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Beta Cell Function After Islet Transplantation

Written By

Morihito Takita, Nigar Seven, Marlon F. Levy and Bashoo Naziruddin

Submitted: April 12th, 2012 Published: February 27th, 2013

DOI: 10.5772/52952

From the Edited Volume

Type 1 Diabetes

Edited by Alan P. Escher and Alice Li

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1. Introduction

1.1. Islet cell transplantation for type 1 diabetes

The transplantation of pancreatic islets of Langerhans is a promising treatment for “brittle” type 1 diabetics, because it is a minimally invasive procedure that replenishes the beta cell mass lost due to autoimmunity. This procedure also provides an opportunity for a “cure” from diabetes based on the achievement of freedom from dependence on exogenous insulin and severe hypoglycemic events. Although islet transplants had been attempted for several decades, they achieved minimum success in terms of post-transplant graft function. The publication of the Edmonton Protocol [1] documenting consistent achievement of insulin independence after islet transplantation, has led to a dramatic increase not only in the number of procedures performed worldwide but also in other related areas in the field of islet transplantation. Breakthroughs have been made in the area of pancreas procurement and preservation with study into ductal preservation, the two layer method, and the type of preservation solution used. Furthermore, there has been much progress in the islet isolation process by bringing standards up to cGMP qualifications, optimization of collagenase enzymes, and using iodixanol for continuous density gradient purification [2]. Some of the hurdles facing further success in this treatment are:

  1. lack of suitable donor pancreases;

  2. difficulties in isolating high quality islets on a consistent basis;

  3. improving the engraftment of transplanted islets;

  4. development of an islet-friendly immunosuppression and

  5. improving long-term survival of transplanted islets.

1.2. Post-transplant outcome

According to a recent report from the Collaborative Islet Transplant Registry, 677 patients have received either an islet transplant alone (ITA) or islets-after-kidney (IAK) transplants [3]. There has been a remarkable improvement in the post-transplant graft function in recent times. Prior to the publication of Edmonton protocol, the achievement of insulin-independent status by islet transplant recipients was <10%. Patients treated initially under the Edmonton protocol showed remarkable achievement of 82% insulin-independent status at one year post-transplant. However, this result proved to be unsustainable when the five year insulin-independence rates fell to 12.5% at the same center [4]. This data resulted in skepticism on the use of allogeneic islet transplantation as a reliable treatment for long-term success. With the introduction of thymoglobulin at induction phase and the combination of prograf, rapamycin and/or mycophenolate mofetil as maintenance immunosuppressive agents, the islet transplant survival rate has significantly improved to 50% at five year post-transplant [5]. Control of inflammatory reaction during peri-transplant period with the use of TNF-α blockers also played a key role in this improvement. These remarkable results necessitated comparison with whole pancreas transplantation which is considered as an established clinical procedure. Although whole organ treatment achieved high levels of graft survival in the years 1994-1997, the islet survival rate at five years has reached around fifty percent in 2010-2011, comparable to the level of whole pancreas graft success [5]. Moreover, islet cell transplantation seems to confer significantly better glycemic control than maximal medical therapy, and essentially eliminates hypoglycemic unawareness. These results have brought back the enthusiasm in this field.


2. Molecular mechanism of beta cell dysfunction

2.1. Early events after islet transplantation

The liver is the most commonly used site for transplantation of islets. Data supporting the use of this transplant site came from autologous islet transplants in patients with chronic pancreatitis, which showed that islets can function inside the liver for several years. There are several drawbacks associated with the liver as a host site for islets. Major factors affecting islet function include hypoxia, drug toxicity and instant blood-mediated inflammatory reaction (IBMIR). Together, these events may lead to loss of up to 75% of islet transplant mass. IBMIR is primarily a response of innate immune system to isolated islets. Major characteristics of IBMIR include activation of coagulation and complement cascades and infiltration of inflammatory cells. Several approaches are adopted to minimize the deleterious effects of IBMIR which include infusion of low molecular weight dextran sulfate and also inclusion of anti-inflammatory molecules during the infusion of islets. Besides the innate immune response, islets transplanted into liver may experience low oxygen tension. Activation of resident Kupffer cells may pose additional risk to islet survival. In addition, high concentrations of immunosuppressive drugs in the portal vein are likely to exert toxic effect on the transplanted islet mass [6].

2.2. Alloimmunity

The exposure of body to allogeneic tissues via organ/cell transplantation, blood transfusions, pregnancy can cause development of anti-human leukocyte antigen (HLA) antibodies [7]. These de novo HLA antibodies have been shown to play a significant role in the early graft loss after solid organ transplantation [8]. Currently, HLA matching between the recipients and donors is not performed before islet cell transplantation. Moreover, to achieve and/or maintain insulin independence and good metabolic control in an islet recipient, multiple islet infusions from multiple donors and high doses of immunosuppressants are generally required. The requirement of multi-donor infusions and reduction or weaning of immunosuppressants due to significant adverse effects could cause patients eventually to develop HLA antibodies against islet graft.

The issue of sensitization of alloantigens after islet cell transplantation has been raised by the Edmonton group in 2007 [9]. 98 islet transplant recipients were screened for HLA antibodies by flow-based methods. Twenty-nine patients (31%) represented de novo donor specific antibodies following islet transplantation. Among 14 recipients who discontinued immunosuppression, 10 recipients (71%) were largely sensitized with panel reactive antibody ≥50%. On the other hand, only 11 of 69 (16%) recipients who continued immunosuppression became broadly sensitized posttransplant. This study suggested that development of HLA antibodies after islet transplantation is concerning and withdrawal of immunosuppression completely following failed islet transplantation raises the risk for broad sensitization. Along with the report of Edmonton group, there are several studies that have demonstrated that islet alone transplant recipients develop donor-specific and/or nondonor-specific HLA antibodies, especially following discontinuation of immunosuppression [10-13].

In contrast, in the report of Geneva group it was shown that multiple islet infusions did not act as a risk factor for appearance of anti-HLA antibodies [14]. The group claimed that transplantation of islets in liver might cause less immunogenicity. After combined kidney-islet transplantation and continued immunosuppression even with failed islet graft function, patients had a low risk for sensitization as long as their kidney remained functional.

It has been known that islets express mainly HLA class I antigens on their surfaces. Previous reports demonstrated that patients develop antibodies posttransplant not only against HLA class I antigens, but also against HLA class II antigens [9]. Jackson et al. showed that there would be an induction of HLA class II expression on human islets under inflammatory conditions, which in return may be a possible cause of allosensitization [15]. For this aim, the group conducted an experiment in which they had two groups of isolated human islets; group 1 was control group and cultured at 37˚C, whereas group 2 was cultured in the same condition and treated with tumor necrosis factor alpha (TNF-α) and interferon gamma (INF-γ). Presence of HLA class II on islet surface was analyzed by real-time polymerase chain reaction (PCR), immunofluorescence and flow cytometry. Expression of class II transactivator, HLA-DR-α and HLA-DR-β1 increased maximum 9.38, 18.95 and 46.5 fold respectively in group 2 compared to control group after 24 hours of incubation with TNF-α and INF-γ which is shown by real-time PCR analysis. Fluorescent imaging and flow cytometric analysis confirmed the significant increase in the expression of HLA class II expression both on islet α and β cells after cytokine treatment. Inflammatory conditions shortly after islet transplantation up-regulates HLA class II antigens on islet surfaces that trigger alloimmunity. Thus, protocols which provide adequate and efficient control of inflammation after islet transplantation should be considered to improve islet transplant outcome.

Collaborative Islet Transplant Registry reported the sensitization rates against HLA class I antigens pre- and posttransplant in islet alone recipients in 2011 [16]. Data is collected from 303 islet alone recipients between January 1999 and December 2008. Panel reactive antibody (PRA) pretransplant and PRA at 6 months and yearly posttransplant correlated to measures of islet graft failure. Pretransplant PRA showed not to be a predictor of islet graft failure; whereas there was 3.6 fold increased hazard ratio for graft failure when the recipient developed PRA ≥20% post-transplant. Each additional islet infusion increased the cumulative number of mismatched HLA alleles from a median of 3 to 9; respectively for one infusion and for 3 infusions. Significantly higher rate of PRA ≥ 20% was observed in recipients who had complete graft loss with discontinued immunosuppression compared to recipients who had functioning grafts with continuing immunosuppression. Development of de novo HLA class I antibodies is less pronounced in recipients with exposure to repeat HLA class I mismatched than increased class I mismatch. Reducing the number of islet donors used for each patient and repeating HLA I mismatches with consequent islet transplantation without presence of donor specific anti-HLA antibodies are vital factors to decrease the risk of allosensitization.

Currently, there is no clearly defined monitoring tool for alloimmunity in islet cell transplantation, but researchers have proposed many experimental tools to assess alloreactivity in islet transplanted patients. Alloantibodies, soluble CD30 level, cytotoxic lymphocyte gene expression and microparticles in peripheral blood are the markers which were shown to detect allogeneic rejection after islet transplantation. Monitoring panel reactive antibody in immunosuppressed recipients had little clinical value to assess islet graft survival [16, 17].

Team Approach Outcome References
Edmonton group  Alloantibodies Pretransplant HLA antibodies reduce graft survival after islet transplantation.
CITR report  Alloantibodies Monitoring PRA in immunosuppressed patients had little clinical value for islet graft survival.
Minnesota group  Soluble CD30
No correlation between sCD30 levels and graft function at 1 year was found.
A greater reduction in sCD30 levels posttransplant was associated with full graft function.
Miami group  Cytotoxic lymphocyte (CL)  gene expression
Increased CL gene levels could predict islet allograft loss. [19]
GRAGIL group  Microparticles MPs and C-peptide showed opposite pattern.
MPs levels in peripheral blood increase with acute rejection of islet allograft.

Table 1.

Immunologic tools to assess alloimmunity after islet cell transplantation

Soluble CD30 (sCD30) is a cell membrane protein of tumor necrosis factor receptor family. sCD30 is released into blood with the activation of CD30 + T cells, leading to speculation that it may act as a marker for immune system activation [21]. Although it has been shown to be predictive for acute rejection in lung, kidney, and heart transplantation [22-24], there are not many reports about the role of sCD30 in the prediction of early graft loss following islet transplantation. In the study of Hire et al., 19 allograft islet recipients treated with three different immunosuppression inductions were evaluated retrospectively for the serum sCD30 levels [18]. Pretransplant, early posttransplant day (day 4−7), one month posttransplant, late posttransplant (day 90−120) sCD30 levels were measured and correlated with islet graft outcomes at 1 year. No correlation between sCD30 levels at any time point and graft function at 1 year was found. However, a greater reduction in SCD30 levels posttransplant was associated with full graft function. Therefore, sCD30 may be of value for immune monitoring of islet allografts.

Cytotoxic lymphocyte (CL) genes granzyme, Fas ligand and perforin may play an active role in the course of acute allograft rejection. University of Miami group studied 13 islet transplant recipients treated with steroid-free immunosuppressive regimen in order to demonstrate whether CL gene expression could be a predictor of allogeneic rejection [19]. All patients attained insulin independence; however, 8 of them restarted insulin therapy. Real-time PCR was used to assess CL gene mRNA levels. The group demonstrated that recipients who restarted insulin therapy had a significant elevation of CL gene mRNA levels and the most reliable measure of ongoing graft loss was granzyme B. Hence, increased blood CL gene levels might be a potential marker to predict islet allograft loss.

Microparticles (MP) are plasma membrane fragments of apoptotic cells in peripheral blood. The quantity of microparticles is correlated with the degree of cell death, so they are considered to be indicators of apoptosis. Kessler et al. demonstrated the elevation of microparticles in peripheral blood at the time of acute rejection following intraportal islet transplantation with a case report [25]. Loss of islet graft function without the presence of GAD65, IA2 or anti-HLA antibodies brought up the diagnosis of acute cellular rejection. With a successful steroid bolus therapy, MPs level declined and the patient regained islet function. In 2011, Toti et al. [20] demonstrated from three islet transplant recipients that in the case of rejection, C-peptide and MPs levels exhibited opposite pattern and a decline in C-peptide was related with increased insulin needs. This data suggested an increment in MPs level might indicate allogeneic rejection. Thus, MPs level in peripheral blood might be a useful tool to monitor allogeneic rejection after islet transplantation.

2.3. Autoimmune recurrence

Type 1 diabetes is an autoimmune disease in which pancreatic beta cells are destroyed through a T-cell mediated mechanism in genetically susceptible individuals [26]. Autoantibodies against pancreatic islets comprise anti-glutamate decarboxylase 65 (GAD65), islet cell autoantibody (ICA), anti-insulin autoantibody (IAA), anti-tyrosine phosphatase autoantibody (IA-2) and against zinc transporter ZnT8. Antibodies present in serum against these pancreatic islet antigens are commonly used to predict and or diagnose the disease in clinical practice. For successful islet cell replacement, it is crucial to prevent recurrent destruction of beta cells through existing autoimmune destruction. The graft failure due to recurrent autoimmunity in a pancreas segment transplanted between identical twins was proven with the demonstration of insulitis in the transplanted tissue [27]. Islet specific T cells seem to have a basic role in the process of autoimmune destruction of beta cells [28].

To investigate T-cell allo- and autoreactivities in peripheral blood following islet transplantation, Roep et al. examined 7 islet allograft recipients [29]. They showed that three patients who got thymoglobulin for induction immunosuppression and retained full islet function for more than 1 year exhibited minor autoreactivites but no alloreactivities. Three patients who did not get thymoglobulin had rapid decline (<3 weeks) in islet function and showed alloreactivities; but one out of these three patients had rapid increase in autoreactivity to several islet autoantigens prior to alloreactivity. One recipient who did not receive thymoglobulin exhibited hyperautoreacivity with no detectable alloreaactivity and developed delayed loss of islet graft function consequently (<33 weeks); which indicated that autoimmune recurrence might be the cause of chronic islet graft dysfunction. In this study, because of the excellent outcomes in thymoglobulin group, the authors evaluated allo- and autoimmunity again in a bigger sample sized group in 2008 [30]. 21 islet recipients under thymoglobulin induction and tacrolimus plus mycophenolate mofetil maintenance immunosuppressive regimen were studied. Immunity against allo- and autoantigens were checked at pretransplant and at 1 year posttransplant. The analyses showed that existence of cellular autoimmunity pretransplant and posttransplant was related with delayed insulin independence and lower levels of circulating C-peptide during the first year posttransplant. Seven out of eight patients with no previous T-cell autoreactivity achieved insulin independence; whereas none of the four patients with autoantibodies against GAD and IA-2 before transplantation became insulin independent. Cellular alloreactivity and autoantibody levels did not show significant involvement with the outcome. Based on these findings, the authors commented that thymoglobulin may cope sufficiently with alloimmunity, but insufficient to control islet autoreactivity in an early period. The issue of autoimmunity remains unaddressed and needs further investigation.

Approach Outcome References
Roep et al. Autoantibodies Autoandibodies increased due to autoimmune activity, but did not indicate loss of graft function.
Roep et al. T-cell autoreactivity
in peripheral blood
Pre- and posttransplant cellular autoimmunity were associated with delayed insulin independence.
Autoantibody levels did not affect islet allograft outcome.
Matsumoto et al. GAD65 specific global immune assay Broad repertoire of islet antigen-specific T cells secreting various cytokines were related with chronic graft failure. [31]

Table 2.

Immunologic tools to assess autoimmunity after islet cell transplantation

Autoimmunity recurrence might be assessed by monitoring islet specific autoantibodies and T-cell autoreactivity. But the association between autoantibodies and insulin independence and islet graft outcome are variable; increase in autoantibody levels were shown due to autoimmune activity but did not indicate loss of islet graft function [29, 32]. Assays that measure anti-islet cellular autoimmunity before and after islet transplantation demonstrated that pre-and posttransplant cellular autoimmunity were related with delayed insulin independence and lower levels of circulating C-peptide during the first year posttransplant [30]. Nonetheless, in this study islet allograft outcome did not seem to be affected by autoantibody levels or cellular alloreactivity.

Matsumoto et al. have reported on a global immune assay specific for GAD65 (EpiMax) in order to analyze the property of autoreactive T-cell responses [31]. Five type 1 diabetic patients were studied 1 year after allogeneic islet transplantation. All patients achieved insulin independence at 1 year. Three out of five patients maintained long-term insulin independence and EpiMax affirmed minimum T-cell responses in these patients. In contrast, the two patients who developed chronic graft failure and lost insulin independence showed broad repertoire of GAD65 specific T-cells secreting various types of cytokines, including IL-5, IL-13, IL-17, TNF- alpha, and IFN-gamma. In addition to those observations, IFN-γ and IL-13 expressing CD4+ T cells and IFN-γ expressing CD8+ T cells were encountered in the other two failed patients. These findings suggested that broad repertoire of islet antigen-specific T cells which secrete variable types of cytokines were related with chronic graft failure, preventing islet recipients from maintaining long-term insulin independence.


Following transplantation of islets, administration of immunosuppression is essential to maintain graft function. However, most of the immunosuppressive drugs also have adverse effects on beta cell function. Careful selection of immunosuppressive regimen is critical for prolonged function of transplanted islets.

2.3.1. Early period of islet cell transplantation

Corticosteroid was a widely used agent as maintenance immunosuppression in the pioneering days of islet cell transplantation in 1990’s (Table 3). During this decade, majority of islet cell transplants were after or performed simultaneously with kidney transplantation. Corticosteroid has antiinflammatory as well as immunosuppressive effects by direct or indirect actions on various leukocytes, including T lymphocytes, monocytes and macrophages, through glucocorticoid receptor [33, 34]. However, steroid therapy leads to β cell dysfunction and insulin resistance. [35, 36] Deterioration of insulin secretion from β cell by steroid treatment has been reported, caused by enhanced α-adrenergic receptor signaling [37], β cell apoptosis [38] and activated K+ channel [39]. Insulin resistance in liver, adipose tissue and skeletal muscle by long-term steroid administration are well known clinically and in basic studies [40-42]. Thus, steroid use for the purpose of maintenance immunosuppression has been averted in the recent decade of islet transplantation (Table 3).

The calcineurin inhibitors (CNIs) have been major players in maintenance immunosuppression of islet cell transplantation. Cyclosporine A and tacrolimus are currently available CNIs in clinic. They inhibit calcineurin, a serine-threonine phosphatase, which is responsible for dephosphorylation of nuclear factor for activated T cells (NF-AT), which in turn results in inactivation of the transcription of cytokine genes. However, CNIs might have β cell toxicity since calcineurin is expressed in β cell and regulates β cell growth as well as function [43, 44].

Azathioprine is a purine analog, serving as a blocker of de novo pathway in purine synthesis in actively proliferative cells such as T cells and B cells [45]. Currently this drug is used for immunosuppression in allogeneic transplantation and autoimmune disease like rheumatoid arthritis as well as therapy in hematologic malignancies [46]. Azathioprine may also prevent the onset of diabetes [47, 48] and no major β cell toxicity of azathioprine has been reported.

2.3.2. Edmonton protocol

Remarkable success in islet transplant survival was achieved by the University of Alberta group using steroid-free immunosuppression regimen that included daclizumab, tacrolimus and sirolimus, resulting in that all 7 recipients achieving insulin independence [1]. The benefit of Edmonton protocol is to eliminate the risk of steroid-induced β cell toxicity as well as insulin resistance and increasing the dose of transplanted islets. However, the protocol uses tacrolimus that has the effect of β cell deterioration.

Publi-cation year Pts no. Induction therapy Maintenance therapy Transplant type Donor no.* Major outcomes Refs
Steroid CNIs Other
1990 9 ✓Tac Islet after liver transplant M/S 5 pts achieved II [49]
1991 3 ✓Pred ✓CsA ✓Aza ITA M/S Rejected 2 weeks after ITA [50]
3 ✓mALG ✓Pred ✓CsA ✓Aza IAK S Partial function**
3 ✓mALG ✓Pred ✓CsA ✓Aza IAK M II for 7, 14 and 121 days
1991 4 ✓ATG
(3 pts)
✓Pred ✓CsA ✓Aza IAK M/S 1 pt achieved II [51]
2 ✓ATG ✓Pred ✓CsA ✓Aza SIK M/S
1992 10 ✓Tac Simultaneous Islet-Liver transplant S 6 pts achieved II [52]
4 ✓Pred ✓Tac Simultaneous Islet-Liver transplant S Partial function**
7 ✓Pred ✓Tac SIK M Partial function**
1993 2 ✓mALG
✓Pred ✓CsA ✓Aza SIK S 1 pt achieved II [53]
1997 6 ✓mPred ✓Tac Simultaneous Islet-Liver-Bone marrow transplant S 3 pts achieved II [54]
1997 8 ✓OKT3 ✓mPred ✓CsA ✓Aza IAK (7 pts)
or SIK (1 pt)
M/S 2 pts achieved II [55]
1997 20 ✓ATG ✓Pred ✓CsA ✓Aza IAK (7 pts)
or SIK (13 pt)
M/S 7 pts achieved II [56]
1997 3 ✓ATG ✓Pred ✓CsA ✓MMF SIK (2 pts)
or IAK (1 pt)
M/S Partial function** [57]
1998 7 ✓ATG (3pts) ✓Pred ✓CsA ✓Aza IAK M 2 pts achieved II [58]
1999 12 ✓ATG ✓Pred ✓CsA ✓Aza IAK (12 pts)
or SIK (12pts)
M/S Partial function** [59]

Table 3.

Immunosuppression protocols in clinical islet transplants published in 1990’s.

*M: Multiple donor transplants, S: Single donor transplant. ** Not achieved II, but positive C-peptide or decreased insulin requirement was confirmed. Abbreviations; 15-DSG: 15-deoxyspergualin, ATG: antithymocyte globulin, Aza: azathioprine, CNIs: Calcineurin inhibitors, CsA: Cyclosporine A, IAK: Islet after kidney transplantation, II: Insulin Independence, ITA: Islet transplantation alone, mALG: Minnesota antilymphoblast globulin, MMF: mycophenolic mofetil, mPred: methylprednisolone, Pred: Prednisone, SIK: Simultaneous islet kidney transplantation, Tac: Tacrolimus.

Publi-cation year Pts no. Induction therapy Maintenance therapy Transplant type Donor no.* Major outcomes Refs
Steroid CNIs Other
2000 13 ✓ATG or
✓Pred ✓CsA ✓Aza or
SIK, IAK or Islet after lung transplant M/S 2 pts achieved II [60]
2000 7 ✓Dac ✓Tac ✓Sir ITA M 100% II [1]
2001 2 ✓ATG or
✓Pred ✓CsA ✓MMF SIK (5 pts) or IAK (2 pts) M/S Partial function** [61]
2001 10 ✓Bas ✓Pred ✓CsA ✓MMF IAK M/S 2 pts achieved II [62]
2003 6 ✓Dac ✓Tac ✓Sir ITA M/S 3 pts achieved II [63]
2004 6 ✓OKT3γ1 ✓Tac ✓Sir ITA S 4 pts achieved II [64]
2004 13 ✓Dac ✓Tac ✓Sir ITA (9 pts) or IAK (4 pts) M 11 pts achieved II [65]
2004 10 ✓Dac ✓Tac ✓Sir ITA M/S 5 pts achieved II [66]
2004 6 ✓Dac ✓Tac ✓Sir SIK M 5 pts achieved II [67]
2005 8 ✓ATG
✓Tac ✓MMF
ITA S 100% II after single infusion [68]
2005 16 ✓Dac
✓Tac ✓Sir ITA M/S 14 pts achieved II [69]
2005 22 ✓Dac/
IAK or ITA M/S 15 pts achieved II [70]
2005 65 ✓Dac ✓Tac ✓Sir ITA M/S 44 pts achieved II [4]
2005 10 ✓ATG or
✓Tac ✓Sir or
ITA M/S 100% II [71]
2006 8 ✓Dac ✓Tac ✓Sir IAK M/S 100% II [72]
2006 6 ✓Dac ✓Tac ✓Sir ITA M 3 pts achieved II [73]
2006 36 ✓Dac ✓Tac ✓Sir ITA M/S 16 pts achieved II [74]
2007 11 ✓Dac ✓Tac ✓Sir or
M/S 8 pts achieved II [75]
2007 10 ✓Dac ✓Tac ✓Sir ITA M/S 6 pts achieved II [76]
2007 19 ✓Dac ✓Tac ✓Sir or
ITA M/S 16 pts achieved II [77]
2008 5 ✓ATG ✓Tac ✓Sir ITA M 3 pts achieved II [78]
5 ✓ATG ✓Sir ITA M Partial function**
2008 13 ✓Dac ✓Tac ✓Sir SIK M/S 7 pts achieved II [79]
2008 7 ✓Dac
✓ Pred (2 pts) or mPred (1 pt) ✓Tac ✓Sir
(2 pts)
IAK M/S 6 pts achieved II [80]
2008 6 ✓ATG
✓CyA ✓Eve
ITA M/S 5 pts achieved II [81]
2008 4 ✓Dac ✓Tac ✓Sir ITA M 100% II [82]
6 ✓Dac
✓Tac ✓Sir
ITA M/S 100% II
2008 3 ✓Ale ✓Tac ✓Sir
ITA M/S 2 pts achieved II [83]
2008 6 ✓Dac
✓Tac ✓Sir Islet transplant with Bone marrow S 3 pts achieved II [84]
2009 14 ✓Dac ✓Tac ✓Sir ITA M 100% II [85]
2009 15 ✓Dac or
✓Tac ✓Sir IAK M/S 100 pts achieved II [86]
2010 8 ✓ATG ✓Sir
ITA M/S 100% II [87]
2010 8 ✓Dac ✓Tac ✓Sir ITA M/S 100% II [88]
4 ✓Dac ✓Tac ✓Sir
ITA S 100% II after single infusion
2010 5 ✓ATG
✓Sir or
ITA M/S 100% II after single infusion [89]
5 ✓ATG
✓Sir or
ITA M/S 100% II after single infusion
2011 3 ✓ATG
✓Tac ✓MMF ITA M/S 100% II after single infusion [90]
3 ✓Dac ✓Tac ✓Sir ITA M 100% II
2011 4 ITA** M/S Partial function*** [91]

Table 4.

Immunosuppression protocols in clinical islet transplants published after 2000.

*M: Multiple donor transplants, S: Single donor transplant. **Microencapsulated islets transplanted. *** Not achieved II, but positive C-peptide or decreased insulin requirement was confirmed. Abbreviations; Ale: Alemtuzumab, ATG: antithymocyte globulin, Aza: azathioprine, Ana: anakinra, Bas: basiliximab, Bela: belatacept, CNIs: Calcineurin inhibitors, CsA: Cyclosporine A, Dac: daclizumab, Efa: efalizumab, Eta: etanercept, Eve: everolimus, Exe: exenatide, IAK: islet after kidney transplantation, II: insulin independence, Inf: infliximab, ITA: islet transplantation alone, mALG: Minnesota antilymphoblast globulin, MMF: mycophenolic mofetil, MPA: mycophenolic acid, mPred: methylprednisolone, Pred: prednisone, SIK: simultaneous islet kidney transplantation, Sir: sirolimus, Tac: tacrolimus

Sirolimus is an inhibitor of mammalian target of rapamycin (mTOR), which plays an important role in cell cycle from late G1 to S phase in T cells [92]. The effect of sirolimus in β cell function is still unclear; impaired β cell proliferation and islet graft function by sirolimus has been reported [93-95] while Melzi et al found no significant adverse effect of sirolimus in islet engraftment [96]. Gao et al reported sirolimus and daclizumab did not show any individual or synergistic negative effects on islet proliferation [97]. However, insulin independence in Edmonton protocol was not sustained for a long-term resulting in 12.5% at 5 year after islet transplant [4].

2.3.3. Newer immunosuppression protocols

Recent clinical trials implementing monoclonal antibodies such as basiliximab (anti-IL-2 receptor)[70], efalizumab (anti-LFA-1)[89], alemtuzumab (anti-CD52)[83] have shown high rate of insulin independence after transplant. These monoclonal antibodies are produced as molecular targeting agents and considered as less likely to have direct effects on β cell function.

Currently major islet transplant centers are increasingly adopting stronger induction immunosuppression comprised of T cell depletion using anti-thymocyte globulin, alemtuzumab or OKT3γ1 (anti-CD3) plus anti-TNF-α treatment. This has resulted in significantly improved long-term maintenance of insulin independence [3, 5].

In maintenance immunosuppression, tacrolimus is still a key medication; although, there is controversy on the use of tacrolimus and its effect to islet graft function as described above (See § 2.5.1). Mycophenolate mofetil (MMF) is also used for maintenance immunosuppression, inhibiting proliferation of T and B cells and promoting apoptosis of activated T cells [98, 99]. Gallo et al recently showed that MMF was able to reduce survival of β cells, impair glucose-stimulated insulin secretion and β cell proliferation [100]. Posselt et al reported excellent islet transplant outcome using CNI-free immunosuppression that included belatacept [89], which is a fusion protein with Fc fragment of a human IgG linked to cytotoxic T lymphocyte-associated antigen 4 (CTLA-4) that allows costimulation blockade of CD80 and CD86 on antigen presenting cells [101]. Overall islet investigators have continued to make efforts to find effective immunosuppression with less effect on β cell function while enhancing β cell function such as exenatide which is a glucagon-like peptide-1 (GLP-1) analog [75].

2.4. Islet encapsulation

The islet encapsulation aims to eliminate or reduce the dose of immunosuppression, which is a major obstacle in current islet transplantation, by isolating islets from blood flow and avoiding direct interaction with antibodies and immune cells such as lymphocytes and macrophages. However, few clinical trials using encapsulation technique have been reported [91, 102]. The University of Peruga group demonstrated the efficacy of microencapsulated human islets with sodium alginate in 4 type 1 diabetic patients, who were able to reduce HbA1c level and the amounts of exogenous insulin injection [91]. Elliot RB et al. showed a case report on xenotransplantation using alginate-encapsulated porcine islets, also allowing reduction of insulin dose [102]. In both reports, islet recipients did not use any immunosuppressants although insulin independence was not achieved, suggesting the advantage and limitation of current encapsulation strategy (Figure 1).

There are several methods of islet encapsulation; macrocapsular devices, microencapsulation and surface modification. A macrocapsular device that is composed of polytetrafluoroethylene membrane enabled delayed onset of diabetes in mice model [103]. Microencapsulation of islets has been prepared using various materials such as alginate, agarose and collagen [104-106]. An issue of microencapsulation is the enlargement of the size of islet mass; microencapsulation of an islet can increase the size by as much as 3 to 5 folds of the original islet. Alternatively, surface modification of islets is a strategy to reduce the tissue volume. Polyethylene glycol (PEG) is a hydrogen polymer and can be used for conformal coating to encapsulate islets in the process of polymerization [107]. PEGylation, i.e. PEG conjugation at the islet surface, is the another way of islet encapsulation without significant increase in tissue size [108]. Recently, PEGylation attached with biologically active agents of heparin, activated protein C, urokinase or thrombomodulin has been developed to prevent the local coagulation immediately after islet infusion [109-112]. These techniques were recently developed and the sustainability of PEGylation needs to be proven.

Figure 1.

Benefits and current limitations of islet encapsulation.


3. Clinical assessment of beta cell function

Monitoring graft function is a major concern in clinical management of islet recipients since islet graft dysfunction in both acute phase after transplant and chronic phase is an obstacle to its widespread use as a standard care for type 1 diabetes. Furthermore, isolated islets are transplanted via the portal vein into the liver, making it difficult to employ biopsy examination of engrafted islets. Hence, several methodologies to predict islet graft function indirectly have been proposed. In this section, indices currently available for clinical assessment of islet graft function are discussed (Table 5).

3.1. Blood tests and clinical indices

3.1.1. Glucose tolerance/stimulation test

Glucose tolerance test (GTT) is a basic assessment method to diagnose diabetes although glucose stimulation; in itself has risk of artificial hyperglycemia for type 1 diabetic patients. Baidal et al reported that acute insulin/C-peptide release, mixed meal stimulation index, time-to-peak C-peptide, 90min glucose level and area under the curve of glucose values could predict islet dysfunction [113]. Arginine stimulation test is also useful for the evaluation of islet graft function. Glucose-potentiation slope and the maximal response in arginine stimulation test were significantly associated with β cell secretory capacity in a report from University of Pennsylvania group [114].

3.1.2. HYPO score and LI

Hypoglycemic (HYPO) score and lability index (LI) are calculated based on patients’ journals of self-monitoring blood glucose (SMBG) for a month, providing a link to graft function through the quality of glycemic control [115]. These assessment tools are beneficial since a major endpoint of clinical allogeneic islet transplantation is to prevent hypoglycemic events; however, HYPO and LI calculations require a number of glucose measurements and hence are only calculated on a monthly or yearly basis using a complex scoring system.

3.1.3. SUITO index

A simple evaluation method using fasting blood glucose and C-peptide levels has been proposed, called secretory unit of islet transplant objects (SUITO) index [116]. The SUITO index was originally developed using the concept of the homeostasis model assessment for insulin secretion (HOMA-β) model, where healthy person has 100 of SUITO index. The calculation uses serum C-peptide levels instead of insulin levels, since islet recipient may be administering exogenous insulin during graft dysfunction and overlapped measurement of endogenous and exogenous insulin amounts are avoided [117]. SUITO index can provide reference value for insulin independence and elimination of hypoglycemia [118]. In addition, SUITO index allows extensive link to quality of life in islet recipients [119].

3.1.4. C-peptide/glucose ratio and C-peptide/glucose*creatinine ratio

C-peptide per glucose ratio (CP/G) is also a simple technique to predict islet graft function using blood glucose and C-peptide, similar to the SUITO index [120]. To correct islet graft function in patients with renal dysfunction, C-peptide/glucose*creatinine ratio has also been proposed. University of Miami group showed that CP/G correlated with 90min glucose level and β score [120].

3.1.5. β score

This scoring system uses data on fasting blood glucose, HbA1c, stimulated C-peptide, and absence of insulin or oral diabetic medication, that cover multiple aspect of glycemic control in islet recipients [121]. Correlation between β score and 90 min glucose level after mixed meal tolerance test has also been reported.

3.1.6. TEF

Transplant estimated function (TEF) is calculated by a formula using daily exogenous insulin requirements and HbA1c, that are routinely measured at clinic, eliminating glucose stimulation test when compared to β score [122]. TEF correlated well with β score and insulin response to arginine stimulation test.

3.1.7. TFIM model

Transplanted functional islet mass (TFIM) model is a recently proposed index that is aimed to guide the decision to use a specific islet preparation [123]. TFIM model is composed of transplanted islet volume, increment of insulin secretion, cold ischemia time and exocrine tissue volume transplanted, and can predict islet graft function.

3.2. Clinical image study

Functional mass of transplanted islets can be observed by the combination of the radioisotope-labeled grafts using 18F-fluorodeoxyglucose ([18F]FDG) and positron emission tomography with computed tomography (PET/CT) [124, 125]. Although this technique is only applicable to capture early phase of transplantation up to 60 min after transplant, islet graft loss as well as transplanted islet distribution in the liver can be observed. Nano-iron particle also visualizes engrafted islet mass using magnetic resonance imaging (MRI) and allows longer follow-up when compared to PET/CT technique [126, 127].

Method Variables required Advantage Disadvantage Reference
GTT A series of glucose or C-peptide values during glucose stimulation Widely available method in clinic The risk of hyperglycemia
Repeated blood collection
[113, 114]
HYPO score and LI Detailed self-recorded journal of glucose levels and hypoglycemic episodes Direct evaluation of hypoglycemia that is a major outcome in islet transplantation Number of records for monthly basis are required
Complex calculation for LI
SUITO index Fasting serum C-peptide and glucose level Simple calculation
Easy prediction of graft function corresponding to insulin independence.
Limited application to other species [118, 119]
CP/G Fasting serum C-peptide and glucose level Simple calculation Limited information on extended outcomes of hypoglycemia [120]
β score Fasting glucose, HbA1c, Daily insulin dose, Stimulated C-peptide To capture multiple aspects of glycemic control Composite scoring system requiring 4 variables including the results from glucose stimulation test [121]
TEF A series of records on HbA1c and daily insulin amounts To eliminate glucose stimulation test compared to β score
Calculation using variables that can be collected in standard diabetes care
Adjustment of coefficients by individual patient [122, 128]
TFIM Model Volume of transplanted islets, increment of insulin secretion, cold ischemia time and volume of transplanted exocrine tissue To follow graft function using isolation results Validated using data on islet after kidney transplantation [123]
Radiologic imaging technique; PET/CT Radioisotope-labeled islets
PET/CT machine
To allow evaluation of islet graft mass and the distribution in the liver The measurement only applicable for early phase of transplantation due to half-time of radioisotope
Labeling procedure required
[124, 125]
Radiologic imaging technique; MRI Iron-nanoparticle labeled islets
MRI machine
To allow longitudinal follow up of islet mass Labeling procedure required
Iron overload
[126, 127]

Table 5.

Clinical assessment of β cell function

3.3. Autologous Islet Transplantation

Patients with refractory chronic pancreatitis undergo total or partial pancreatectomy to alleviate pain and also autologous islet transplantation to retain pancreatic endocrine function after surgery. Islets isolated from pancreas are infused intraportally into the liver. Assessment of beta cell function in such autologous islet transplant patients typically follows the methods described for allogeneic islet transplantation. For example, the SUITO index can be applicable to autologous islet transplantation and was founded as an excellent predictor of insulin independence [129]. However, no immune response against infused islets is expected in these patients. Post-transplant function of autologous islets has been shown to be much better than in allogeneic combination; β cell mass more than 10,000 IEQ/kg of islet yield is considered for a factor of insulin independence in allogeneic transplants while islet yield over 5,000 IEQ/kg is the successful factor in autologous transplantation [130]. After achievement of insulin independent status, patients receiving autologous islets have better long term survival of graft. Most patients also achieve significant relief from pain and improve their quality of life.


4. Conclusion

Islet transplantation has been shown to be a very promising treatment that could result in freedom from requirement of exogenous insulin in type 1 diabetic patients. One of the major advantages of islet transplantation is the minimally invasive nature of the procedure when compared to whole organ pancreas transplantation. Despite its wide spread use at several major transplant centers, the volume of patients receiving islet transplants remain low when compared to the number of “brittle” type 1 diabetic patients eligible for this procedure. Recently impressive gains have been made in the improvement of post-transplant islet function. This is primarily due to the use of T-cell depleting immunosuppression during induction phase after transplant followed by use of tacrolimus, rapamycin and or mycophenolic mofetil during the maintenance phase. In addition several advances made in donor selection, pancreas procurement, enzymatic digestion, islet purification and islet culture seem to have contributed to this success. Recent completion of a large scale phase III clinical trial sponsored by the NIH has given hope that soon this procedure may be approved for clinical use. In light of these advances, there is optimism that the remaining hurdles could be overcome to improve the long term function of the transplanted islets.



This work was supported by grants from the National Institute of Diabetes and Digestive and Kidney Diseases (1R21DK090513-01 to M.F.L.), the Juvenile Diabetes Research Foundation (#5-2010-668 to B.N. and #3-2011-447 to M.T.) and by the Baylor Health Care System Foundation.


  1. 1. Shapiro A. M. Lakey J. R. Ryan E. A. Korbutt G. S. Toth E. Warnock G. L. et al. 2000 Islet transplantation in seven patients with type 1 diabetes mellitus using a glucocorticoid-free immunosuppressive regimen. N Engl J Med 343 4 230 8
  2. 2. Matsumoto S. 2010 Islet cell transplantation for Type 1 diabetes J Diabetes 2 1 16 22
  3. 3. Barton F. B. Rickels M. R. Alejandro R. Hering B. J. Wease S. Naziruddin B. et al. 2012 Improvement in outcomes of clinical islet transplantation: 1999-2010. Diabetes Care 35 7 1436 45
  4. 4. Ryan E. A. Paty B. W. Senior P. A. Bigam D. Alfadhli E. Kneteman N. M. et al. 2005 Five-year follow-up after clinical islet transplantation. Diabetes 54 7 2060 9
  5. 5. Bellin MD Barton F. B. Heitman A. Harmon J. V. Kandaswamy R. Balamurugan A. N. et al. 2012 Potent induction immunotherapy promotes long-term insulin independence after islet transplantation in type 1 diabetes Am J Transplant 12 6 1576 83
  6. 6. Carlsson P. O. 2011 Influence of microenvironment on engraftment of transplanted β-cells. Ups J Med Sci 116 1 1 7
  7. 7. Terasaki P. I. Cai J. 2005 Humoral theory of transplantation: further evidence. Curr Opin Immunol 17 5 541 5
  8. 8. Terasaki P. I. 2003 Humoral theory of transplantation. Am J Transplant 3 6 665 73
  9. 9. Campbell P. M. Senior P. A. Salam A. Labranche K. Bigam D. L. Kneteman N. M. et al. 2007 High risk of sensitization after failed islet transplantation. Am J Transplant 7 10 2311 7
  10. 10. Rickels M. R. Kamoun M. Kearns J. Markmann J. F. Naji A. 2007 Evidence for allograft rejection in an islet transplant recipient and effect on beta-cell secretory capacity. J Clin Endocrinol Metab 92 7 2410 4
  11. 11. Campbell P. M. Salam A. Ryan E. A. Senior P. Paty B. W. Bigam D. et al. 2007 Pretransplant HLA antibodies are associated with reduced graft survival after clinical islet transplantation. Am J Transplant 7 5 1242 8
  12. 12. Mohanakumar T. Narayanan K. Desai N. Ramachandran S. Shenoy S. Jendrisak M. et al. 2006 A significant role for histocompatibility in human islet transplantation. Transplantation 82 2 180 7
  13. 13. Kessler L. Parissiadis A. Bayle F. Moreau F. Pinget M. Froelich N. et al. 2009 Evidence for humoral rejection of a pancreatic islet graft and rescue with rituximab and IV immunoglobulin therapy. Am J Transplant 9 8 1961 6
  14. 14. Ferrari-Lacraz S. Berney T. Morel P. Marangon N. Hadaya K. Demuylder-Mischler S. et al. 2008 Low risk of anti-human leukocyte antigen antibody sensitization after combined kidney and islet transplantation Transplantation 86 2 357 9
  15. 15. Jackson A. M. Connolly J. E. Matsumoto S. Noguchi H. Onaca N. Levy M. F. et al. 2009 Evidence for Induced Expression of HLA Class II on Human Islets: Possible Mechanism for HLA Sensitization in Transplant Recipients Transplantation 87 4 500 6
  16. 16. Naziruddin B. Wease S. Stablein D. Barton F. B. Berney T. Rickels M. R. et al. 2012 HLA Class I Sensitization in Islet Transplant Recipients- Report from the Collaborative Islet Transplant Registry. Cell Transplant 21 5 901 908
  17. 17. Cardani R. Pileggi A. Ricordi C. Gomez C. Baidal D. A. Ponte G. G. et al. 2007 Allosensitization of islet allograft recipients. Transplantation 84 11 1413 27
  18. 18. Hire K. Hering B. Bansal-Pakala P. 2010 Relative reductions in soluble CD30 levels post-transplant predict acute graft function in islet allograft recipients receiving three different immunosuppression protocols Transpl Immunol 23 4 209 14
  19. 19. Han D. Xu X. Baidal D. Leith J. Ricordi C. Alejandro R. et al. 2004 Assessment of cytotoxic lymphocyte gene expression in the peripheral blood of human islet allograft recipients: elevation precedes clinical evidence of rejection. Diabetes 53 9 2281 90
  20. 20. Toti F. Bayle F. Berney T. Egelhofer H. Richard MJ Greget M. et al. 2011 Studies of circulating microparticle release in peripheral blood after pancreatic islet transplantation Transplant Proc 43 9 3241 5
  21. 21. Del Prete G. De Carli M. D’Elios MM Daniel K. C. Almerigogna F. Alderson M. et al. 1995 CD30-mediated signaling promotes the development of human T helper type 2-like T cells J Exp Med 182 6 1655 61
  22. 22. Platt R. E. Wu K. S. Poole K. Newstead C. G. Clark B. 2009 Soluble CD30 as a prognostic factor for outcome following renal transplantation J Clin Pathol 62 7 662 3
  23. 23. Shah A. S. Leffell M. S. Lucas D. Zachary A. A. 2009 Elevated pretransplantation soluble CD30 is associated with decreased early allograft function after human lung transplantation. Hum Immunol 70 2 101 3
  24. 24. Spiridon C. Hunt J. Mack M. Rosenthal J. Anderson A. Eichhorn E. et al. 2006 Evaluation of soluble CD30 as an immunologic marker in heart transplant recipients Transplant Proc 38 10 3689 91
  25. 25. Kessler L. Toti F. Egelhofer H. Richard MJ Greget M. N. K. Moreau F. et al. 2011 Acute cellular rejection of a pancreatic islet graft and rescue by steroid therapy: study of microparticles release in peripheral blood. In 151
  26. 26. Kolb H. Kolb-Bachofen V. Roep B. O. 1995 Autoimmune versus inflammatory type I diabetes: a controversy? Immunol Today 16 4 170 2
  27. 27. Sutherland D. E. Goetz F. C. Sibley R. K. 1989 Recurrence of disease in pancreas transplants. Diabetes 38 1 85 7
  28. 28. Roep B. O. 2003 The role of T-cells in the pathogenesis of Type 1 diabetes: from cause to cure. Diabetologia 46 3 305 21
  29. 29. Roep B. O. Stobbe I. Duinkerken G. van Rood J. J. Lernmark A. Keymeulen B. et al. 1999 Auto- and alloimmune reactivity to human islet allografts transplanted into type 1 diabetic patients. Diabetes 48 3 484 90
  30. 30. Huurman V. A. Hilbrands R. Pinkse G. G. Gillard P. Duinkerken G. van de Linde P. et al. 2008 Cellular islet autoimmunity associates with clinical outcome of islet cell transplantation. PLoS One 3 6 e2435
  31. 31. Matsumoto S. Chujo D. Shimoda M. Takita M. Sugimoto K. Itoh T. et al. 2011 Analysis of long-term insulin independence cases after allogeneic islet transplantation. Am J Transplant 11 2 175 176
  32. 32. Braghi S. Bonifacio E. Secchi A. Di Carlo V. Pozza G. Bosi E. 2000 Modulation of humoral islet autoimmunity by pancreas allotransplantation influences allograft outcome in patients with type 1 diabetes. Diabetes 49 2 218 24
  33. 33. Ashwell J. D. Lu F. W. Vacchio M. S. 2000 Glucocorticoids in T cell development and function*. Annu Rev Immunol 18 309 45
  34. 34. Mc Ewen B. S. Biron C. A. Brunson K. W. Bulloch K. Chambers W. H. Dhabhar F. S. et al. 1997 The role of adrenocorticoids as modulators of immune function in health and disease: neural, endocrine and immune interactions. Brain Res Brain Res Rev 23 1-2 79 133
  35. 35. Daneman D. 2006 Type 1 diabetes. Lancet 367 9513 847 58
  36. 36. Association A. D. 2012 Diagnosis and classification of diabetes mellitus. Diabetes Care 35 1 S64 71
  37. 37. Davani B. Portwood N. Bryzgalova G. Reimer M. K. Heiden T. Ostenson C. G. et al. 2004 Aged transgenic mice with increased glucocorticoid sensitivity in pancreatic beta-cells develop diabetes. Diabetes 53 1 S51 9
  38. 38. Ranta F. Avram D. Berchtold S. Düfer M. Drews G. Lang F. et al. 2006 Dexamethasone induces cell death in insulin-secreting cells, an effect reversed by exendin-4. Diabetes 55 5 1380 90
  39. 39. Ullrich S. Berchtold S. Ranta F. Seebohm G. Henke G. Lupescu A. et al. 2005 Serum- and glucocorticoid-inducible kinase 1 (SGK1) mediates glucocorticoid-induced inhibition of insulin secretion. Diabetes 54 4 1090 9
  40. 40. Vegiopoulos A. Herzig S. 2007 Glucocorticoids, metabolism and metabolic diseases Mol Cell Endocrinol;275 1-2 43 61
  41. 41. Walker B. R. 2007 Glucocorticoids and cardiovascular disease. Eur J Endocrinol 157 5 545 59
  42. 42. Schäcke H. Döcke W. D. Asadullah K. 2002 Mechanisms involved in the side effects of glucocorticoids Pharmacol Ther 96 1 23 43
  43. 43. Heit J. J. Apelqvist A. A. Gu X. Winslow M. M. Neilson J. R. Crabtree G. R. et al. 2006 Calcineurin/NFAT signalling regulates pancreatic beta-cell growth and function. Nature 443 7109 345 9
  44. 44. Soleimanpour S. A. Crutchlow M. F. Ferrari A. M. Raum J. C. Groff D. N. Rankin M. M. et al. 2010 Calcineurin signaling regulates human islet {beta}-cell survival. J Biol Chem 285 51 40050 9
  45. 45. Elion G. B. 1993 The George Hitchings and Gertrude Elion Lecture. The pharmacology of azathioprine. Ann N Y Acad Sci 685 400 7
  46. 46. Maltzman J. S. Koretzky G. A. 2003 Azathioprine: old drug, new actions. J Clin Invest 111 8 1122 4
  47. 47. Calafiore R. Basta G. Falorni A. Pietropaolo M. Picchio M. L. Calcinaro F. et al. 1993 Preventive effects of azathioprine (AZA) on the onset of diabetes mellitus in NOD mice. J Endocrinol Invest 16 11 869 73
  48. 48. Harrison L. C. Colman P. G. Dean B. Baxter R. Martin F. I. 1985 Increase in remission rate in newly diagnosed type I diabetic subjects treated with azathioprine. Diabetes 34 12 1306 8
  49. 49. Tzakis A. G. Ricordi C. Alejandro R. Zeng Y. Fung J. J. Todo S. et al. 1990 Pancreatic islet transplantation after upper abdominal exenteration and liver replacement. Lancet 336 8712 402 5
  50. 50. Scharp D. W. Lacy P. E. Santiago J. V. Mc Cullough C. S. Weide L. G. Boyle P. J. et al. 1991 Results of our first nine intraportal islet allografts in type 1, insulin-dependent diabetic patients. Transplantation 51 1 76 85
  51. 51. Socci C. Falqui L. Davalli A. M. Ricordi C. Braghi S. Bertuzzi F. et al. 1991 Fresh human islet transplantation to replace pancreatic endocrine function in type 1 diabetic patients Report of six cases. Acta Diabetol 28 2 151 7
  52. 52. Ricordi C. Tzakis A. G. Carroll P. B. Zeng Y. J. Rilo H. L. Alejandro R. et al. 1992 Human islet isolation and allotransplantation in 22 consecutive cases. Transplantation 53 2 407 14
  53. 53. Gores P. F. Najarian J. S. Stephanian E. Lloveras J. J. Kelley S. L. Sutherland D. E. 1993 Insulin independence in type I diabetes after transplantation of unpurified islets from single donor with 15-deoxyspergualin. Lancet 341 8836 19 21
  54. 54. Ricordi C. Alejandro R. Angelico M. C. Fernandez L. A. Nery J. Webb M. et al. 1997 Human islet allografts in patients with type 2 diabetes undergoing liver transplantation. Transplantation 63 3 473 5
  55. 55. Alejandro R. Lehmann R. Ricordi C. Kenyon N. S. Angelico M. C. Burke G. et al. 1997 Long-term function (6 years) of islet allografts in type 1 diabetes. Diabetes 46 12 1983 9
  56. 56. Secchi A. Socci C. Maffi P. Taglietti M. V. Falqui L. Bertuzzi F. et al. 1997 Islet transplantation in IDDM patients. Diabetologia 40 2 225 31
  57. 57. Tibell A. Brendel M. Wadström J. Brandhorst D. Brandhorst H. Eckhard M. et al. 1997 Early experience with a long-distance collaborative human islet transplant programme. Transplant Proc 29 7 3124 5
  58. 58. Keymeulen B. Ling Z. Gorus F. K. Delvaux G. Bouwens L. Grupping A. et al. 1998 Implantation of standardized beta-cell grafts in a liver segment of IDDM patients: graft and recipients characteristics in two cases of insulin-independence under maintenance immunosuppression for prior kidney graft. Diabetologia 41 4 452 9
  59. 59. Bretzel R. G. Brandhorst D. Brandhorst H. Eckhard M. Ernst W. Friemann S. et al. 1999 Improved survival of intraportal pancreatic islet cell allografts in patients with type-1 diabetes mellitus by refined peritransplant management. J Mol Med (Berl) 77 1 140 3
  60. 60. Oberholzer J. Triponez F. Mage R. Andereggen E. Bühler L. Crétin N. et al. 2000 Human islet transplantation: lessons from 13 autologous and 13 allogeneic transplantations. Transplantation 69 6 1115 23
  61. 61. Tibell A. Bolinder J. Hagström-Toft E. Tollemar J. Brendel M. Eckhard M. et al. 2001 Experience with human islet transplantation in Sweden. Transplant Proc 33 4 2535 6
  62. 62. Benhamou P. Y. Oberholzer J. Toso C. Kessler L. Penfornis A. Bayle F. et al. 2001 Human islet transplantation network for the treatment of Type I diabetes: first data from the Swiss-French GRAGIL consortium (1999-2000). Groupe de Recherche Rhin Rhĵne Alpes Genève pour la transplantation d’Ilots de Langerhans. Diabetologia 44 7 859 64
  63. 63. Hirshberg B. Rother K. I. Digon B. J. Lee J. Gaglia J. L. Hines K. et al. 2003 Benefits and risks of solitary islet transplantation for type 1 diabetes using steroid-sparing immunosuppression: the National Institutes of Health experience. Diabetes Care 26 12 3288 95
  64. 64. Hering B. J. Kandaswamy R. Harmon J. V. Ansite JD Clemmings S. M. Sakai T. et al. 2004 Transplantation of cultured islets from two-layer preserved pancreases in type 1 diabetes with anti-CD3 antibody Am J Transplant 4 3 390 401
  65. 65. Frank A. Deng S. Huang X. Velidedeoglu E. Bae Y. S. Liu C. et al. 2004 Transplantation for type I diabetes: comparison of vascularized whole-organ pancreas with isolated pancreatic islets. Ann Surg 240 4 631 40discussion 640-3.
  66. 66. Goss J. A. Goodpastor S. E. Brunicardi F. C. Barth M. H. Soltes G. D. Garber A. J. et al. 2004 Development of a human pancreatic islet-transplant program through a collaborative relationship with a remote islet-isolation center. Transplantation 77 3 462 6
  67. 67. Lehmann R. Weber M. Berthold P. Züllig R. Pfammatter T. Moritz W. et al. 2004 Successful simultaneous islet-kidney transplantation using a steroid-free immunosuppression: two-year follow-up. Am J Transplant 4 7 1117 23
  68. 68. Hering B. J. Kandaswamy R. JD Ansite Eckman. P. M. Nakano M. Sawada T. et al. 2005 Single-donor, marginal-dose islet transplantation in patients with type 1 diabetes. JAMA 293 7 830 5
  69. 69. Froud T. Ricordi C. Baidal D. A. Hafiz M. M. Ponte G. Cure P. et al. 2005 Islet transplantation in type 1 diabetes mellitus using cultured islets and steroid-free immunosuppression: Miami experience. Am J Transplant 5 8 2037 46
  70. 70. Kempf M. C. Andres A. Morel P. Benhamou P. Y. Bayle F. Kessler L. et al. 2005 Logistics and transplant coordination activity in the GRAGIL Swiss-French multicenter network of islet transplantation. Transplantation 79 9 1200 5
  71. 71. Warnock G. L. Meloche R. M. Thompson D. Shapiro R. J. Fung M. Ao Z. et al. 2005 Improved human pancreatic islet isolation for a prospective cohort study of islet transplantation vs best medical therapy in type 1 diabetes mellitus. Arch Surg 140 8 735 44
  72. 72. Toso C. Baertschiger R. Morel P. Bosco D. Armanet M. Wojtusciszyn A. et al. 2006 Sequential kidney/islet transplantation: efficacy and safety assessment of a steroid-free immunosuppression protocol Am J Transplant 6 5 Pt 1 1049 1058
  73. 73. O’Connell P. J. Hawthorne W. J. Holmes-Walker D. J. Nankivell B. J. Gunton J. E. Patel A. T. et al. 2006 Clinical islet transplantation in type 1 diabetes mellitus: results of Australia’s first trial. Med J Aust 184 5 221 5
  74. 74. Shapiro A. M. Ricordi C. Hering B. J. Auchincloss H. Lindblad R. Robertson R. P. et al. 2006 International trial of the Edmonton protocol for islet transplantation. N Engl J Med 355 13 1318 30
  75. 75. Ghofaili K. A. Fung M. Ao Z. Meloche M. Shapiro R. J. Warnock G. L. et al. 2007 Effect of exenatide on beta cell function after islet transplantation in type 1 diabetes. Transplantation 83 1 24 8
  76. 76. Badet L. Benhamou P. Y. Wojtusciszyn A. Baertschiger R. Milliat-Guittard L. Kessler L. et al. 2007 Expectations and strategies regarding islet transplantation: metabolic data from the GRAGIL 2 trial. Transplantation 84 1 89 96
  77. 77. Maffi P. Bertuzzi F. De Taddeo F. Magistretti P. Nano R. Fiorina P. et al. 2007 Kidney function after islet transplant alone in type 1 diabetes: impact of immunosuppressive therapy on progression of diabetic nephropathy. Diabetes Care 30 5 1150 5
  78. 78. Gillard P. Ling Z. Mathieu C. Crenier L. Lannoo M. Maes B. et al. 2008 Comparison of sirolimus alone with sirolimus plus tacrolimus in type 1 diabetic recipients of cultured islet cell grafts Transplantation 85 2 256 63
  79. 79. Gerber P. A. Pavlicek V. Demartines N. Zuellig R. Pfammatter T. Wüthrich R. et al. 2008 Simultaneous islet-kidney vs pancreas-kidney transplantation in type 1 diabetes mellitus: a 5 year single centre follow-up Diabetologia 51 1 110 9
  80. 80. Cure P. Pileggi A. Froud T. Messinger S. Faradji RN Baidal D. A. et al. 2008 Improved metabolic control and quality of life in seven patients with type 1 diabetes following islet after kidney transplantation Transplantation 85 6 801 12
  81. 81. Bellin M. D. Kandaswamy R. Parkey J. Zhang H. J. Liu B. Ihm S. H. et al. 2008 Prolonged insulin independence after islet allotransplants in recipients with type 1 diabetes. Am J Transplant 8 11 2463 70
  82. 82. Gangemi A. Salehi P. Hatipoglu B. Martellotto J. Barbaro B. Kuechle J. B. et al. 2008 Islet transplantation for brittle type 1 diabetes: the UIC protocol. Am J Transplant 8 6 1250 61
  83. 83. Froud T. Baidal D. A. Faradji R. Cure P. Mineo D. Selvaggi G. et al. 2008 Islet transplantation with alemtuzumab induction and calcineurin-free maintenance immunosuppression results in improved short- and long-term outcomes Transplantation 86 12 1695 701
  84. 84. Mineo D. Ricordi C. Xu X. Pileggi A. Garcia-Morales R. Khan A. et al. 2008 Combined islet and hematopoietic stem cell allotransplantation: a clinical pilot trial to induce chimerism and graft tolerance Am J Transplant 8 6 1262 74
  85. 85. Vantyghem M. C. Kerr-Conte J. Arnalsteen L. Sergent G. Defrance F. Gmyr V. et al. 2009 Primary graft function, metabolic control, and graft survival after islet transplantation. Diabetes Care 32 8 1473 8
  86. 86. Borot S. Niclauss N. Wojtusciszyn A. Brault C. Demuylder-Mischler S. Müller Y. et al. 2011 Impact of the number of infusions on 2-year results of islet-after-kidney transplantation in the GRAGIL network Transplantation 92 9 1031 8
  87. 87. Posselt A. M. Bellin M. D. Tavakol M. Szot G. L. Frassetto L. A. Masharani U. et al. 2010 Islet transplantation in type 1 diabetics using an immunosuppressive protocol based on the anti-LFA-1 antibody efalizumab. Am J Transplant 10 8 1870 80
  88. 88. Turgeon N. A. Avila J. G. Cano J. A. Hutchinson J. J. Badell I. R. Page A. J. et al. 2010 Experience with a novel efalizumab-based immunosuppressive regimen to facilitate single donor islet cell transplantation. Am J Transplant 10 9 2082 91
  89. 89. Posselt A. M. Szot G. L. Frassetto L. A. Masharani U. Tavakol M. Amin R. et al. 2010 Islet transplantation in type 1 diabetic patients using calcineurin inhibitor-free immunosuppressive protocols based on T-cell adhesion or costimulation blockade Transplantation 90 12 1595 601
  90. 90. Matsumoto S. Takita M. Chaussabel D. Noguchi H. Shimoda M. Sugimoto K. et al. 2011 Improving Efficacy of Clinical Islet Transplantation with Iodixanol Based Islet Purification, Thymoglobulin Induction and Blockage of IL-1-beta and TNF-alpha. Cell Transplant 20 10 1641 1647
  91. 91. Basta G. Montanucci P. Luca G. Boselli C. Noya G. Barbaro B. et al. 2011 Long-term metabolic and immunological follow-up of nonimmunosuppressed patients with type 1 diabetes treated with microencapsulated islet allografts: four cases. Diabetes Care 34 11 2406 9
  92. 92. Raught B. Gingras A. C. Sonenberg N. 2001 The target of rapamycin (TOR) proteins. Proc Natl Acad Sci U S A 98 13 7037 44
  93. 93. Niclauss N. Bosco D. Morel P. Giovannoni L. Berney T. Parnaud G. 2011 Rapamycin impairs proliferation of transplanted islet β cells. Transplantation 91 7 714 22
  94. 94. Zhang N. Su D. Qu S. Tse T. Bottino R. Balamurugan A. N. et al. 2006 Sirolimus is associated with reduced islet engraftment and impaired beta-cell function. Diabetes 55 9 2429 36
  95. 95. Tanemura M. Ohmura Y. Deguchi T. Machida T. Tsukamoto R. Wada H. et al. 2012 Rapamycin causes upregulation of autophagy and impairs islets function both in vitro and in vivo. Am J Transplant 12 1 102 14
  96. 96. Melzi R. Maffi P. Nano R. Sordi V. Mercalli A. Scavini M. et al. 2009 Rapamycin does not adversely affect intrahepatic islet engraftment in mice and improves early islet engraftment in humans. Islets 1 1 42 9
  97. 97. Gao R. Ustinov J. Korsgren O. Otonkoski T. 2007 Effects of immunosuppressive drugs on in vitro neogenesis of human islets: mycophenolate mofetil inhibits the proliferation of ductal cells Am J Transplant 7 4 1021 6
  98. 98. Allison A. C. Eugui E. M. 2005 Mechanisms of action of mycophenolate mofetil in preventing acute and chronic allograft rejection. Transplantation 80 2 S181 90
  99. 99. Cohn R. G. Mirkovich A. Dunlap B. Burton P. Chiu S. H. Eugui E. et al. 1999 Mycophenolic acid increases apoptosis, lysosomes and lipid droplets in human lymphoid and monocytic cell lines. Transplantation 68 3 411 8
  100. 100. Gallo R. Natale M. Vendrame F. Boggi U. Filipponi F. Marchetti P. et al. 2012 In vitro effects of mycophenolic acid on survival, function, and gene expression of pancreatic beta-cells Acta Diabetol
  101. 101. Vincenti F. Dritselis A. Kirkpatrick P. 2011 Belatacept. Nat Rev Drug Discov 10 9 655 6
  102. 102. Elliott R. B. Escobar L. Tan P. L. Muzina M. Zwain S. Buchanan C. 2007 Live encapsulated porcine islets from a type 1 diabetic patient 9.5 yr after xenotransplantation Xenotransplantation 14 2 157 61
  103. 103. Lee S. H. Hao E. Savinov A. Y. Geron I. Strongin A. Y. Itkin-Ansari P. 2009 Human beta-cell precursors mature into functional insulin-producing cells in an immunoisolation device: implications for diabetes cell therapies. Transplantation 87 7 983 91
  104. 104. Siebers U. Horcher A. Bretzel R. G. Federlin K. Zekorn T. 1997 Alginate-based microcapsules for immunoprotected islet transplantation. Ann N Y Acad Sci 831 304 12
  105. 105. Kobayashi T. Aomatsu Y. Iwata H. Kin T. Kanehiro H. Hisanaga M. et al. 2003 Indefinite islet protection from autoimmune destruction in nonobese diabetic mice by agarose microencapsulation without immunosuppression. Transplantation 75 5 619 25
  106. 106. Lee B. R. Hwang J. W. Choi Y. Y. Wong S. F. Hwang Y. H. Lee D. Y. et al. 2012 In situ formation and collagen-alginate composite encapsulation of pancreatic islet spheroids. Biomaterials 33 3 837 45
  107. 107. Cruise G. M. Scharp D. S. Hubbell J. A. 1998 Characterization of permeability and network structure of interfacially photopolymerized poly(ethylene glycol) diacrylate hydrogels. Biomaterials 19 14 1287 94
  108. 108. Lee D. Y. Lee S. Nam J. H. Byun Y. 2006 Minimization of immunosuppressive therapy after islet transplantation: combined action of heme oxygenase-1 and PEGylation to islet. Am J Transplant 6 8 1820 8
  109. 109. Cabric S. Sanchez J. Lundgren T. Foss A. Felldin M. Källen R. et al. 2007 Islet surface heparinization prevents the instant blood-mediated inflammatory reaction in islet transplantation. Diabetes 56 8 2008 15
  110. 110. Contreras J. L. Eckstein C. Smyth C. A. Bilbao G. Vilatoba M. Ringland S. E. et al. 2004 Activated protein C preserves functional islet mass after intraportal transplantation: a novel link between endothelial cell activation, thrombosis, inflammation, and islet cell death. Diabetes 53 11 2804 14
  111. 111. Stabler C. L. Sun X. L. Cui W. Wilson J. T. Haller CA Chaikof E. L. 2007 Surface re-engineering of pancreatic islets with recombinant azido-thrombomodulin. Bioconjug Chem 18 6 1713 5
  112. 112. Totani T. Teramura Y. Iwata H. 2008 Immobilization of urokinase on the islet surface by amphiphilic poly(vinyl alcohol) that carries alkyl side chains. Biomaterials 29 19 2878 83
  113. 113. Baidal D. A. Faradji R. N. Messinger S. Froud T. Monroy K. Ricordi C. et al. 2009 Early metabolic markers of islet allograft dysfunction. Transplantation 87 5 689 97
  114. 114. Rickels M. R. Schutta M. H. Markmann J. F. Barker C. F. Naji A. Teff K. L. 2005 {beta}-Cell function following human islet transplantation for type 1 diabetes. Diabetes 54 1 100 6
  115. 115. Ryan E. A. Shandro T. Green K. Paty B. W. Senior P. A. Bigam D. et al. 2004 Assessment of the severity of hypoglycemia and glycemic lability in type 1 diabetic subjects undergoing islet transplantation. Diabetes 53 4 955 62
  116. 116. Matsumoto S. Noguchi H. Hatanaka N. Shimoda M. Kobayashi N. Jackson A. et al. 2009 SUITO index for evaluation of efficacy of single donor islet transplantation. Cell Transplant 18 5 557 62
  117. 117. Yamada Y. Fukuda K. Fujimoto S. Hosokawa M. Tsukiyama K. Nagashima K. et al. 2006 SUIT, secretory units of islets in transplantation: An index for therapeutic management of islet transplanted patients and its application to type 2 diabetes. Diabetes Res Clin Pract 74 3 222 6
  118. 118. Takita M. Matsumoto S. Qin H. Noguchi H. Shimoda M. Chujo D. et al. 2011 Secretory Unit of Islet Transplant Objects (SUITO) Index can predict severity of hypoglycemic episodes in clinical islet cell transplantation Cell Transplant.
  119. 119. Takita M. Matsumoto S. 2012 SUITO Index for Evaluation of Clinical Islet Transplantation Cell Transplant.
  120. 120. Faradji R. N. Monroy K. Messinger S. Pileggi A. Froud T. Baidal D. A. et al. 2007 Simple measures to monitor beta-cell mass and assess islet graft dysfunction. Am J Transplant 7 2 303 8 .
  121. 121. Ryan E. A. Paty B. W. Senior P. A. Lakey J. R. Bigam D. Shapiro A. M. 2005 Beta-score: an assessment of beta-cell function after islet transplantation. Diabetes Care 28 2 343 7
  122. 122. Caumo A. Maffi P. Nano R. Bertuzzi F. Luzi L. Secchi A. et al. 2008 Transplant estimated function: a simple index to evaluate beta-cell secretion after islet transplantation. Diabetes Care 31 2 301 5
  123. 123. Friberg A. S. Lundgren T. Malm H. Felldin M. Nilsson B. Jenssen T. et al. 2012 Transplanted functional islet mass: donor, islet preparation, and recipient factors influence early graft function in islet-after-kidney patients Transplantation 93 6 632 8
  124. 124. Eriksson O. Eich T. Sundin A. Tibell A. Tufveson G. Andersson H. et al. 2009 Positron emission tomography in clinical islet transplantation. Am J Transplant 9 12 2816 24
  125. 125. Eich T. Eriksson O. Lundgren T. 2007 Transplantation NNfCI. Visualization of early engraftment in clinical islet transplantation by positron-emission tomography. N Engl J Med 356 26 2754 5
  126. 126. Saudek F. Jirák D. Girman P. Herynek V. Dezortová M. Kríz J. et al. 2010 Magnetic resonance imaging of pancreatic islets transplanted into the liver in humans. Transplantation 90 12 1602 6
  127. 127. Medarova Z. Moore A. 2009 MRI as a tool to monitor islet transplantation Nat Rev Endocrinol 5 8 444 52
  128. 128. Caumo A. Maffi P. Nano R. Luzi L. Hilbrands R. Gillard P. et al. 2011 Comparative evaluation of simple indices of graft function after islet transplantation. Transplantation 92 7 815 21
  129. 129. Matsumoto S. Takita M. Shimoda M. Itoh T. Iwahashi S. Chujo D. et al. 2011 Usefulness of the Secretory Unit of Islet Transplant Objects (SUITO) Index for Evaluation of Clinical Autologous Islet Transplantation Transplant Proc 43 9 3246 9
  130. 130. Sutherland D. E. Gruessner A. C. Carlson A. M. Blondet J. J. Balamurugan A. N. Reigstad K. F. et al. 2008 Islet autotransplant outcomes after total pancreatectomy: a contrast to islet allograft outcomes. Transplantation 86 12 1799 802

Written By

Morihito Takita, Nigar Seven, Marlon F. Levy and Bashoo Naziruddin

Submitted: April 12th, 2012 Published: February 27th, 2013