL-Fas (CD95L-CD95) interactions, hydrogen peroxide and free radicals (Mukherjee & DiLorenzo, 2010).
Numerous adhesion molecules and signalling proteins, can amplify activation of the CD3/TCR complex leading to self-reactive T cells proliferation within panLN.Experimental NOD mice studies highlighted three principal costimulation pathways for such activation: CD28-B7, CD40-CD40L (CD 154) (Bour-Jordan et al., 2004) and NKG2D-RAE-1 (von Boehmer, 2004). Therefore, it has been previously shown that the T1D occurrence is decreased by injection of anti-B7.2 mAb’s (Lenschow et al., 1995). Meanwhile, invalidation of B7.2 (CD86) (NOD/B7.2–/–) confers protection against the disease (Salomon et al., 2001). Additionally, ablation of CD40-CD40L pathway with neutralizing antibodies (anti-CD40L mAb’s) or with invalidation of CD40L (NOD/B7.2–/–) prevents the early stages of T cell activation in the panLN(Green et al., 2000). Moreover, it has been demonstrated that the activated islet-infiltrated CD8+ T cells express NKG2D molecules and that the treatment of NOD mice with anti-NKG2D mAb’s can prevent T1D development (Ogasawara et al., 2004).
2.2.10 Vitamin D status
The gradual increase in the frequency of T1D from the Equator to the Poles, especially among children born in spring or early summer and in the winter months has been interpreted as the consequence of limited exposure to sun and low vitamin D status. Additionally, case-control studies have consistently demonstrated an association between the incidence of T1D and vitamin D status in children and pregnant women, and an inverse relationship between vitamin D intake from diet and supplements and seasonal variations in the incidence of T1D (Pittas & Dawson-Hughes, 2010).
Experimental data could also confront the observation about the relationship between vitamin D and T1D. Indeed, the insulin-producing beta-cells, as well as other cell types of the immune system (Stoffels et al., 2006), express the vitamin D receptor (VDR) and 1-alpha-hydroxylase enzyme (Nikalji & Bargman, 2011). By regulating the extracellular calcium concentration and transmembrane calcium fluxes, vitamin D may extend to preservation of insulin secretion and insulin sensitivity. Besides, vitamin D has immunomodulatory properties and is able to affect the autoimmune process leading to T1D (Bobryshev, 2010).
3. Immunotherapy of type 1 diabetes
Intervention and prevention strategies currently under consideration for T1D aim to reverse immune autoreactivity and restore beta-cell mass (Boettler & von Herrath, 2010; Bougneres et al., 1988).Immunotherapy can be used to induce immunological tolerance to beta-cell antigens using various protocols(Haase et al., 2010),involving both islets antigen-non-specific and antigen-specific approaches, but so far success has been limited.
Immunomodulation strategies have been generally achieved in two stages of the disease: prior to clinical onset but after the appearance of islet autoantibodies (secondary prevention) and immediately after diagnosis (intervention) (Staeva-Vieira et al., 2007)(Fig. 3). Based on the preclinical and clinical outcomes of studies using these therapies, combination with islet
transplantation or stem cells for beta-cell regenerationare required in order to re-establishperipheral tolerance and to achieve a lasting remission (Marin-Gallen et al., 2010).Nevertheless, it is important to select eligible patients for such therapy, both to avoid toxicity and improve the chances of successful treatment (June & Blazar, 2006).
3.1. Non-antigen-specific immunotherapeutic approach for type 1 diabetes
For non-antigen-specific immunomodulationapproch, many protocols using chemical- and antibody-mediated therapies have shown promise to the effects of various immunosuppressive drugs, including cyclosporine A (CsA), corticoïdes, azathioprine, T cell modulators (anti-CD3, anti-thymocyte globulin (ATG)), B cell-depleting agents (Rituximab: anti-CD20), anti-inflammatory molecules (anti-interleukin (IL)-1, anti-tumour necrosis factor (TNF)-α and anti-TNF-γ), cytokine-receptor-directed therapies and small-molecule protease inhibitors (Boettler & von Herrath, 2011, Luo et al., 2010, Sia, 2005, Silverstein et al., 1988) (Table 1). However, we have to acknowledge that these drugs increase the risk of developing infections and malignancies, favor the occurrence of metabolic complications such as dyslipidemia and hypertension and that some of them have been shown to inhibit beta-cell regeneration (Nir et al., 2007, Vantyghem et al., 2009). In addition to the immunosuppressant toxicity, recurrence or persistence of the autoimmune process has been observed after withdrawal of the immunosuppressive agents.
Immunomodulation therapies with nicotinamide and Bacillus Calmette-Guérin (BCG) have been tested in many clinical T1D prevention trials, but they showed no advantageous effects (Huppmann et al., 2005). Despite these negative results, large placebo-controlled clinical trials continue to illustrate the efficacy of these drugs in preventing T1D in newly diagnosed patients or in first-degree relatives of subjects with the disease.
Other immunomodulatory drugs that directly target immune cells have also been tested with success, especially in animal models of T1D, but some of them have run into major difficulties. They include DCs-based therapy, mainly the endocytic receptor involved in antigen processing and presentation DCs (DEC-205 (Ly75/CD205)), drugs targeting T cells(CTLA4-Ig:anti-CD4, anti-CD45) (Staeva-Vieira et al., 2007, Gregori et al., 2005), AgPCs (antibodies to CD40L or CD40) and NK T cells (alpha-galactosyl-ceramide (α-Gal-Cer), etc. (Chen et al., 2005c, Hong et al., 2001, Rewers & Gottlieb, 2009).
Although most of the immunomodulator treatments induce Treg cells activation, the direct infusion of ex vivo-expanded regulatory T cells has been considered to be a potential to prevent T1D (Lundsgaardet al., 2005, Tang et al., 2004, Tarbellet al., 2004)as well as other diseases, such as systemic lupus erythematosus (SLE)(Zheng et al., 2004), multiple sclerosis (MS) (Kohm et al., 2002) and inflammatory bowel disease (IBD) (Mottet et al., 2003). Treg-based cell therapy must meet at least four important therapeutic criteria: to (1) avoid the induction of immunogenicity of the infused cells; (2) prevent or delay cellular immunosenescence; (3) maximize help; and (4) be cognizant of the known differences between mouse and human T-cell biology (June & Blazar, 2006).
Moreover, drugs targetingadhesion molecules, such as Alefacept (antibody to leucocyte function-associated antigen-3 (LFA-3)), Efalizumab (antibody to LFA-1), FTY720 (immunosuppressive drug inhibiting activated T cell extravasation and trafficking to sites of inflammation), show promise in a significant proportion of patients with other diseases and are therefore of high potential interest for testing in T1D (Staeva-Vieira et al., 2007).
Therapeutic agent | Methodof delivery | Phase | Population targeted | ClinicalTrials.gov identifier |
Otelixizumab | SC | III | ND | NCT00946257 NCT00451321 NCT00678886 NCT01123083 |
Teplizumab | IV, SC | I/II | ND | NCT01030861 NCT00378508 NCT00870818 NCT00806572 |
INGAP peptide | SC | II | EP | NCT00995540 NCT00071409 |
Peptide-MHC class II dimmers | PRT | // | // | No trials on humans |
CsA | O | PS | ND | NCT/URL links no longer available |
Nicotinamide | O | ES | SR | NCT/URL links no longer available |
Atorvastatin | O | I | ND | NCT00974740 |
BCG | ID | I | ND | NCT00607230 |
Gluten-free diet | O | OG | NR | NCT01115621 NCT00279318 |
DHA | O | II | CR | NCT00333554 |
BP/Hyd. casein | O | II | CR | NCT01055080 NCT00607230 |
Vitamin D3 | O | I | NR | NCT00141986 |
Diazoxide | O | IV | ND | NCT00131755 |
hrIFN-α | O | II | ND | NCT00024518 |
hrIL-1Ra | SC | III | ND | NCT00711503 NCT00645840 |
Canakinumab | SC | II | ND | NCT00947427 |
AAT | O | I | ND | NCT01319331 |
Rituximab | IV | III | ND | NCT00279305 |
Alemtuzumab | IV | I | ND | NCT00214214 |
ATG | IV | II | ND | NCT00515099 |
CTLA4-Ig | IV | II | ND | NCT00505375 |
Auto UCB | INF | II | EP | NCT00305344 |
Auto ODN DC | INF | I | EP | NCT00445913 |
Prochymal | IV | II | ND | NCT00690066 |
3.2. Antigen-specific tolerance strategies for type 1 diabetes
The interest in induction of antigen-specific tolerance to beta-cell antigens for immune prevention of T1D development increased due to the lack of mild non-antigen-specific immunosuppressive agents. This therapeutic approach improves remarkable longevity and long term health in T1D patients and allows most of them to escape the major degenerative complications (Bach, 2003). It can occur as a result of clonal anergy and deletion of antigen-specific autoreactive T cells or induction of regulatory cells and immune deviation (Peakman & Dayan, 2001).
Paradoxically, the induction of tolerance may not be limitedto the immune response against the injected antigen, but could be extended to responses against other antigens by a close proximity mechanism involving immunosuppressive cytokines(Bach, 2003).Therefore, the administration of the antigenic epitope specifically recognized by receptors on autoreactive T cells as part of the beta-cells would be more attractive than the whole antigen administration, given the higher levels of its specificity, but also the relatively modest costs of its synthesis (Atassi & Casali, 2008) (Fig. 4).
Different antigen-specific therapeutic approaches have shown efficacy in mouse models of T1D and have been studied most intensively in terms of inducing tolerance in humans (Boettler &von Herrath, 2010). They mainly include administration of immunogenic epitope peptide or whole protein from islet autoantigen, through parenteral, oral and nasal routes. Most of these approaches have been translated into clinic, but none of them have shown convincing promise in recent-onset T1D so far.
The most important clinical trials that have been reported with particular interest have focused on oral administration of parenteral and oral insulin clinical trials, efficacy and safety study on subcutaneous administration of heat-shock protein peptide (hsp60), DiaPep277, in C-peptide positive type 1 diabetes patients and safety experience on subcutaneous injection with the 65kDa isoform of glutamic acid decarboxylase in alum (GAD-alum) and an altered peptide ligand based on putative major autoantigenic sites in the insulin B9-23 chain, which had induced strong Th2 responses in animal models (Alleva et al., 2006, Alleva et al., 2002, Thrower & Bingley, 2009) (Table 2).
It has been observed in the Diabetes Prevention trial – Type1 (DPT-1) that oral administration of insulin in a group of patients with high IAA titers might allowan important delay in T1D onset (Skyler et al., 2005). TrialNet is now testing the efficacy of oral insulin in decreasing the chances of high-risk individuals converting to T1D (Haller et al., 2007). The immunomodulation with hsp60 has shown to provide some preservation of C-peptide in newly diagnosed adult type 1 diabetics and a significant reduction in inflammation of the pancreas with continued insulin production, suggesting that the progression of the disease may be prevented (Elias et al., 2006, Lazar et al., 2007, Raz et al., 2001). Additionally, the safety experience with subcutaneous GAD65 (Diamyd’s GAD65) has been demonstrated in latent autoimmune diabetes of adulthood (LADA) patients (Agardh et al., 2005). The results indicate that this treatment increases fasting p-C-peptide concentrations after 24 weeks in subjects treated with a moderate dose (20 μg) but not in subjects treated with higher doses (100 or 500 μg) or lower doses (4 μg) (Stenström et al., 2005).
Other trials using a DNA vaccine-based approaches include BHT-3021(Bayhill Therapeutics) (Burn, 2010), a plasmid encoding proinsulin, designed to target specific pathogenic immune cells. BHT-3021 has shown considerable effectiveness in the new-onset
diabetes in the NOD mice. In the current phase I/II clinical trial, BHT-3021, administered by intra-muscular route, demonstrated preservation of C-peptide and an acceptable safety and tolerance in patients with T1D (Sanjeevi, 2009).
Therapeutic agent | Methodof delivery | Phase | Population targeted | ClinicalTrials.gov identifier |
Insulin | O | III | RR | NCT00004984 |
IN | III | CR | NCT00223613 NCT00336674 |
|
PRT | II | RR | NCT00654121 | |
IBC-VS01 | IM | I | ND | NCT00057499 |
NBI-6024 | SC | I | ND | NCT00873561 |
BHT-3021 | IM | I | EP | NCT00453375 |
rhGAD-alum | SC | II | ND | NCT00529399NCT01129232 |
DiaPep277 | SC | III | ND | NCT01103284 NCT00615264 NCT00644501 |
3.3.Combination immunotherapy approaches
Failureto induce a lasting complete remission in patients with T1D using any single agent suggests that combination therapies may be needed for effective prevention of the disease or reversal of new-onset T1D (Luo et al., 2010).Among these approaches that are currently being tried, combinations between immunosuppressive or anti-inflammatory and antigen-specific vaccines are of particular interest, because of their quite promising early preclinical trial results. The most potent and promising ones were schemes based on a combination of anti-CD3 treatment with GAD-alum, intranasal proinsulin peptide (Bresson et al., 2006), proinsulin DNA (BHT-3021), oral insulin or anti-inflammatory drugs (Matthews et al., 2010) (Fig. 5).
4. Conclusions
T1D results from selective autoimmune destruction of insulin-producing pancreatic islet beta-cells.
Although the cause of the disease is still not fully understood, multiple immune abnormalities, involving dysfunctional regulation of the immune system that leads to the activation of self-reactive CD4+ and CD8+ T cells as well as DCs and macrophages, are believed to be a major component behind beta-cells destruction.
Given that there is evidence that the inflammatory phase preceding the destruction of beta-cells may be reversible and that humoral markers of the autoimmunity are usually present many years prior to and at the time of diagnosis, various approaches are being explored in order to slow down the progression of diabetes using antigen-specific and non-antigen-specific immunotherapies. The most promising results could be based on the induction of specific immunotolerance, because of the harmful health effects that could be observed when non-antigen-specific drugs are used.
Finally, it is possible that the etiological factors may be different from one patient to another and humoral immune response would be a relatively late marker for the disease progression. Most clinical trials have therefore been hampered by the lack of cellular markers of the immune processes that cause the disease.
Acknowledgments
I would like to thank most sincerely Maliha Meziane for proofreading of this chapter.
References
- 1.
Achenbach P. Koczwara K. Knopff A. Naserke H. Ziegler A. G. Bonifacio E. 2004 Mature high-affinity immune responses to (pro)insulin anticipate the autoimmune cascade that leads to type 1 diabetes.114 4 (August 2004),589 597 ,0021-9738 - 2.
Achenbach P. Bonifacio E. Ziegler A. G. 2005 Predicting type 1 diabetes.5 2 (April 2005),98 103 ,1534-4827 - 3.
Agardh C. D. Cilio C. M. Lethagen A. Lynch K. Leslie R. D. G. Palmer M. Harris R. A. Robertson J. A. Lernmark Å. 2005 Clinical evidence for the safety of GAD65 immunomodulation in adult-onset autoimmune diabetes.19 4 (July-August 2005),238 246 ,1056-8727 - 4.
Albina J. E. Abate J. A. Henry Jr W. L. 1991 Nitric oxide production is required for murine resident peritoneal macrophages to suppress mitogen-stimulated T cell proliferation. Role of IFN-g in the induction of the nitric oxide-synthesizing pathway. (July 1991),147 1 144 148 ,0022-1767 - 5.
Alleva D. G. Gaur A. Jin L. Wegmann D. Gottlieb P. A. Pahuja A. Johnson E. B. Motheral T. Putnam A. Crowe P. D. Ling N. Boehme S. A. Conlon P. J. 2002 Immunological characterization and therapeutic activity of an altered-peptide ligand, NBI-6024, based on the immunodominant type 1 diabetes autoantigen insulin B-chain (9-23) peptide. (July 2002),51 7 2126 2134 ,0012-1797 - 6.
Alleva D. G. Maki R. A. Putnam A. L. Robinson J. M. Kipnes M. S. Dandona P. Marks J. B. Simmons D. L. Greenbaum C. J. Jimenez R. G. Conlon P. J. Gottlieb P. A. 2006 Immunomodulation in type 1 diabetes by NBI-6024, an altered peptide ligand of the insulin B epitope. (January 2006),63 1 59 69 ,0300-9475 - 7.
Amrani A. Verdaguer J. Thiessen S. Bou S. Santamaria P. 2000 IL-1alpha, IL-1beta, and IFN-gamma mark beta cells for Fas-dependent destruction by diabetogenic CD4(+) T lymphocytes. (February 2000),105 4 459 468 ,0021-9738 - 8.
Anderson B. Park B. J. Verdaguer J. Amrani A. Santamaria P. 1999 Prevalent CD8(+) T cell response against one peptide/MHC complex in autoimmune diabetes. (August 1999),96 16 9311 9316 ,0027-8424 - 9.
Aribi M. 2008 Candidate genes implicated in type 1 diabetes susceptibility. (May 2008),4 2 110 121 ,1573-3998 - 10.
Aribi M. Moulessehoul S. Kendouci-Tani M. Benabadji A. B. Hichami A. Khan N. A. 2007 Relationship between interleukin-1beta and lipids in type 1 diabetic patients. (August 2007),13 8 CR372 CR378 ,1234-1010 - 11.
Atassi M. Z. Casali P. 2008 Molecular mechanisms of autoimmunity. (March 2008),41 2 123 132 ,0891-6934 - 12.
Atkinson M. A. Eisenbarth G. S. 2001 Type 1 diabetes: New perspectives on disease pathogenesis and treatment. , (July 2001),358 9277 221 229 ,0140-6736 - 13.
Atkinson M. A. Maclaren N. K. 1993 Islet cell autoantigens in insulin-dependent diabetes. (October 1993),92 4 1608 1616 ,0021-9738 - 14.
Azar S. T. Tamim H. Beyhum H. N. Habbal M. Z. Almawi W. Y. 1999 Type I (insulin-dependent) diabetes is a Th1- and Th2-mediated autoimmune disease. Clinical (May 1999),6 3 306 310 ,0107-1412 X - 15.
Bach J. F. 2002 Immunotherapy of type 1 diabetes: lessons for other autoimmune diseases. (May 2002),4 No.Suppl 3,S3 S15 ,1465-9905 - 16.
Bach J. F. 2003 Prevent and cure insulin-dependent diabetes. (April 2003),51 3 151 155 ,0369-8114 - 17.
Baekkeskov S. Aanstoot H. J. Christgau S. Reetz A. Solimena M. Cascalho M. Folli F. Richter-Olesen H. De Camilli P. 1990 Identification of the 64K autoantigen in insulin-dependent diabetes as the GABA-synthesizing enzyme glutamic acid decarboxylase. (September 1990),347 6289 151 0028-0836 - 18.
Baekkeskov S. Nielsen J. H. Marner B. Bilde T. Ludvigsson J. Lernmark A. 1982 Autoantibodies in newly diagnosed diabetic children immunoprecipitate human pancreatic islet cell proteins. (July 1982),298 5870 167 0028-0836 - 19.
Barker J. M. 2006 Clinical review: Type 1 diabetes associated autoimmunity: Natural History, Genetic Associations and Screening. (April 2006),91 4 ,1210 1217 ,0002-1972 X - 20.
Barker J. M. Barriga K. J. Yu L. Miao D. Erlich H. A. Norris J. M. Eisenbarth G. S. Rewers M. 2004 Diabetes Autoimmunity Study in the Young. Prediction of autoantibody positivity and progression to type 1 diabetes: Diabetes Autoimmunity Study in the Young (DAISY). (August 2004),89 8 3896 3902 ,0002-1972 X - 21.
Barker J. M. Ide A. Hostetler C. Yu L. Miao D. Fain P. R. Eisenbarth G. S. Gottlieb P. A. 2005 Endocrine and immunogenetic testing in individuals with type 1 diabetes and 21-hydroxylase autoantibodies: Addison’s disease in a high-risk population. , (January 2005),90 1 128 134 ,0002-1972 X - 22.
Baxter A. G. Kinder S. J. Hammond K. J. Scollay R. Godfrey D. I. 1997 Association between alphabetaTCR+CD4-CD8- T-cell deficiency and IDDM in NOD/Lt mice. (April 1997),46 4 572 582 ,0012-1797 - 23.
Bedoui S. Velkoska E. Bozinovski S. Jones J. E. Anderson G. P. Morris M. J. 2005 Unaltered TNF-alpha production by macrophages and monocytes in diet-induced obesity in the rat. , (March 2005),2 1 2 ESSN 1476-9255 - 24.
Bekris L. M. Shephard C. Peterson M. Hoehna J. Van Yserloo B. Rutledge E. Farin F. Kavanagh T. J. Lernmark A. 2005 Glutathione-s-transferase M1 and T1 polymorphisms and associations with type 1 diabetes age-at-onset. (December 2005),38 8 567 575 ,0891-6934 - 25.
Belz G. T. Behrens G. M. Smith C. M. Miller J. F. Jones C. Lejon K. Fathman C. G. Mueller S. N. Shortman K. Carbone F. R. Heath W. R. 2002 The CD8alpha(+) dendritic cell is responsible for inducing peripheral self-tolerance to tissue-associated antigens. (October 2002),196 8 1099 1104 ,0022-1007 - 26.
Bennett C. L. Huynh H. M. Chance P. F. Glass I. A. Gospe S. M. Jr 2005 Genetic heterogeneity for autosomal recessive pyridoxine-dependent seizures. , (September 2005),6 3 143 149 ,1364-6745 - 27.
Berzins S. P. Venanzi E. S. Benoist C. Mathis D. 2003 T-cell compartments of prediabetic NOD mice. February 2003),52 2 327 334 ,0012-1797 - 28.
Bingley P. J. 1996 Interactions of age, islet cell antibodies, insulin autoantibodies, and first-phase insulin response in predicting risk of progression to IDDM in ICA+ relatives: the ICARUS data set. Islet Cell Antibody Register Users Study. (December 1996),45 12 1720 1728 ,0012-1797 - 29.
Bingley P. J. Williams A. J. Gale E. A. 1999 Optimized autoantibody-based risk assessment in family members. Implications for future intervention trials. (November 1999),22 11 1796 1801 ,0149-5992 - 30.
Bobryshev Y. V. 2010 Vitamin D3 suppresses immune reactions in atherosclerosis, affecting regulatory T cells and dendritic cell function. (December 2010),30 12 2317 2319 ,1079-5642 - 31.
Boettler T. von Herrath. M. 2010 Immunotherapy of type 1 diabetes--how to rationally prioritize combination therapies in T1D. (December 2010)10 12 1491 1495 ,1567-5769 - 32.
Boettler T. von Herrath. M. 2011 Protection against or triggering of Type 1 diabetes? Different roles for viral infections. (January 2011),7 1 45 53 ,0174-4666 X - 33.
Bonifacio E. Christie M. R. 1997 Islet cell antigens in the prediction and prevention in insulin-dependent diabetes mellitus. (October 1997),29 5 405 412 ,0785-3890 - 34.
Bonifacio E. Atkinson M. Eisenbarth G. Serreze D. Kay T. W. Lee-Chan E. Singh B. 2001 International Workshop on Lessons From Animal Models for Human Type 1 Diabetes: identification of insulin but not glutamic acid decarboxylase or IA-2 as specific autoantigens of humoral autoimmunity in nonobese diabetic mice. (November 2001),50 11 2451 2458 ,0012-1797 - 35.
Bonifacio E. Bingley P. J. Shattock M. Dean B. M. Dunger D. Gale E. A. Bottazzo G. F. 1990 Quantification of islet-cell antibodies and prediction of insulin-dependent diabetes. January 1990),335 8682 147 149 ,0140-6736 - 36.
Bonifacio E. Genovese S. Braghi S. Bazzigaluppi E. Lampasona V. Bingley P. J. Rogge L. Pastore M. R. Bognetti E. Bottazzo G. F. et al. 1995a Islet autoantibody markers in IDDM: risk assessment strategies yielding high sensitivity. (July 1995),38 7 816 822 ,0001-2186 X - 37.
Bonifacio E. Lampasona V. Genovese S. Ferrari M. Bosi E. 1995b Identification of protein tyrosine phosphatase-like IA-2 (islet cell antigen 512) as the insulin-dependent diabetes-related 37/40K autoantigen and a target of islet-cell antibodies. (December 1995),155 11 5419 5426 ,0022-1767 - 38.
Borg H. Gottsater A. Fernlund P. Sundkvist G. 2002a A 12-year prospective study of the relationship between islet antibodies and beta-cell function at and after the diagnosis in patients with adult-onset diabetes. (June 2002),51 6 1754 1762 ,0012-1797 - 39.
Borg H. Gottsater A. Landin-Olsson M. Fernlund P. Sundkvist G. 2001 High levels of antigen-specific islet antibodies predict future beta-cell failure in patients with onset of diabetes in adult age. (July 2001),86 7 3032 3038 ,0002-1972 X - 40.
Borg H. Marcus C. Sjoblad S. Fernlund P. Sundkvist G. 2002b Insulin autoantibodies are of less value compared with islet antibodies in the clinical diagnosis of autoimmune type 1 diabetes in children older than 3 yr of age. (September 2002),3 3 149 154 ,0139-9543 X - 41.
Bottazzo G. F. Dean B. M. Gorsuch A. N. Cudworth A. G. Doniach D. 1980 Complement-fixing islet-cell antibodies in type-I diabetes: possible monitors of active beta-cell damage. (March 1980),1 8170 668 672 ,0140-6736 - 42.
Bottazzo G. F. Florin-Christensen A. Doniach D. 1974 Islet cell antibodies in diabetes mellitus with autoimmune polyendocrine deficiencies. (November 1974),2 7892 1279 1283 ,0140-6736 - 43.
Bougneres P. F. Carel J. C. Castano L. Boitard C. Gardin J. P. Landais P. Hors J. Mihatsch M. J. Paillard M. Chaussain J. L. et al. 1988 Factors associated with early remission of type I diabetes in children treated with cyclosporine. (March 1988),318 11 663 670 ,0028-4793 - 44.
Bour-Jordan H. Salomon B. L. Thompson H. L. Szot G. L. Bernhard M. R. Bluestone J. A. 2004 Costimulation controls diabetes by altering the balance of pathogenic and regulatory T cells. (October 2004),114 7 979 987 ,0021-9738 - 45.
Breidert M. Temelkova-Kurktschiev T. Hanefeld M. Leonhardt W. Schmoeckel A. Seissler J. 1998 Prevalence of diabetes-specific autoantibodies in patients at risk for adult onset diabetes mellitus. (1998),106 2 113 116 ,0947-7349 - 46.
Bresson D. Togher L. Rodrigo E. Chen Y. Bluestone J. A. Herold K. C. von Herrath. M. 2006 Anti-CD3 and nasal proinsulin combination therapy enhances remission from recent-onset autoimmune diabetes by inducing Tregs. (May 2006),116 5 1371 1381 ,0021-9738 - 47.
Brusko T. M. Putnam A. L. Bluestone J. A. 2008 Human regulatory T cells: role in autoimmune disease and therapeutic opportunities. (June 2008),223 1 371 390 ,0105-2896 - 48.
Bu D. F. Erlander M. G. Hitz B. C. Tillakaratne N. J. Kaufman D. L. Wagner Mc Pherson. C. B. Evans G. A. Tobin A. J. 1992 Two human glutamate decarboxylases, 65-kDa GAD and 67-kDa GAD, are each encoded by a single gene. , (March 1992),89 6 2115 0027-8424 - 49.
Burn P. 2010 Type 1 diabetes. , (March 2010),9 3 187 188 ,1474-1776 - 50.
Cameron M. J. Arreaza G. A. Zucker P. Chensue S. W. Strieter R. M. Chakrabarti S. Delovitch T. L. 1997 IL-4 prevents insulitis and insulin-dependent diabetes mellitus in nonobese diabetic mice by potentiation of regulatory T helper-2 cell function. , Md.: 1950), (November 1997),159 10 4686 4692 ,0022-1767 - 51.
Caramalho I. Lopes-Carvalho T. Ostler D. Zelenay S. Haury M. Demengeot J. 2003 Regulatory T cells selectively express Toll-like receptors and are activated by lipopolysaccharide. (2003),197 4 403 411 ,0022-1007 - 52.
Carel J. C. Lotton C. Timisit J. Bougnères P. Boitard C. 1999 Auto-anticorps dans le diabète auto-immun. Signification et utilisation pratique. , (May-June 1999),1 1 47 54 ,1295-9359 - 53.
Chen S. Willis J. Maclean C. Ananieva-Jordanova R. Amoroso M. A. Brooking H. Powell M. Collins A. Bennett S. Mitchell S. Burne P. Furmaniak J. Smith B. R. 2005a Sensitive non-isotopic assays for autoantibodies to IA-2 and to a combination of both IA-2 and GAD65. , (July 2005),357 1 74 83 ,0009-8981 - 54.
Chen Y. G. Choisy-Rossi C. M. Holl T. M. Chapman H. D. Besra G. S. Porcelli S. A. Shaffer D. J. Roopenian D. Wilson S. B. Serreze D. V. 2005b Activated NKT cells inhibit autoimmune diabetes through tolerogenic recruitment of dendritic cells to pancreatic lymph nodes. (February 2005),174 3 1196 1204 ,0022-1767 - 55.
Chen Z. Herman A. E. Matos M. Mathis D. Benoist C. 2005c Where CD4+CD25+ T reg cells impinge on autoimmune diabetes. (November 2005),202 10 1387 1397 ,0022-1007 - 56.
Chimienti F. Devergnas S. Favier A. Seve M. . 8 localized into insulin secretory granules. , (September 2004),53 9 2330 2337 ,0012-1797 - 57.
Christen U. Wolfe T. Möhrle U. Hughes A. C. Rodrigo E. Green E. A. Flavell R. A. von Herrath. M. G. 2001 A dual role for TNF-alpha in type 1 diabetes: islet-specific expression abrogates the ongoing autoimmune process when induced late but not early during pathogenesis.June 2001),166 12 7023 7032 ,0022-1767 - 58.
Christianson S. W. Shultz L. D. Leiter E. H. 1993 Adoptive transfer of diabetes into immunodeficient NOD-scid/scid mice. Relative contributions of CD4+ and CD8+ T-cells from diabetic versus prediabetic NOD. NON-Thy-1a donors. (January 1993),42 1 44 55 ,0012-1797 - 59.
Clare-Salzler M. J. Brooks J. Chai A. Van Herle K. . Anderson C. 1992 ).Prevention of diabetes in nonobese diabetic mice by dendritic cell transfer (September 1992),90 3 3 741 748 ,0021-9738 - 60.
Concannon P. Rich S. S. Nepom G. T. 2009 Genetics of type 1A diabetes. (April 2009),360 16 1646 1654 ,0028-4793 - 61.
Corvaisier-Chiron M. Beauvillaina C. 2010 T regulator and Th17 lymphocytes: physiological and pathological functions. (July-August 2010),40 424 31 40 0177-3035 X - 62.
Costa M. Saiz A. Casamitjana R. Castañer M. F. Sanmartí A. Graus F. Jaraquemada D. 2002 T-cell reactivity to glutamic acid decarboxylase in stiff-man syndrome and cerebellar ataxia associated with polyendocrine autoimmunity. (September 2002),129 3 471 478 ,0009-9104 - 63.
Criswell L. A. Pfeiffer K. A. Lum R. F. Gonzales B. Novitzke J. Kern M. Moser K. L. Begovich A. B. Carlton V. E. Li W. Lee A. T. Ortmann W. Behrens T. W. Gregersen P. K. 2005 Analysis of families in the multiple autoimmune disease genetics consortium (MADGC) collection: the PTPN22 620W allele associates with multiple autoimmune phenotypes. (April 2005),76 4 561 571 ,0002-9297 - 64.
Damanhouri L. H. Dromey J. A. Christie M. R. Nasrat H. A. Ardawi M. S. Robins R. A. Todd I. 2005 Autoantibodies to GAD and IA-2 in Saudi Arabian diabetic patients. (April 2005),22 4 448 452 ,0742-3071 - 65.
Dang M. Rockell J. Wagner R. Wenzlau J. M. Yu L. Hutton J. C. Gottlieb P. A. Davidson H. W. 2011 Human Type 1 Diabetes Is Associated with T Cell Autoimmunity to Zinc Transporter 8. (April 2011) [Epub ahead of print],0022-1767 0022 1767 - 66.
Davenport C. Radford P. M. Al-Bukhari T. A. Lai M. Bottazzo G. F. Todd I. 1998 Heterogeneity in the occurrence of a subset of autoantibodies to glutamic acid decarboxylase in autoimmune polyendocrine patients with islet cell antibodies. (March 1998),111 3 497 505 ,0009-9104 - 67.
de Vries I. J. Lesterhuis W. J. Scharenborg N. M. Engelen L. P. Ruiter D. J. Gerritsen M. J. Croockewit S. Britten C. M. Torensma R. Adema G. J. Figdor C. G. Punt C. J. 2003 Maturation of dendritic cells is a prerequisite for inducing immune responses in advanced melanoma patients. (November 2003),9 14 5091 5100 ,1078-0432 - 68.
Di Mario U. Perfetti R. Anastasi E. Contreas G. Crisà L. Tiberti C. MA Amendolea Masala. C. 1990 Autoantibodies to insulin do appear in non-diabetic patients with autoimmune disorders: comparison with anti-immunoglobulin antibodies and other autoimmune phenomena. (March 1990),122 3 303 0001-5598 - 69.
Di Lorenzo T. P. Peakman M. . Roep B. O. (2007 2007 .Translational mini-review series on type 1 diabetes: systematic analysis of T cell epitopes in autoimmune diabetes (April 2007)148 1 1 16 ,0009-9104 - 70.
Ding A. H. Nathan C. F. Stuehr D. J. 1988 Release of reactive nitrogen intermediates and reactive oxygen intermediates from mouse peritoneal macrophages. Comparison of activating cytokines and evidence for independent production. (October 1988),141 7 2407 2412 ,0022-1767 - 71.
Dirkx R. Jr Thomas A. Li L. Lernmark A. Sherwin R. S. De Camilli P. Solimena M. 1995 Targeting of the 67-kDa isoform of glutamic acid decarboxylase to intracellular organelles is mediated by its interaction with the NH2-terminal region of the 65-kDa isoform of glutamic acid decarboxylase. (February 1995),270 5 2241 2246 ,0021-9258 - 72.
Dorman J. 1997 Molecular epidemiology of insulin-dependent diabetes mellitus: WHO DiaMond Project. WHO DiaMond Molecular Epidemiology Sub-Project Group.151 154 .133 No.Suppl 1,0016-3813 - 73.
Dozio N. Belloni C. Girardi A. M. Genovese S. Sodoyez J. C. Bottazzo G. F. Pozza G. Bosi E. 1994 Heterogeneous IgG subclass distribution of islet cell antibodies. (February 1994),7 1 45 53 ,0896-8411 - 74.
Duarte N. Stenström M. Campino S. Bergman M. L. Lundholm M. Holmberg D. Cardell S. L. 2004 Prevention of diabetes in nonobese diabetic mice mediated by CD1d-restricted nonclassical NKTcells. (September 2004),3112 3118 .173 5 0022-1767 - 75.
Durum S. K. Schmidt J. A. Oppenheim J. J. 1985 Interleukin 1: an immunological perspective. (April 1985),3 1 263 287 ,0732-0582 - 76.
Eizirik D. L. Darville M. I. 2001 Beta-cell apoptosis and defense mechanisms: lessons from type 1 diabetes.50 No. Suppl 1,S64 S69 ,0012-1797 - 77.
Elfving A. M. Lindberg B. A. Nystrom L. Sundkvist G. Lernmark A. Ivarsson S. A. Study D. I. S. S. Group 2003 Islet autoantibodies in cord blood from patients who developed type 1 diabetes mellitus at 15-30 years of age. (June 2003),36 4 227 231 ,0891-6934 - 78.
Elias D. Avron A. Tamir M. Raz I. 2006 DiaPep277 preserves endogenous insulin production by immunomodulation in type 1 diabetes. (October 2006),1079 1 340 344 ,0077-8923 - 79.
Erbağci A. B. Tarakçioğlu M. Coşkun Y. Sivasli E. Namiduru E. S. 2001 Mediators of inflammation in children with type 1 diabetes mellitus: cytokines in type 1 diabetic children. , (November 2001),645 650 .34 4 0009-9120 - 80.
Erlander M. G. Tillakaratne N. J. Feldblum S. Patel N. Tobin A. J. 1991 Two genes encode distinct glutamate decarboxylases. (July 1991),7 1 91 0896-6273 - 81.
Ernerudh J. Ludvigsson J. Berlin G. Samuelsson U. 2004 Effect of photopheresis on lymphocyte population in children with newly diagnosed type 1 diabetes. (September 2004),11 5 856 861 ,0107-1412 X - 82.
Falcone M. Yeung B. Tucker L. Rodriguez E. Sarvetnick N. 1999 A defect in interleukin 12-induced activation and interferon gamma secretion of peripheral natural killer T cells in nonobese diabetic mice suggests new pathogenic mechanisms for insulin-dependent diabetes mellitus. (October 1999),963 972 .190 7 0022-1007 - 83.
Feutren G. Papoz L. Assan R. Vialettes B. Karsenty G. Vexiau P. Du Rostu. H. Rodier M. Sirmai J. Lallemand A. et al. 1986 Cyclosporin increases the rate and length of remissions in insulin-dependent diabetes of recent onset. Results of a multicentre double-blind trial. (July 1986),2 8499 119 124 ,0140-6736 - 84.
Filippi C. M. von Herrath. M. G. 2010 99th Dahlem conference on infection, inflammation and chronic inflammatory disorders: viruses, autoimmunity and immunoregulation. (2010),160 1 113 119 ,0009-9104 - 85.
Fiorentino D. F. Zlotnik A. Mosmann T. R. Howard M. O’Garra A. 1991 IL-10 inhibits cytokine production par activated macrophages. (December 1991),3815 3822 .147 11 0022-1767 - 86.
Fontenot J. D. Gavin M. A. Rudensky A. Y. 2003 Foxp3 programs the development and function of CD4+CD25+ regulatory T cells. (April 2003),4 4 330 336 ,1529-2908 - 87.
Foulis A. K. 1996 The pathology of the endocrine pancreas in type 1 (insulin-dependent) diabetes mellitus. (March 1996),104 3 161 167 ,0903-4641 - 88.
Fox C. J. Danska J. S. 1997 IL-4 expression at the onset of islet inflammation predicts nondestructive insulinitis in nonobese dibetic mice. (March 1997),158 5 2414 2424 ,0022-1767 - 89.
Furtado G. C. Olivares-Villagomez D. Curotto de Lafaille. M. A. Wensky A. K. Latkowski J. A. Lafaille J. J. 2001 Regulatory T cells in spontaneous autoimmune encephalomyelitis. (August 2001),182 1 122 134 ,0105-2896 - 90.
Gianani R. . Eisenbarth G. S. 2005 The stages of type 1A diabetes: 2005 (April 2005),204 1 232 249 ,0105-2896 - 91.
Gilliam L. K. Palmer J. P. Lernmark Å. 2004 Autoantibodies and the disease process of type 1 diabetes mellitus, In: D. LeRoith,S.I. Taylor & J.M., Olefsky, (Eds),499 518 , Lippincott,0-78174-097-5 , Philadelphia PA 19106, USA - 92.
Giulietti A. Stoffels K. Decallonne B. Overbergh L. Mathieu C. 2004 Monocytic expression behavior of cytokines in diabetic patients upon inflammatory stimulation. , (December 2004),1037 1 74 78 ,0077-8923 - 93.
Gorsuch A. N. Spencer K. M. Lister J. Mc Nally J. M. Dean B. M. Bottazzo G. F. Cudworth A. G. 1981 Evidence for a long prediabetic period in type I (insulin-dependent) diabetes mellitus. (December 1981),2 8260-61 .,1363 1365 ,0140-6736 - 94.
Graser R. T. Di Lorenzo T. P. Wang F. Christianson G. J. Chapman H. D. Roopenian D. C. Nathenson S. G. Serreze D. V. 2000 Identification of a CD8 T cell that can independently mediate autoimmune diabetes development in the complete absence of CD4 T cell helper functions. (April 2000),164 7 3913 3918 ,0022-1767 - 95.
Green E. A. Wong F. S. Eshima K. Mora C. Flavell R. A. 2000 Neonatal tumor necrosis factor alpha promotes diabetes in nonobese diabetic mice by CD154-independent antigen presentation to CD8(+) T cells. (January 2000),191 2 225 238 ,0022-1007 - 96.
Gregori S. Mangia P. Bacchetta R. Tresoldi E. Kolbinger F. Traversari C. Carballido J. M. de Vries J. E. Korthäuer U. Roncarolo M. G. 2005 An anti-CD45RO/RB monoclonal antibody modulates T cell responses via induction of apoptosis and generation of regulatory T cells. (April 2005),201 8 1293 1305 ,0022-1007 - 97.
Haase C. Yu L. Eisenbarth G. Markholst H. 2010 Antigen-dependent immunotherapy of non-obese diabetic mice with immature dendritic cells. , (June 2010),160 3 331 339 ,0009-9104 - 98.
Hagopian W. A. Karlsen A. E. Gottsäter A. Landin-Olsson M. Grubin C. E. Sundkvist G. Petersen J. S. Boel E. Dyrberg T. Lernmark A. 1993 Quantitative assay using recombinant human islet glutamic acid decarboxylase (GAD65) shows that 64k autoantibody positivity at onset predicts diabetes type. (January 1993),91 1 368 0021-9738 - 99.
Haller M. J. Gottlieb P. A. Schatz D. A. 2007 Type 1 diabetes intervention trials 2007: where are we and where are we going? (August 2007),14 4 283 287 ,0175-2296 X - 100.
Han G. Li Y. Wang J. Wang R. Chen G. Song L. Xu R. Yu M. Wu X. Qian J. Shen B. 2005 Active tolerance induction and prevention of autoimmune diabetes by immunogene therapy using recombinant adenoassociated virus expressing glutamic acid decarboxylase 65 peptide GAD(500-585). (April 2005),174 8 4516 4524 ,0022-1767 - 101.
Hanninen A. Jalkanen S. Salmi M. Toikkanen S. Nikolakaros G. Simel O. 1992 Macrophages, T cell receptor usage, and endothelial cell activation in the pancreas at the onset of insulin-dependent diabetes mellitus. The Journal of Clinical Investigation,0021-9738 (November 1992),90 5 1901 1910 , ISSN - 102.
Harrington L. E. Hatton R. D. Mangan P. R. Turner H. Murphy T. L. Murphy K. M. Weaver C. T. 2005 Interleukin 17-produc- producing CD4+ effector T cells develop via a lineage distinct from the T helper type 1 and 2 lineages. (November 2005),1123 1132 .6 11 1529-2908 - 103.
Hermann R. Bartsocas C. S. Soltész G. Vazeou A. Paschou P. Bozas E. Malamitsi-Puchner A. Simell O. Knip M. Ilonen J. 2004 (July-August 2004),20 4 322 329 ,1520-7552 - 104.
Holz A. Brett K. Oldstone M. B. 2001 Constitutive beta cell expression of IL-12 does not perturb self-tolerance but intensifies established autoimmune diabetes. , (December 2001),108 12 1749 1758 ,0021-9738 - 105.
Hong S. Wilson M. T. Serizawa I. Wu L. Singh N. Naidenko O. V. Miura T. Haba T. Scherer D. C. Wei J. Kronenberg M. Koezuka Y. Van Kaer L. 2001 The natural killer T-cell ligand alpha-galactosylceramide prevents autoimmune diabetes in nonobese diabetic mice. (September 2001),7 9 1052 1056 ,1078-8956 - 106.
Honkanen J. Nieminen J. K. Gao R. Luopajarvi K. Salo H. M. Ilonen J. Knip M. Otonkoski T. Vaarala O. 2010 IL-17 immunity in human type 1 diabetes. (August 2010),185 3 1959 1967 ,0022-1767 - 107.
Hori S. Nomura T. Sakaguchi S. 2003 Control of regulatory T cell development by the transcription factor Foxp3. (February 2003),299 5609 1057 1061 ,0036-8075 - 108.
Hsieh C. S. Macatonia S. E. Tripp C. S. Wolf S. F. O’Garra A. Murphy K. M. 1993 Development of Th1 CD4+ T cells through IL-12 produced by listeria-induced macrophages. (1993),547 549 .260 No.,0036-8075 - 109.
Hugues S. Mougneau E. Ferlin W. Jeske D. Hofman P. Homann D. Beaudoin L. Schrike C. Von Herrath. M. Lehuen A. Glaichenhaus N. 2002 Tolerance to islet antigens and prevention from diabetes induced by limited apoptosis of pancreatic β cells. (February 2002),16 2 169 181 ,1074-7613 - 110.
Huppmann M. Baumgarten A. Ziegler A. G. Bonifacio E. 2005 Neonatal Bacille Calmette-Guerin vaccination and type 1 diabetes. (May 2005),28 5 1204 0149-5992 - 111.
Imagawa A. Hanafusa T. Tamura S. Moriwaki M. Itoh N. Yamamoto K. Iwahashi H. Yamagata K. Waguri M. Nanmo T. Uno S. Nakajima H. Namba M. Kawata S. Miyagawa J. I. Matsuzawa Y. 2001 Pancreatic biopsy as a procedure for detecting in situ autoimmune phenomena in type 1 diabetes: close correlation between serological markers and histological evidence of cellular autoimmunity. (June 2001),1269 1273 .50 6 0012-1797 - 112.
Ishii T. Itoh K. Sato H. Bannai S. 1999 Oxidative stress-inducible proteins in macrophages. (1999),351 355 .31 No.,1071-5762 - 113.
Itoh N. Hanafusa T. Miyazaki A. Miyagawa J. Yamagata K. Yamamoto K. Waguri M. Imagawa A. Tamura S. Inada M. Kawata S. Tarui S. Kono N. Matsuzawa Y. 1993 Mononuclear cell infiltration and its relation to the expression of major histocompatibility complex antigens and adhesion molecules in pancreas biopsy specimens from newly diagnosed insulin-dependent diabetes mellitus patients. (November 1993),92 5 2313 2322 ,0021-9738 - 114.
Ivanov I. I. Mc Kenzie B. S. Zhou L. Tadokoro C. E. Lepelley A. Lafaille J. J. Cua D. J. Littman D. R. 2006 The orphan nuclear receptor RORgammat directs the differentiation program of proinflammatory IL-17+ T helper cells. (September 2006),1121 1133 .126 6 0092-8674 - 115.
Jiang H. Stewart C. A. Fast D. J. Leu R. W. 1992 Tumor target-derived soluble factor synergizes with IFN-g and IL-2 to activate macrophages for tumor necrosis factor and nitric oxide production to mediate cytotoxicity of the same target. (September 1992),2137 2146 .149 6 0022-1767 - 116.
Jun H. S. Yoon J. W. 1994 Initiation of autoimmune type 1 diabetes and molecular cloning of a gene encoding for islet cell-specific 37kd autoantigen. January 1994),347 1 207 220 ,0065-2598 - 117.
June C. H. Blazar B. R. 2006 Clinical application of expanded CD4+25+ cells. , (April 2006),78 88 .18 2 1044-5323 - 118.
Kajander M. Moltchanova E. Libman I. La Porte R. Tuomilehto J. 2000 Incidence of childhood type 1 diabetes worldwide. Diabetes Mondiale (DiaMond) Project Group. , (October 2000),23 10 1516 1526 ,0149-5992 - 119.
Kaminitz A. Stein J. Yaniv I. Askenasy N. 2007 The vicious cycle of apoptotic β-cell death in type 1 Diabetes. (November-December 2007),85 8 582 589 ,0818-9641 - 120.
Karlsen A. E. Hagopian W. A. Grubin C. E. Dube S. Disteche C. M. Adler D. A. Bärmeier H. Mathewes S. Grant F. J. Foster D. et al. 1991 Cloning and primary structure of a human islet isoform of glutamic acid decarboxylase from chromosome 10. (0ctober 1991),8337 8341 ,88 19 0027-8424 - 121.
Kawasaki E. Eisenbarth G. S. 2000 High-throughput radioassays for autoantibodies to recombinant autoantigens. (November 2000),5 1 E181 E190 ,1093-9946 - 122.
Kent S. C. Chen Y. Bregoli L. Clemmings S. M. Kenyon N. S. Ricordi C. Hering B. J. Hafler D. A. 2005 Expanded T cells from pancreatic lymph nodes of type 1 diabetic subjects recognize an insulin epitope. (May 2005),435 7039 224 228 ,0028-0836 - 123.
Kessler L. 2010 Human pancreatic islet transplantation in type 1 diabetes. State of this art. , (October 2010),34 10 589 596 ,0928-1258 - 124.
Khattri R. Cox T. Yasayko S. A. Ramsdell F. 2003 An essential role for Scurfin in CD4+CD25+ T regulatory cells. (April 2003),4 4 337 342 ,1529-2908 - 125.
Kida K. Kaino Y. It,o T. Hirai H. 1998 Controversies on the prevention of insulin-dependent diabetes mellitus by immunomodulation: lessons from NOD mice treated with beta-1,6;1,3-D-glucan and rhIGF-I. (April 1998),11 Suppl2 327 333 ,0033-4018 X - 126.
Kida K. Kaino Y. Ito T. Hirai H. Nakamura K. 1999 Immunogenetics of insulin-dependent diabetes mellitus. (January 1999),82 Suppl427 3 7 ,0000-1656 X - 127.
Kimura A. Kishimoto T. 2011 Th17 cells in inflammation. (March 2011),319 322 ,11 3 1567-5769 - 128.
Knip M. Vahasalo P. Karjalainen J. Lounamaa R. Akerblom H. K. 1994 Natural history of preclinical IDDM in high risk siblings. Childhood Diabetes in Finland Study Group. (April 1994),37 4 388 393 ,0001-2186 X - 129.
Knowles C. H. Lang B. Clover L. Scott S. M. Gotti C. Vincent A. Martin J. E. 2002 A role for autoantibodies in some cases of acquired non-paraneoplastic gut dysmotility. , (February 2002),37 2 166 170 ,0036-5521 - 130.
Ko K. S. Lee M. Koh J. J. Kim S. W. 2001 Combined administration of plasmids encoding IL-4 and IL-10 prevents the developments of autoimmune diabetes in nonobese diabetic mice. (October 2001),4 4 313 316 ,1525-0016 - 131.
Kobayashi T. Tanaka S. Okubo M. Nakanishi K. Murase T. Lernmark A. 2003 Unique epitopes of glutamic acid decarboxylase autoantibodies in slowly progressive type 1 diabetes. (October 2003),88 10 4768 4775 ,0002-1972 X - 132.
Kohm A. P. Carpentier P. A. Anger H. A. Miller S. D. 2002 Cutting edge: CD4+CD25+ regulatory T cells suppress antigen-specific autoreactive immune responses and central nervous system inflammation during active experimental autoimmune encephalomyelitis. (November 2002),169 9 4712 4716 ,0022-1767 - 133.
Kotani R. Nagata M. Moriyama H. Nakayama M. Yamada K. Chowdhury S. A. Chakrabarty S. Jin Z. Yasuda H. Yokono K. 2002 Detection of GAD65-reactive T-Cells in type 1 diabetes by immunoglobulin-free ELISPOT assays. (August 2002),25 8 1390 1397 ,0149-5992 - 134.
Koulmanda M. Bhasin M. Hoffman L. Fan Z. Qipo A. Shi H. Bonner-Weir S. Putheti P. Degauque N. Libermann T. A. Auchincloss H. Jr Flier J. S. Strom T. B. 2008 Curative and beta cell regenerative effects of alpha1-antitrypsin treatment in autoimmune diabetic NOD mice. (October 2008),105 42 16242 16247 ,0027-8424 - 135.
MA Kriegel Lohmann. T. Gabler C. Blank N. Kalden J. R. Lorenz H. M. 2004 Defective suppressor function of human CD4+ CD25+ regulatory T cells in autoimmune polyglandular syndrome type II. (May 2004),199 9 1285 1291 ,0022-1007 - 136.
Krischer J. P. Cuthbertson D. D. Yu L. Orban T. Maclaren N. Jackson R. Winter W. E. Schatz D. A. Palmer J. P. Eisenbarth G. S. 2003 Screening strategies for the identification of multiple antibody-positive relatives of individuals with type 1 diabetes. (January 2003),88 1 103 108 ,0002-1972 X - 137.
Kristiansen O. P. Mandrup-Poulsen T. 2005 Interleukin-6 and diabetes: the good, the bad, or the indifferent? December 2005),54 No.Suppl 2,S114 S124 ,0012-1797 - 138.
Kukreja A. Cost G. Marker J. Zhang C. Sun Z. Lin-Su K. Ten S. Sanz M. Exley M. Wilson B. Porcelli S. Maclaren N. 2002 Multiple immuno-regulatory defects in type-1 diabetes. , (January 2002),109 1 131 140 ,0941-0198 - 139.
Kulmala P. Savola K. Petersen J. S. Vähäsalo P. Karjalainen J. Löppönen T. Dyrberg T. Akerblom H. K. Knip M. 1998 Prediction of insulin-dependent diabetes mellitus in siblings of children with diabetes. A population-based study. The Childhood Diabetes in Finland Study Group.January 1998),101 2 327 336 ,0021-9738 - 140.
Lampasona V. Petrone A. Tiberti C. Capizzi M. Spoletini M. di Pietro S. Songini M. Bonicchio S. Giorgino F. Bonifacio E. Bosi E. Buzzetti R. Non Insulin. Requiring Autoimmune. Diabetes . N. I. R. A. D. Study Group. 2010 Zinc transporter 8 antibodies complement GAD and IA-2 antibodies in the identification and characterization of adult-onset autoimmune diabetes: Non Insulin Requiring Autoimmune Diabetes (NIRAD) 4. (January 2010),33 1 104 108 ,0149-5992 - 141.
Landin-Olsson M. Palmer J. P. Lernmark A. Blom L. Sundkvist G. Nyström L. Dahlquist G. 1992 Predictive value of islet cell and insulin autoantibodies for type 1 (insulin-dependent) diabetes mellitus in a population-based study of newly-diagnosed diabetic and matched control children. (November 1992),35 11 1068 1073 ,0001-2186 X - 142.
Lawrence T. Bebien M. Liu G.Y. Nizet V. Karin M. 2005 IKKalpha limits macrophage NF-kappaB activation and contributes to the resolution of inflammation. (April 2005),434 7037 1138 1143 ,0028-0836 - 143.
Lazar L. Ofan R. Weintrob N. Avron A. Tamir M. Elias D. Phillip M. Josefsberg Z. 2007 Heat-shock protein peptide DiaPep277 treatment in children with newly diagnosed type 1 diabetes: a randomised, double-blind phase II study. (May 2007),23 4 286 291 ,1520-7552 - 144.
Lee L. F. Xu B. Michie S. A. Beilhack G. F. Warganich T. Turley S. Mc Devitt H. O. 2005 The role of TNF-alpha in the pathogenesis of type 1 diabetes in the nonobese diabetic mouse: analysis of dendritic cell maturation. (November 2005),102 44 15995 16000 ,0027-8424 - 145.
Lehuen A. Lantz O. Beaudoin L. Laloux V. Carnaud C. Bendelac A. Bach J. F. Monteiro R. C. 1998 Overexpression of natural killer T cells protects Vα14- Jα281 transgenic nonobese diabetic mice against diabetes. (November 1998),188 10 1831 1839 ,0022-1007 - 146.
Lenschow D. J. Ho S. C. Sattar H. Rhee L. Gray G. Nabavi N. Herold K. C. Bluestone J. A. 1995 Differential effects of anti-B7-1 and anti-B7-2 monoclonal antibody treatment on the development of diabetes in the nonobese diabetic mouse. (March 1995),181 3 1145 1155 ,0022-1007 - 147.
Levin L. Ban Y. Concepcion E. Davies T. F. Greenberg D. A. Tomer Y. 2004 Analysis of HLA genes in families with autoimmune diabetes and thyroiditis. (June 2004),65 6 640 647 ,0198-8859 - 148.
Li Q. Borovitskaya A. E. De Silva M. G. Wasserfall C. Maclaren N. K. Notkins A. L. Lan M. S. 1997 Autoantigens in insulin-dependent diabetes mellitus: molecular cloning and characterization of human IA-2 beta. (July 1995),109 4 429 439 ,0108-1650 X - 149.
Lindley S. Dayan C. M. Bishop A. Roep B. O. Peakman M. Tree T. I. 2005 Defective suppressor function in CD4(+)CD25(+) T-cells from patients with type 1 diabetes. (January 2005),54 1 92 99 ,0012-1797 - 150.
Lo H. C. Lin S. C. Wang Y. M. 2004 The relationship among serum cytokines, chemokine, nitric oxide, and leptin in children with type 1 diabetes mellitus. August 2004),37 8 666 672 ,0009-9120 - 151.
Lu J. Li Q. Xie H. Chen Z. J. Borovitskaya A. E. Maclaren N. K. Notkins A. L. Lan M. S. 1996 Identification of a second transmembrane protein tyrosine phosphatase, IA-2beta, as an autoantigen in insulin-dependent diabetes mellitus: precursor of the 37-kDa tryptic fragment. (March 1996),93 6 2307 2311 ,0027-8424 - 152.
Lundsgaard D. Holm T. L. Hornum L. Markholst H. 2005 In Vivo Control of Diabetogenic T-Cells by Regulatory CD4+CD25+ T-Cells Expressing Foxp3. (April 2005),54 4 1040 1047 ,0012-1797 - 153.
Luo X. Herold K. C. Miller S. D. 2010 Immunotherapy of type 1 diabetes: where are we and where should we be going? (April 2010),32 4 488 499 ,1074-7613 - 154.
Luo X. Tarbell K. V. Yang H. Pothoven K. Bailey S. L. Ding R. Steinman R. M. Suthanthiran M. 2007 Dendritic cells with TGF-β1 differentiate naïve CD4+CD25- T cells into islet-protective Foxp3+ regulatory T cells. (February 2007),104 8 2821 2826 ,0027-8424 - 155.
Maloy K. J. Powrie F. 2001 Regulatory T cells in the control of immune pathology. (September 2001),2 9 816 822 ,1529-2908 - 156.
Mangan P. R. Harrington L. E. O’Quinn D. B. Helms W. S. Bullard D. C. Elson C. O. Hatton R. D. Wahl S. M. Schoeb T. R. Weaver C. T. 2006 Transforming growth factor-beta induces development of the T(H)17 lineage. (2006),441 7090 231 234 ,0028-0836 - 157.
Marin-Gallen S. Clemente-Casares X. Planas R. Pujol-Autonell I. Carrascal J. Carrillo J. Ampudia R. Verdaguer J. Pujol-Borrell R. Borràs F. E. Vives-Pi M. 2010 Dendritic cells pulsed with antigen-specific apoptotic bodies prevent experimental type 1 diabetes. , (May 2010),160 2 207 214 ,0009-9104 - 158.
Martin S. Wolf-Eichbaum D. Duinkerken G. Scherbaum W. A. Kolb H. Noordzij J. G. Roep B. O. 2001 Development of type 1 diabetes despite severe hereditary B-lymphocyte deficiency. (October 2001),345 14 1036 1040 ,0028-4793 - 159.
Mathis D. Vence L. . Benoist C. 2001 Beta-Cell death during progression to diabetes (December 2001),414 6865 792 798 ,0028-0836 - 160.
Matthews J. B. Staeva T. P. Bernstein P. L. Peakman M. von Herrath. M. 2010 ITN-JDRF Type 1 Diabetes Combination Therapy Assessment Group. Developing combination immunotherapies for type 1 diabetes: recommendations from the ITN-JDRF Type 1 Diabetes Combination Therapy Assessment Group. , (May 2010),176 184 .160 2 0009-9104 - 161.
Maugendre D. Chaillous L. Rohmer V. Lecomte P. Marechaud R. Sai P. Marre M. Charbonnel B. Allannic H. Delamaire M. 1997 Multiple antibody status in type 1 diabetic patients and subjects at various risk with islet-cell antibodies. (September 1997),23 4 320 326 ,1262-3636 - 162.
Mc Gregor C. M. Schoenberger S. P. Green E. A. 2004 CD154 is a negative regulator of autoaggressive CD8+ T cells in type 1 diabetes. (June 2004),101 25 9345 9350 ,0027-8424 - 163.
Miller B. J. Appel M. C. O’Neil J. Wicker L. S. 1988 Both the Lyt-2+ and L3T4+ T cell subsets are required for the transfer of diabetes in nonobese diabetic mice. (January 1988),140 1 52 58 ,0022-1767 - 164.
Miossec P. Korn T. Kuchroo V. K. 2009 Interleukin-17 and type 17 helper T cells. (August 2009),361 9 888 898 ,0028-4793 - 165.
Mire-Sluis A. R. Das R. G. Lernmark Å. 2000 The World Health Organization International Collaborative Study for Islet Cell Antibodies. (October 2000),43 10 1282 0001-2186 X - 166.
Montana E. Fernandez-Castaner M. Rosel P. Gomez J. Soler J. 1991 Age, sex and ICA influence on beta-cell secretion during the first year after the diagnosis of type 1 diabetes mellitus. , (September-October 1991),460 468 .17 5 0338-1684 - 167.
Mottet C. Uhlig H. H. Powrie F. 2003 Cutting edge: cure of colitis by CD4+CD25+ regulatory T cells. (April 2003),170 8 3939 3943 ,0022-1767 - 168.
Muir A. Peck A. Clare-Salzler M. 1995 Insulin immunization of nonobese diabetic mice induces a protective insulitis characterized by adminished intraislet interferon-r transcription. (February 1995),95 2 628 634 ,0021-9738 - 169.
Mukherjee G. Dilorenzo T. P. 2010 The immunotherapeutic potential of dendritic cells in type 1 diabetes. (August 2010),161 2 197 207 ,0009-9104 - 170.
Murata Y. Shimamura T. Hamuro J. 2002 The polarization of T(h)1/T(h)2 balance is dependent on the intracellular thiol redox status of macrophages due to the distinctive cytokine production. (February 2002),14 2 201 212 ,0953-8178 - 171.
Murayama H. Matsuura N. Kawamura T. Maruyama T. Kikuchi N. Kobayashi T. Nishibe F. Nagata A. 2006 A sensitive radioimmunoassay of insulin autoantibody: Reduction of non-specific binding of [(125)I]insulin. (March 2006),26 2 127 132 ,0896-8411 - 172.
Nakanishi K. Yoshimoto T. Tsutsui H. Okamura H. 2001 Interleukin-18 is a unique cytokine that stimulates both Th1 and Th2 responses depending on its cytokine milieu. March 2001),12 1 53 72 ,1359-6101 - 173.
Nemni R. Braghi S. Natali-Sora M. G. Lampasona V. Bonifacio E. Comi G. Canal N. 1994 Autoantibodies to glutamic acid decarboxylase in palatal myoclonus and epilepsy. (October 1994),36 4 665 667 ,0364-5134 - 174.
Nikalji R. Bargman J. M. 2011 Severe hypoglycemia with endogenous hyperinsulinemia in a nondiabetic hemodialysis patient following parathyroidectomy. , (June 2011),26 6 2050 2053 0931-0509 - 175.
Nir T. Melton D. A. Dor Y. 2007 Recovery from diabetes in mice by beta cell regeneration. (September 2007),2553 25561 .117 9 0021-9738 - 176.
Ogasawara K. Hamerman J. A. Ehrlich L. R. Bour-Jordan H. Santamaria P. Bluestone J. A. Lanier L. L. 2004 NKG2D blockade prevents autoimmune diabetes in NOD mice. NKG2D blockade prevents autoimmune diabetes in NOD mice. (June 2004),20 6 757 767 ,1074-7613 - 177.
Palmer J. P. Asplin C. M. Clemons P. Lyen K. Tatpati O. Raghu P. K. Paquette T. L. 1983 Insulin antibodies in insulin-dependent diabetics before insulin treatment. (December 1983),222 4630 1337 1339 ,0036-8075 - 178.
Park H. Li Z. Yang X. O. Chang S. H. Nurieva R. Wang Y. H. Wang Y. Hood L. Zhu Z. Tian Q. Dong C. 2005 A distinct lineage of CD4 T cells regulates tissue inflammation by producing interleukin 17. (November 2005),6 11 1133 1141 ,1529-2908 - 179.
Patterson C. C. Dahlquist G. G. Gyürüs E. Green A. Soltész G. StudyE. U. R. O. D. I. A. B.Group 2009 Incidence trends for childhood type 1 diabetes in Europe during 1989-2003 and predicted new cases 2005-20: a multicentre prospective registration study. , (June 2009),373 9680 2027 2033 ,0140-6736 - 180.
Payton M. A. Hawkes C. J. Christie M. R. 1995 Relationship of the 37,000- and 40,000-Mr tryptic fragments of islet antigens in insulin-dependent diabetes to the protein tyrosine phosphatase-like molecule IA-2 (ICA512). (September 1995),96 3 1506 1511 ,0021-9738 - 181.
Peakman M. Dayan C. M. 2001 Antigen-specific immunotherapy for autoimmune disease: fighting fire with fire? (December 2001),104 4 361 366 ,0019-2805 - 182.
Pearl-Yafe M. Kaminitz A. Yolcu E. S. Yaniv I. Stein J. Askenasy N. 2007 Pancreatic islets under attack: cellular and molecular effectors. (December 2007),749 760 .13 7 1381-6128 - 183.
Perez-Bravo F. Santos J. L. Carrasco E. Calvillan M. Albala C. Puig-Domingo M. Piquer S. De Leiva A. 2001 Transmission of high-risk HLA-DQB1 alleles in Chilean type 1 diabetic patients and their parents: stratification by the presence of ICA or GAD65 autoantibodies. (April 2001),285 291 .33 4 0891-6934 - 184.
Petersen J. S. Russel S. Marshall M. O. Kofod H. Buschard K. Cambon N. Karlsen A. E. Boel E. Hagopian W. A. Hejnaes K. R. et al. 1993 Differential expression of glutamic acid decarboxylase in rat and human islets. (March 1993),42 3 484 495 ,0012-1797 - 185.
Peterson J. Haskins K. 1996 Transfer of diabetes in the NOD-scid mouse by CD4 T cell clones. Differential requirement for CD8 T cells. (March 1996),45 3 328 336 ,0012-1797 - 186.
Piccirillo C. A. Tritt M. Sgouroudis E. Albanese A. Pyzik M. Hay V. 2005 Control of type 1 autoimmune diabetes by naturally occurring cd4+cd25+ regulatory T lymphocytes in neonatal NOD mice. , (June 2005),1051 1 72 87 ,0077-8923 - 187.
Piquer S. Belloni C. Lampasona V. Bazzigaluppi E. Vianello M. Giometto B. Bosi E. Bottazzo G. F. Bonifacio E. 2005 Humoral autoimmune responses to glutamic acid decarboxylase have similar target epitopes and subclass that show titer-dependent disease association. (October 2005),117 1 31 35 ,1521-6616 - 188.
Pittas A. G. Dawson-Hughes B. 2010 Vitamin D and diabetes. (July 2010),121 1-2 ,425 429 ,0960-0760 - 189.
Pugliese A. Zeller M. Fernandez A. Jr Zalcberg L. J. Bartlett R. J. Ricordi C. Pietropaolo M. Eisenbarth G. S. Bennett S. T. Patel D. D. 1997 The insulin gene transcribed in the human thymus and transcription level correlate with allelic variation at the INS VNTR-IDDM2 susceptibility locus for type 1 diabetes. (March 1997),15 3 293 297 ,1061-4036 - 190.
Rabinovitch A. 1994 Immunoregulatory and cytokine imbalance in the pathogenesis of IDDM. (May 1994),43 5 613 621 ,0012-1797 - 191.
Raz I. Elias D. Avron A. Tamir M. Metzger M. Cohen I. R. 2001 Beta-cell function in new-onset type 1 diabetes and immunomodulation with a heat-shock protein peptide (DiaPep277): a randomised, double-blind, phase II trial. , (November 2001),358 9295 1749 1753 ,0140-6736 - 192.
Rewers M. Gottlieb P. 2009 Immunotherapy for the prevention and treatment of type 1 diabetes: human trials and a look into the future. , (October 2009),32 10 1769 1782 ,0149-5992 - 193.
Riley W. J. Maclaren N. K. Krischer J. Spillar R. P. Silverstein J. H. Schatz D. A. Schwartz S. Malone J. Shah S. Vadheim C. et al. 1990 A prospective study of the development of diabetes in relatives of patients with insulin-dependent diabetes. (October 1990),323 17 1167 1172 ,0028-4793 - 194.
Rothe H. Ito Y. Kolb H. 2001 Disease resistant, NOD related strains reveal checkpoints of immunoregulation in the pancreas. (May 2001),79 4 190 197 ,0037-7046 X - 195.
Rozenberg O. Rosenblat M. Coleman R. Shih D. M. Aviram M. 2003 Paraoxonase (PON1) deficiency is associated with increased macrophage oxidative stress: studies in PON1-knockout mice. (March 2003),34 6 774 784 ,0891-5849 - 196.
Sai P. Rivereau A. S. Granier C. Haertle T. H. Martignat L. 1996 Immunization of non-obese diabetic (NOD) mice with glutamic acid decarboxylase-derived peptide 524-543 reduces cyclophosphamide-accelerated diabetes. (August 1996),105 2 330 337 ,0009-9104 - 197.
Sainio-Pollanen S. Liukas A. Pollanen P. Simell O. 1999 The role of CD8+ cells, cell degeneration, and Fas ligand in insulitis after intraperitoneal transfer of NOD splenocytes. (April 1999),282 293 .18 3 0885-3177 - 198.
Sakaguchi S. Sakaguchi N. Asano M. Itoh M. Toda M. 1995 Immunologic self-tolerance maintained by activated T cells expressing IL-2 receptor alpha-chains (CD25). Breakdown of a single mechanism of self-tolerance causes various autoimmune diseases. (August 1995),155 3 1151 1164 ,0022-1767 - 199.
Salomon B. Rhee L. Bour-Jordan H. Hsin H. Montag A. Soliven B. Arcella J. Girvin A. M. Padilla J. Miller S. D. Bluestone J. A. 2001 Development of spontaneous autoimmune peripheral polyneuropathy in B7-2-deficient NOD mice. (September 2001),194 5 677 684 ,0022-1007 - 200.
Sanjeevi C. B. 2009 Type 1 diabetes research: Newer approaches and exciting developments. (April 2009),49 51 .29 2 0973-3930 - 201.
Savola K. Bonifacio E. Sabbah E. Kulmala P. Vahasalo P. Karjalainen J. Tuomilehto-Wolf E. Merilainen J. Akerblom H. K. Knip M. 1998 IA-2 antibodies--a sensitive marker of IDDM with clinical onset in childhood and adolescence. Childhood Diabetes in Finland Study Group. (April 1998),41 4 424 429 ,0001-2186 X - 202.
Savola K. 2000 . Academic Dissertation to be presented with the assent of the Faculty of Medicine, University of Oulu, for public discussion in Auditorium 12 of the University Hospital of Oulu, on June 16th, 2000, at 12 noon. Oulu University Library,9-51425-677-8 Finland - 203.
Schatz D. Krischer J. Horne G. Riley W. Spillar R. Silverstein J. Winter W. Muir A. Derovanesian D. Shah S. et al. 1994 Islet cell antibodies predict insulin-dependent diabetes in United States school age children as powerfully as in unaffected relatives. (June 1994),93 6 2403 2407 ,0021-9738 - 204.
Scheen J. 2004 Pathophysiology of insulin secretion. (February 2004),29 36 65 1 0003-4266 - 205.
Schlosser M. Strebelow M. Rjasanowski I. Kerner W. Wassmuth R. Ziegler M. 2004 Prevalence of diabetes-associated autoantibodies in schoolchildren: the Karlsburg Type 1 Diabetes Risk Study. , (December 2004),1037 1 114 117 ,0077-8923 - 206.
Schmidli R. S. Colman P. G. Cui L. Yu W. P. Kewming K. Jankulovski C. Harrison L. C. Pallen C. J. De Aizpurua H. J. 1998 Antibodies to the protein tyrosine phosphatases IAR and IA-2 are associated with progression to insulin-dependent diabetes (IDDM) in first-degree relatives at-risk for IDDM. (January 1998),28 1 15 23 ,0891-6934 - 207.
Schneider B. Staraus E. Yalow R. S. 1976 Some considerations in the preparation of raioiodoisulin for radioimmunoassay and receptor assay. (April 1976),25 4 260 267 ,0012-1797 - 208.
Seyfert-Margolis V. Gisler T. D. Asare A. L. Wang R. S. Dosch H. M. Brooks-Worrell B. Eisenbarth G. S. Palmer J. P. Greenbaum C. J. Gitelman S. E. Nepom G. T. Bluestone J. A. Herold K. C. 2006 Analysis of T-cell assays to measure autoimmune responses in subjects with type 1 diabetes: results of a blinded controlled study. September 2006),55 9 2588 2594 ,0012-1797 - 209.
Sharif S. Arreaza G. A. Zucker P. Delovitch T. L. 2002 Regulatory natural killer T cells protect against spontaneous and recurrent type 1 diabetes. , (April 2002),958 1 77 88 ,0077-8923 - 210.
Shi B. Wang Z. Jin H. Chen Y. W. Wang Q. Qian Y. 2009 Immunoregulatory Cordyceps sinensis increases regulatory T cells to Th17 cell ratio and delays diabetes in NOD mice. (May 2009),582 586 .9 5 1567-5769 - 211.
Shimada A. Charlton B. Taylor-Edwards C. Fathman G. 1996 B-cell destruction may be a late consequence of the autoimmune process in nonobese diabetic mice. (August 1996),45 8 1063 1067 ,0012-1797 - 212.
Sia C. 2005 Imbalance in Th cell polarization and its relevance in type 1 diabetes mellitus. (Winter 2005),2 4 182 186 ,1613-6071 - 213.
Silveira P. A. Serreze D. V. Grey S. T. 2007 Invasion of the killer B’s in type 1 diabetes. (January 2007),2183 2193 .12 1 1093-9946 - 214.
Silverstein J. Maclaren N. Riley W. Spillar R. Radjenovic D. Johnson S. 1988 Immunosuppression with azathioprine and prednisone in recent-onset insulin-dependent diabetes mellitus. (September 1988),319 10 599 604 ,0028-4793 - 215.
Skyler J. S. Krischer J. P. Wolfsdorf J. Cowie C. Palmer J. P. Greenbaum C. Cuthbertson D. Rafkin-Mervis L. E. Chase H. P. Leschek E. 2005 Effects of oral insulin in relatives of patients with type 1 diabetes: The Diabetes Prevention Trial--Type 1. (May 2005),28 5 1068 1076 ,0149-5992 - 216.
Sobel D. O. Goyal D. Ahvazi B. Yoon J. W. Chung Y. H. Bagg A. Harlan D. M. 1998 Low dose poly I:C prevents diabetes in the diabetes prone BB rat. (August 1998),11 4 343 352 ,0896-8411 - 217.
Solimena M. Folli F. Aparisi R. Pozza G. De Camilli P. 1990 Autoantibodies to GABA-ergic neurons and pancreatic beta cells in stiff-man syndrome. (May 1990),1555 1560 .322 22 0028-4793 - 218.
Solimena M. Folli F. Denis-Donini S. Comi G. C. Pozza G. De Camilli P. Vicari A. M. 1988 Autoantibodies to glutamic acid decarboxylase in a patient with stiff-man syndrome, epilepsy, and type I diabetes mellitus. (April 1988),318 16 1012 1020 ,0028-4793 - 219.
Sparre T. Larsen M. R. Heding P. E. Karlsen A. E. Jensen O. N. Pociot F. 2005 Unraveling the pathogenesis of type 1 diabetes with proteomics: present and future directions. April 2005),4 4 441 457 ,1535-9476 - 220.
Staeva-Vieira T. Peakman M. von Herrath. M. 2007 Translational mini-review series on type 1 diabetes: Immune-based therapeutic approaches for type 1 diabetes. (April 2007),148 1 17 31 ,0009-9104 - 221.
Steinman R. M. . Banchereau J. 2007 ).Taking dendritic cells into medicine (September2007 449 7171 419 426 ,0028-0836 - 222.
Steinman R. M. Hawiger D. . Nussenzweig M. C. 2003 Tolerogenicdendritic.cells Annual Review of Immunology, (December2003 685 711 .21 No.,0732-0582 - 223.
Stenström G. Gottsäter A. Bakhtadze E. Berger B. Sundkvist G. 2005 Latent Autoimmune Diabetes in Adults Definition, Prevalence, β-Cell Function, and Treatment. (December 2005),54 Suppl2 S68 S72 ,0012-1797 - 224.
Stoffels K. Overbergh L. Giulietti A. Verlinden L. Bouillon R. Mathieu C. 2006 Immune regulation of 25-hydroxyvitamin-D3-1alpha-hydroxylase in human monocytes. (January 2006),37 47 .21 1 0884-0431 - 225.
Suarez-Pinzon W. L. Rabinovitch A. 2001 Approaches to type 1 diabetes prevention by intervention in cytokine immunoregulatory circuits. (January 2001),2 1 3 17 ,1560-4284 - 226.
Sutmuller R. P. den Brok. M. H. Kramer M. Bennink E. J. Toonen L. W. Kullberg B. J. Joosten L. A. Akira S. Netea M. G. Adema G. J. 2006 Toll-like receptor 2 controls expansion and function of regulatory T cells. (February 2006),116 2 485 494 ,0021-9738 - 227.
Szeszko J. S. Howson J. M. Cooper J. D. Walker N. M. Twells R. C. Stevens H. E. Nutland S. L. Todd J. A. 2006 Analysis of polymorphisms of the interleukin-18 gene in type 1 diabetes and Hardy-Weinberg equilibrium testing., (February 2006),55 2 559 562 ,0012-1797 - 228.
Takahashi K. Tasaka H. Hasegawa Y. 1995 Sensitivity and specificity for detection of islet cell cytoplasmic antibodies using rat pancreatic sections. , (April 1995),18 2 188 196 ,0911-4300 - 229.
Tang Q. Henriksen K. J. Bi M. Finger E. B. Szot G. Ye J. Masteller E. L. Mc Devitt H. Bonyhadi M. Bluestone J. A. 2004 In vitro-expanded antigen-specific regulatory T cells suppress autoimmune diabetes (June 2004),199 11 1455 1465 ,0022-1007 - 230.
Tarbell K. V. Yamazaki S. Olson K. Toy P. Steinman R. M. 2004 CD25+ CD4+ T cells, expanded with dendritic cells presenting a single autoantigenic peptide, suppress autoimmune diabetes. (June 2004),1467 1477 .199 11 0022-1007 - 231.
Targher G. Zenari L. Bertolini L. Muggeo M. Zoppini G. 2001 Elevated levels of interleukin-6 in young adults with type 1 diabetes without clinical evidence of microvascular and macrovascular complications. May 2001),24 5 956 957 ,0149-5992 - 232.
Taylor A. W. Yee D. G. Streilein J. W. 1998 Suppression of nitric oxide generated by inflammatory macrophages by calcitonin gene-related peptide in aqueous humor. (July 1998), pp.39 8 1372-1378,0146-0404 - 233.
Thivolet C. Carel J. C. 1996 Screening and prediction of diabetes mellitus in children. (March 1996),46 5 565 569 ,0035-2640 - 234.
Thivolet C. Nicolino M. Monbeig S. Estour B. Halimi S. Robert M. Orgiazzi J. ChatelainP.studyG. R. A. D. I. 2002 Combination of autoantibody markers and risk for development of type 1 diabetes: results from a large french cohort of family members. (September 2002),28 4 Pt 1,279 285 ,1262-3636 - 235.
Thorvaldson L. Johansson S. E. Hoglund P. Sandler S. 2005 Impact of plastic adhesion in vitro on analysis of Th1 and Th2 cytokines and immune cell distribution from mice with multiple low-dose streptozotocin-induced diabetes. (December 2005),73 81 .307 1-2 ,0022-1759 - 236.
Thrower S. L. Bingley P. J. 2009 Strategies to prevent type 1 diabetes. (October 2009),931 938 .11 10 1462-8902 - 237.
Timist J. 1996 Etiopathogenesis of type 1 diabetes mellitus. (March 1996),560 564 .46 5 0035-2640 - 238.
Toma A. Haddouk S. Briand J. P. Camoin L. Gahery H. Connan F. Dubois-Laforgue D. Caillat-Zucman S. Guillet J. G. Carel J. C. Muller S. Choppin J. Boitard C. 2005 Recognition of a subregion of human proinsulin by class I-restricted T cells in type 1 diabetic patients. (July 2005),102 30 10581 10586 ,0027-8424 - 239.
Trajkovski M. Mziaut H. Altkruger A. Ouwendijk J. Knoch K. P. Muller S. Solimena M. 2004 Nuclear translocation of an ICA512 cytosolic fragment couples granule exocytosis and insulin expression in {beta}-cells. (December 2004),1063 1074 .167 6 0021-9525 - 240.
Tree T. I. Morgenthaler N. G. Duhindan N. Hicks K. E. Madec A. M. Scherbaum W. A. Banga J. P. 2000 Two amino acids in glutamic acid decarboxylase act in concert for maintenance of conformational determinants recognised by Type I diabetic autoantibodies. (July 2000),881 889 .43 7 0001-2186 X - 241.
Tuomi T. Groop L. C. Zimmet P. Z. Rowley M. J. Knowles W. Mackay I. R. 1993 Antibodies to glutamic acid decarboxylase reveal latent autoimmune diabetes mellitus in adults with a non-insulin-dependent onset of disease. (February 1993),42 2 359 362 ,0012-1797 - 242.
Vafiadis P. Bennett S. T. Todd J. A. Nadeau J. Grabs R. Goodyer C. G. Wickramasinghe S. Colle E. Polychronakos C. 1997 Insulin expression in human thymus is modulated by INS VNTR alleles at the IDDM2 locus. (March 1997),289 292 ,15 3 1061-4036 - 243.
van den Brandt J. Fischery H. J. Waltery L. Hünigy T. Klötingy I. Reichardty H. M. 2010 Type 1 diabetes in BioBreeding rats is critically linked to an imbalance between Th17 and regulatory T cells and an altered TCR repertoire. (August 2010),185 4 2285 2294 ,0022-1767 - 244.
Vantyghem M. C. Balavoiney A. S. Kerr-Contey J. Pattouy F. Noely C. 2009 Who should benefit from diabetes cell therapy? (December 2009),70 6 443 448 ,0003-4266 - 245.
Velloso L. A. Eiziricky D. L. Karlsson F. A. Kämpe O. 1994 Absence of autoantibodies against glutamate decarboxylase (GAD) in the non-obese diabetic (NOD) mouse and low expression of the enzyme in mouse islets. (April 1994),96 1 129 137 ,0009-9104 - 246.
Verge C. F. Stenger D. Bonifacio E. Colman P. G. Pilcher C. Bingley P. J. Eisenbarth G. S. 1998 Combined use of autoantibodies (IA-2 autoantibody, GAD autoantibody, insulin autoantibody, cytoplasmic islet cell antibodies) in type 1 diabetes: combinatorial islet autoantibody workshop. (December 1998),47 12 1857 1866 ,0012-1797 - 247.
Verge C. F. Gianani R. Kawasaki E. Yu L. Pietropaolo M. Jackson R. A. Chase H. P. Eisenbarth G. S. 1996 Prediction of type I diabetes in first-degree relatives using a combination of insulin, GAD, and ICA512bdc/IA-2 autoantibodies. (July 1996),45 7 926 933 ,0012-1797 - 248.
Vija L. Farge D. Gautier J. F. Vexiau P. Dumitrache C. Bourgarit A. Verrecchia F. Larghero J. 2009 Mesenchymal stem cells: Stem cell therapy perspectives for type 1 diabetes. (April 2009),35 2 85 93 ,1262-3636 - 249.
von Boehmer. H. 2004 Type 1 diabetes: focus on prevention. (August 2004),10 8 783 784 ,1078-8956 - 250.
von Herrath. M. 2009 Diabetes: A virus-gene collaboration. (May 2009),459 7246 518 519 ,0028-0836 - 251.
Wahlberg J. Fredriksson J. Nikolic E. Vaarala O. Ludvigsson J. 2005 The ABIS-Study Group. Environmental factors related to the induction of beta-cell autoantibodies in 1-yr-old healthy children. (December 2005),6 4 199 205 ,0139-9543 X - 252.
Wallace D. J. Hahn B. Dubois E. L. 2007 , Lippincott Williams & Wilkins,13978078179394 0, Philadelphia PA 19106, USA - 253.
Wang B. Gonzalez A. Benoist C. Mathis D. 1996 The role of CD8+ T cells in the initiation of insulin-dependent diabetes mellitus. (August 1996),26 8 1762 1769 ,0014-2980 - 254.
Wenzlau J. M. Frisch L. M. Gardner T. J. Sarkar S. Hutton J. C. Davidson H. W. 2009 Novel antigens in type 1 diabetes: the importance of ZnT8. (April 2009),9 2 105 112 ,1534-4827 - 255.
Wenzlau J. M. Juhl K. Yu L. Moua O. Sarkar S. A. Gottlieb P. Rewers M. Eisenbarth G. S. Jensen J. Davidson H. W. Hutton J. C. 2007 The cation efflux transporter ZnT8 (Slc30A8) is a major autoantigen in human type 1 diabetes. , (October 2007),104 43 17040 17045 ,0027-8424 - 256.
Wenzlau J. M. Moua O. Sarkar S. A. Yu L. Rewers M. Eisenbarth G. S. Davidson H. W. Hutton J. C. 2008 SlC30A8 is a major target of humoral autoimmunity in type 1 diabetes and a predictive marker in prediabetes. , (December 2008),1150 12 256 259 ,0077-8923 - 257.
Wie J. Davis K. M. Wu H. Wu J. Y. 2004 Protein phosphorylation of human brain glutamic acid decarboxylase (GAD)65 and GAD67 and its physiological implications. (May 2004),43 20 6182 6189 ,0006-2960 - 258.
Wild S. Roglic G. Green A. Sicree R. King H. 2004 Global prevalence of diabetes: estimates for the year 2000 and projections for 2030. (May 2004),27 5 1047 1053 ,0149-5992 - 259.
Wilkin T. Palmer J. Kurtz A. Bonifacio E. Diaz J. L. 1988 The second international workshop on the standardization of insulin autoantibody (IAA) measurement. (July 1988),31 7 449 450 ,0001-2186 X - 260.
Wilson S. B. Kent S. C. Patton K. T. Orban T. Jackson R. A. Exley M. Porcelli S. Schatz D. A. Atkinson M. A. Balk S. P. Strominger J. L. Hafler D. A. 1998 Extreme Th1 bias of invariant Valpha24JalphaQ T cells in type 1 diabetes. (January 1998),391 6663 177 181 ,0028-0836 - 261.
Winnock F. Christie M. R. Batstra M. R. Aanstoot H. J. Weets I. Decochez K. Jopart P. Nicolaij D. Gorus F. K. BelgianDiabetes.Registry 2001 Autoantibodies to a 38-kDa glycosylated islet cell membrane-associated antigen in (pre)type 1 diabetes: association with IA-2 and islet cell autoantibodies. (July 2001),24 7 1181 1186 ,0149-5992 - 262.
Yagui H. Matsumoto M. Kunimoto K. Kawaguchi J. Makino S. Harada M. 1992 Analysis of the roles of CD4+ and CD8+ T cells in autoimmune diabetes of NOD mice using transfer to NOD athymic nude mice. (September 1992),22 9 2387 2393 ,0014-2980 - 263.
Yamada K. Yuan X. Inada C. Hayashi H. Koyama K. Ichikawa F. Eisenbarth G. S. Nonaka K. 1997 Combined measurements of GAD65 and ICA512 antibodies in acute onset and slowly progressive IDDM. , (March 1997),35 2-3 ,91 98 ,0168-8227 - 264.
Yamada S. Irie J. Shimada A. Kodama K. Morimoto J. Suzuki R. Oikawa Y. Saruta T. 2003 Assessment of beta cell mass and oxidative peritoneal exudate cells in murine type 1 diabetes using adoptive transfer system. (March 2003),36 2 63 70 ,0891-6934 - 265.
Yamamoto A. M. Deschamps I. Garchon H. J. Roussely H. Moreau N. Beaurain G. Robert J. J. Bach J. F. 1998 Young age and HLA markers enhance the risk of progression to type 1 diabetes in antibody-positive siblings of diabetic children (December 1998),11 6 643 650 ,0896-8411 - 266.
Yamazaki S. Iyoda T. Tarbell K. Olson K. Velinzon K. Inaba K. Steinman R. M. 2003 Direct expansion of functional CD25+CD4+ regulatory T cells by antigen-processing dendritic cells. (July 2003),198 2 235 247 ,0022-1007 - 267.
Yang L. Luo S. Huang G. Peng J. Li X. Yan X. Lin J. Wenzlau J. M. Davidson H. W. Hutton J. C. Zhou Z. 2010 The diagnostic value of zinc transporter 8 autoantibody (ZnT8A) for type 1 diabetes in Chinese. , (October 2010),26 7 579 584 ,1520-7552 - 268.
Yang W. Hussain S. Mi Q. S. Santamaria P. Delovitch T. L. 2004 Perturbed homeostasis of peripheral T cells elicits decreased susceptibility to anti-CD3-induced apoptosis in prediabetic nonobese diabetic mice. (October 2004),173 7 4407 4416 ,0022-1767 - 269.
Yoon J. W. Jun H. S. 2005 Autoimmune destruction of pancreatic beta cells. (November-December 2005),12 6 580 591 ,1075-2765 - 270.
Yoon J. W. Jun H. S. 2001 Cellular and molecular pathogenic mechanisms of insulin-dependent diabetes mellitus. , (April 2001),928 1 200 211 ,0077-8923 - 271.
Zamaklar M. Jotic A. Lalic N. Lalic K. Rajkovic N. Milicic T. 2002 Relation between course of disease in type 1 diabetes and islet cell antibodies. , (April 2002),958 1 251 253 ,0077-8923 - 272.
Zhang X. Mc Murray D. N. 1998 Suppression of lymphoproliferation by alveolar macrophages in the guinea pig. (January 1998),119 126 .79 2 0962-8479 - 273.
Zheng S. G. Wang J. H. Koss M. N. Quismorio Jr F. Gray J. D. Horwitz D. A. 2004 CD4+ and CD8+ regulatory T cells generated ex vivo with IL-2 and TGF-beta suppress a stimulatory graft-versus-host disease with a lupus-like syndrome. (February 2004),172 3 1531 1539 ,0022-1767 - 274.
Ziegler A. G. Standl E. Albert E. Mehnert H. 1991 HLA-associated insulin autoantibody formation in newly diagnosed type I diabetic patients. (September 1991),40 9 1146 1149 ,0012-1797 - 275.
Ziegler A. G. Ziegler R. Vardi P. Jackson R. A. Soeldner J. S. Eisenbarth G. S. 1989 Life-table analysis of progression to diabetes of anti-insulin autoantibody-positive relatives of individuals with type I diabetes. (October 1989),38 10 1320 1325 ,0012-1797