MOG prophylactic procedures in EAE.
\r\n\tThe WHO classification in 2007; was based on the histogenesis and cell origin of the tumor. In the latest classification made in 2016; to better characterize the tumor and obtain better data on its prognosis; The combination of molecular and genetic biomarkers and histopathological features of the tumor was used. Despite all current treatment approaches, the median survival time is around 12 months in most GBM patients. Compared with the situation of some types of successfully treated cancers; the survival time of GBM patients is not at an acceptable level today. In the treatment of CNS tumors; surgery, chemotherapy, and radiation treatments (x-rays, gamma rays, electron and proton beams) are used. The therapeutic potential of chemotherapy; New strategies are needed to increase drug concentration at the diseased site, as this largely depends on the ability of the chemotherapeutic agent to achieve effective concentrations at tumor localization. Based on our better understanding of the genetic and molecular characteristics of CNS tumors; Targeted therapies, including vaccines, and treatment protocols such as immunotherapy are promising developments.
\r\n\r\n\tThis book supposes to be written by many authors who have an internationally honored place in their field to share their ideas about the treatment of CNS tumors. Surgery, Radiotherapy, Chemotherapy and Antiangiogenic Therapy Protocols, Immunotherapy, Molecular Therapy, Specific target-agents therapy with Nanoparticles and Gene Therapy for CNS tumors among the book chapters.
\r\n\tIn these sections; there are many practical pieces of information that can help the students who graduated from the Medicine Faculty and specialist doctors who are interested in Neurosurgery.
The immune system is well known by its ability to defend the host against infections. In this sense, it is academically subdivided into innate and adaptive immune responses. Innate immunity is the first defense line and includes the microbicidal activity of macrophages and polymorphonuclear cells. Host defense against microorganisms is dependent upon recognition of pathogen-associated molecular patterns, mainly by toll-like receptors (TLRs) present in these cells. Otherwise, adaptive immunity requires specific antigen recognition by B and T lymphocytes. Differently from B cells that can directly recognize the antigens, T cells require previous antigen processing and interaction of epitopes with major histocompatibility complex proteins that are then expressed at the surface of antigen-presenting cells (APCs) as, for example, dendritic cells (DCs). Due to their strong potential for proliferation and activation, B and T cell activity needs to be regulated. A special T-cell subpopulation called regulatory T (Treg) cell plays a major role in controlling inflammatory immune responses. To maintain its homeostasis, the immune system has to manage a balance between inflammatory and anti-inflammatory responses. The imbalance of these immune responses leads to the development of many diseases such as autoimmune pathologies. In this context, other T-cell subpopulations such as T helper type 1 (Th1) and type 17 (Th17) cells, which are inflammatory, and type 2 cells (Th2), which are predominantly anti-inflammatory, are also involved. Besides its ability to eliminate pathogens and restore the host homeostasis, the immune system has also a mechanism to hamper the development of an immune response against the body’s own tissues. This mechanism, called self-tolerance, can be disrupted by the combination of a variety of genetic, environmental, and immunological factors that lead to autoimmunity. The relevance of vitamin D (VitD) in multiple sclerosis (MS), which is an autoimmune disease involving the central nervous system (CNS), is discussed in this chapter.
\nThe history of VitD is strongly linked to rickets and its treatment with cod liver oil. In 1922, McCollum [1] coined the term vitamin D to refer to the antirachitic factor found in cod liver oil [2]. For this reason and for a long time, the most widely accepted physiological role of VitD was related to calcium and phosphorus metabolism and bone mineralization [3]. However, since the 1980s, many researches implicated VitD on the cardiovascular, endocrine, and central nervous system (CNS), as well as on the immune system physiology. The active form of VitD (1α,25-dihydroxyvitamin D3) determines pleiotropic effects in human body through binding to vitamin D receptor (VDR), which is a member of the steroid hormone receptor superfamily found in a variety of human cells. The biological effects of VitD can be elicited by non-genomic and genomic mechanisms depending on the cell location of VDR. The non-genomic (rapid) mechanisms consist in VitD direct effect on the cells through membrane VDR binding. These effects include, for example, the activation of protein kinase C in different organs [4]. The genomic mechanism is determined by intracellular VDR that heterodimerizes with retinoic X receptor after binding to active VitD. This heterodimer is then translocated to the nucleus leading to activation or inhibition of a vast diversity of genes [5].
\nSome of the most important aspects of VitD epidemiology have been established by the scientist Michael Holick and his collaborators. As many people do not have an adequate sunlight exposure due to skin cancer risk, sedentary lifestyle, darker skin, or during the winter in countries far from the equator, there is an increasing number of persons with VitD deficiency around the world [6]. In the past few years, VitD deficiency has been associated with the etiology of many chronic diseases, like Crohn’s disease, infections of the upper respiratory tract, cancer, myocardial infarction, Alzheimer’s disease, autoimmune diseases, and others [7]. According to current knowledge, VitD serum levels should be between 30 and 100 ng/mL in healthy humans. VitD insufficiency is related to levels between 21 and 29 ng/mL, whereas a pronounced VitD deficiency is considered in individuals whose VitD levels are below 20 ng/mL. On the other hand, serum levels over 150 ng/mL can determine intoxication VitD intoxication [8]. Excessive oral intake of VitD may cause a hypervitaminosis condition with toxic effects such as hypercalcemia and hypercalciuria. Theories concerning the mechanisms of VitD toxicity involve elevated plasma concentration of VitD itself or its metabolites that culminates in overexpression of a variety of genes [9]. Although solubility of vitamins (fat or water) has no direct effect on toxicity, the ability of fat-soluble vitamins such as VitD to accumulate in the adipose tissue determines their higher toxic potential than water-soluble vitamins. For example, subcutaneous fat necrosis releases tissue-accumulated VitD that leads to hypervitaminosis and its toxic effects [10].
\nThe highest amounts of VitD are synthesized by the skin exposed to sunlight. Ultraviolet radiation converts 7-dehydrocholesterol in pre-vitamin D3. Then pre-vitamin D3 suffers a spontaneous thermal isomerization into vitamin D3, named cholecalciferol [11]. Due to this essential role of sunlight, this vitamin has been called “sunshine vitamin” [12]. Smaller amounts of VitD can be obtained from intake of certain foods such as mushrooms, fish, milk, and eggs [13]. To become a metabolically active hormone, cholecalciferol needs to be hydroxylated twice. The first hydroxylation takes place in the liver and converts cholecalciferol into 25-dyhidroxyvitamin D (calcidiol) via the enzyme 25-hydroxilase [14]. Plasma calcidiol levels are usually used as a parameter of VitD status because it increases in proportion to VitD intake [15]. After that, calcidiol binds to a carrier molecule, known as the vitamin D-binding protein, to be systemically transported to tissues that express 1α-hydroxylase (CYP27B1) [16]. The second hydroxylation, which generates the bioactive metabolite 1,25-dihydroxyvitamin D3 (calcitriol), occurs at the renal proximal tubular cells that are rich in CYP27B1 [17]. This reaction involves the sequential reduction of flavoprotein, renal ferredoxin, and cytochrome P-450 [18]. A critical physiological role in skeletal homeostasis is mediated by calcitriol. Concisely, hypocalcemia stimulates parathyroid glands to release parathyroid hormone, which activates renal CYP27B1 enzyme function, resulting in calcitriol production. Besides, parathyroid hormone stimulates osteoclast maturation to release calcium and phosphate from the bones. Calcitriol also reduces renal calcium excretion and increases calcium absorption from foods in the intestine. When normal calcium levels are obtained, calcitriol exerts a feedback regulation in the parathyroid gland, downregulating CYP27B1 activity to avoid VitD intoxication [14]. Besides the kidneys, 1α-hydroxylase has been reported in many tissues including bone, placenta, prostate, and parathyroid gland. In addition, several cancer cells and immune cells, such as macrophages, T lymphocytes, and DCs, are also able to produce this enzyme [19,20].
\nFirst evidences of VitD role in the immune system regulation date from the 80s. Haq [21] demonstrated that active VitD, but not its non-active form, blocked the production of IL (interleukin)-2 and consequently inhibited T-cell proliferation. Based on this downmodulatory effect, the potential of VitD to increase organ survival in experimental allograft transplantation was also evaluated. First studies in this field were based on the
It is well known that VitD stimulates the innate immune system by enhancing the antimicrobial ability of monocytes and macrophages. This effect is mainly associated with TLRs activation and increased release of cathelicidin and IL-1β by these cells [26]. Clinical evidences suggested a strong correlation between a poor VitD status and an increased susceptibility to infections. VitD has also been linked to more severe infectious diseases [27–29]. Moreover, Nouari et al. [30] recently demonstrated that active VitD can enhance the microbicidal activity of human monocyte-derived macrophages against
Conversely, VitD has an inhibitory effect on the adaptive immune system. It directly targets APCs, which are a very important link between the innate and adaptive immunity. In this sense, conventional APCs as DCs are profoundly affected by VitD. The mechanisms underlying the effects of VitD on DC function were recently reviewed by Barragan et al. [31].
The direct effect of VitD on T cells was the first evidence of the immunomodulatory activity of this hormone. Active VitD suppresses Th1 inflammatory immune response through inhibition of IL-2 and IFN-γ production, which are the main cytokines produced by this Th cell subset. This subject was revised by Lemire et al. [37]. These authors described that VitD preferentially inhibited Th1 functions having little effects over Th2 cells. At that time, they already suggested that this vitamin could have a potential therapeutic application in Th1-mediated diseases as is the case of some autoimmune pathologies.
\nMany inflammatory responses are also related to the development of Th17 cells and its signature cytokine named IL-17. It is largely known that this T-cell subpopulation is involved in the pathogenesis of a variety of inflammatory and autoimmune disorders [38]. In this context, Th17 cell pathogenicity is frequently related to a Th17-Th1 functional plasticity that is regulated by the cytokine milieu [39]. The immunomodulatory effects of VitD on Th17 cells are not clear and depend upon the disease. Most of what is known concerning VitD effect on these cells is based on experimental studies. For example, oral treatment with active VitD prevented and partly reversed experimental autoimmune uveitis in mice. This effect was related to both decreased IL-17 production and impaired development of Th17 cells [40]. Moreover, Chang et al. [41] demonstrated that active VitD treatment protected mice from experimental autoimmune encephalomyelitis (EAE) by inhibiting the differentiation and further migration of Th17 cells to the central nervous system (CNS). Even though the effect of VitD on animal models is evident, human data are controversial and there is not a consensus in the literature yet.
\nData on the effects of VitD on the development of Th2 cells are also conflicting. This T-cell subset is able to suppress Th1 inflammatory immune response through the production of anti-inflammatory cytokines such as IL-4 and IL-5. A direct effect of active VitD on Th2 cells was demonstrated by Boonstra et al. [42]. Even in the absence of APCs, these authors observed an increased frequency of IL-4-, IL-5-, and IL-10-producing murine CD4+ T cells after
Other T-cell subsets such as CD8+ T cells and natural-killer T cells (NKT) are also targets of VitD. Chen et al. [44] demonstrated that active VitD signaling through VDR is essential to control pathogenic CD8+ T cells in inflammatory bowel diseases. The importance of VDR was also highlighted by Yu et al. [45] who demonstrated a critical role of VDR expression in the development of induced NKT cells from mice fed with synthetic diets containing active VitD. There are few studies concerning the impact of VitD on B cells.
VitD action on the immune and the central nervous systems. (A) Effect of active VitD on the innate and the adaptive immunity cells and (B) direct and indirect effects of active VitD on the central nervous system.
The immunomodulatory potential of VitD has been widely explored in the field of autoimmune diseases. Epidemiological studies demonstrated that low VitD is correlated with a higher incidence of autoimmune diseases. Besides, genetic factors as VDR polymorphisms are also linked to autoimmune disorder susceptibility. The association between VitD and systemic and organ-specific autoimmune diseases, including multiple sclerosis (MS), was carefully reviewed by Agmon-Levin et al. [49].
\nMS is an autoimmune disease characterized by the activation of self-reactive T cells specific for CNS antigens. This immune response triggers an initial inflammation in brain and spinal cord that is then followed by demyelination, axonal damage, and scar formation [50]. The pathogenic immune response observed in MS is mainly mediated by Th1 and Th17 [51]. About 85% of MS patients present with a biphasic disease characterized by alternating episodes of neurological disability and recovery, which is entitled as relapsing remitting MS (RRMS). Within 20–25 years, 60–70% of these patients progress to a secondary-progressive disease that is characterized by progressive neurological deterioration. Approximately 10% of the patients display a disease course classified as primary progressive MS, which is characterized by a continuous decline in neurological performance without any recovery episode [52]. Magnetic resonance imaging (MRI) is playing a prominent role in the diagnosis and also in the analysis of MS therapy efficacy [53]. As mentioned before, autoimmune diseases result from the interactions of environmental and genetic risk factors. Environmental risk factors considered essential for MS development include infections and non-infectious factors that comprise differences in diet and other behaviors, such as cigarette smoking and sunlight exposure [54,55]. The development of MS has been strongly associated with viral and bacterial infections [54,56]. More recently, a possible relationship between MS and Candida species was proposed [57–59]. Our research team recently demonstrated that previous infection with
Epidemiological data on MS incidence and prevalence drew attention to a possible link between the geographical distribution of the disease and exposure to the sun, UV radiation/intensity, and VitD levels. This sunshine hypothesis also known as latitude-gradient effect was initially proposed by Limburg [61] that suggested a correlation between higher MS occurrence and increasing distance from the equator. According to the World Health Organization [62], the highest prevalence of MS occurs in Europe (80 per 100,000 people) and the lowest prevalence in Africa (0.3 per 100,000). More recently it was reported that, until 2013, the number of MS was higher in northern hemisphere and lower in southern hemisphere, with the exception of Australia and New Zealand [63]. A latitudinal variation was also identified in the continents. For example, geospatial analysis carried out in North American regions showed an inverse correlation between MS and UV radiation, that is, higher MS rates have been associated with lower UV radiation due to a south-north latitudinal gradient [64]. Interestingly, a series of lifestyle changes that include sun evasion associated with skin protection and extra time indoors, or increased charter tourism to warmer countries during the winter, seems to abolish latitude effects on UV radiation exposure [65]. According to these authors, this association between sun exposure and MS can be determined by distinct effects: by the VitD generated by sun exposure, by direct sun effects, or by a combination of both. These possibilities are reinforced by data from experimental animals and also from dietary studies in human populations. Dermal application of VitD ointments and UV radiation in VDR knockout mice were both able to induce Treg cells [66]. Further study indicated that these UV-induced Treg cells were able to migrate to the CNS of mice with EAE where they downregulated the inflammatory activity [67].
\nA lower prevalence of MS in some northern countries, which in a general way are expected to have a higher number of patients with the disease, could be explained by VitD-related dietary factors. For example, VitD sufficiency could be achieved through a traditional diet that includes fatty fish and cod liver oil. This possibility has been suggested to explain the reduced risk of MS in Norway that is located at the north of the Arctic Circle [68]. The relevant role of dietary VitD intake in MS was examined in two large cohorts of women: the Nurses\' Health Study (NHS; 92,253 women followed between 1980 and 2000) and the Nurses\' Health Study II (NHS II; 95,310 women followed between 1991 and 2001). The authors concluded that intake of VitD from supplements had a protective effect on the risk of developing MS [69]. A recent study with 953 MS patients indicated an inverse association between MS risk and the dose of cod liver oil during adolescence, suggesting that this stage of life is an important susceptible period for adult-onset MS, reinforcing the importance of dietary VitD as a risk factor for MS [70]. Altogether these data supported the possibility that MS patients could have lower levels of VitD. Regarding this, the largest study to date compared VitD levels present in Iranian MS patients (
The recent identification of VitD as a risk factor for MS susceptibility, and more recently as a potential modifier of disease course, inspired several clinical trials in relapsing MS [77]. It has been proposed that VitD supplementation is a low-cost and a low-risk intervention that may potentiate the efficacy of certain treatments against MS, without the risk of provoking serious adverse events as occurs with other combination therapies [76]. In effect, many patients are being already supplemented with VitD. However, it is not known whether supplementation has a significant impact on MS progression. A clinical trial (NCTO1339676) employing oral supplementation with active VitD (20,000 IU/week, cholecalciferol, Dekristol) administered once a week during 12 months together with IFN-β-1b resulted in reduction of MRI lesions in the brain of MS patients [78]. In another clinical trial (NCT 00785473), this same dose (20,000 IU/week, cholecalciferol, Dekristol) was administered during 24 months in RRMS patients under treatment with IFN-β-1b, GA, or natalizumab. Even though the patients presented a significant increase in serum VitD levels, the markers of systemic inflammation were not modified. The authors suggested that the anti-inflammatory effects of VitD supplementation are limited to RRMS patients with VitD insufficiency or to earlier stages of the disease [79]. A higher dose of VitD3 (50,000 IU/week) administered by oral route during a short period (2 months) reduced disability in RRMS patients and surprisingly upregulated IL-6 and IL-17 gene expression in the peripheral blood mononuclear cells of these patients [80]. Similarly, the same VitD dose (50,000 IU) administered by oral route every five days for 3 months in 94 RRMS patients under treatment with IFN-β-1b reduced disability of these patients but also increased IL-17 serum levels in comparison to a placebo group [81]. Investigations in this area suggested that changes in IL-17 levels could be related to the adopted VitD doses. For example, Golan et al. [82] demonstrated that IL-17 serum levels were significantly increased in a lower dose group (800 IU/per day), whereas patients that were taking higher doses (4370 IU/per day) presented heterogeneous IL-17 responses: 40% of them had decreased serum IL-17 levels, whereas 45% had increased IL-17 levels after three months of supplementation. These authors suggested that IL-17 data must be interpreted with caution as serum IL-17 is not an established biomarker of MS disease activity. Furthermore, IL-17 serum levels before treatment with IFN-β could not be correlated to disease activity parameters [83]; IL-17 also showed a trend toward higher levels in MS patients with inactive disease compared to those with active disease [84]. More recently, 40 patients with RRMS were randomized to receive 10,400 IU or 800 IU of cholecalciferol daily for 6 months. Mean increase of VitD levels from baseline to the ones detected at final visit was larger in the high-dose group than in the low-dose one and adverse events were minor and did not differ between the two groups. Interestingly, in the high-dose group, but not in the low-dose one, there was a reduction in the proportion of IL-17+CD4+ T cells. The authors concluded that daily cholecalciferol supplementation with 10,400 IU is safe and well tolerated in patients with MS and determines
The researches done so far strongly suggest that VitD supplementation could be useful in MS treatment. However, the exact doses to be prescribed to patients presenting different clinical symptoms are still waiting to be determined [86]. Regarding the side effects of VitD that include hypercalcemia [87] and the imbalance in serum concentration of parathyroid hormone [88], monitoring serum VitD would also be extremely important. In spite of the findings that VitD directly regulates the nervous system development and function [89], there is no scientific evidence to support its use as a monotherapy for MS in clinical practice [90]. Recent human trials concerning VitD supplementation in MS patients suggest that higher VitD doses are more efficient to control the symptoms and disease inflammatory markers. Nonetheless, to fix the ideal dose, it is essential to measure VitD serum levels before supplementation and to follow up the patients by constantly monitoring side effects. It is important, however, to highlight that the ideal dose could vary from one patient to another. The possible use of VitD analogs devoid of side effects must be also evaluated. World Health Organization (WHO) and Multiple Sclerosis International Federation (MSIF) published in 2008 the first Atlas of MS [62], correlating the epidemiology, diagnosis, and therapy. To the best of our knowledge, WHO did not define a specific VitD dose to treat MS.
\nExperimental autoimmune encephalomyelitis (EAE) is an animal model universally employed to investigate mechanisms of inflammation in the CNS in the context of MS. EAE is mainly induced in rodents either by active immunization with CNS antigens associated with adjuvant or by passive transfer of CNS-specific T cells. Most of the therapeutic procedures adopted nowadays were initially tested in murine EAE [91]. In 1991, it was demonstrated that VitD administration every other day for 15 days, starting 3 days before EAE induction, significantly prevented disease development and prolonged the survival of SJL/J mice [92]. This was the first report concerning the therapeutic potential of VitD on EAE. To avoid undesirable hypercalcemia
Critical effects of VitD on CD4+ T cells have been reported, whereas it is not evident if this vitamin affects CD8+ T cells, which express the highest concentrations of VDR. The effect of VitD on CD8+ T cells in EAE was evaluated in one report. The authors demonstrated that VitD inhibits EAE development even in mice lacking functional CD8+ cells, suggesting that they were not essential for VitD-suppressive effect in murine EAE [101]. The conception that the CD4+ T-cell subset was the main VitD target during EAE therapy was then established. VitD treatment triggered a reduction in the total number of lymphocytes, while the amount of IL-4 and TGF-β-1 transcripts increased in the CNS of EAE mice [102]. Still regarding anti-inflammatory cytokines, VitD therapy was reported to be much less effective in preventing EAE symptoms in IL-4-deficient mice [103] and also failed to inhibit EAE in mice with a disrupted IL-10 or IL-10R gene [104]. A more recently described profile of CD4+ T cells termed Th17 plays a critical role in numerous inflammatory conditions and autoimmune diseases. In this context, researchers showed that VitD can inhibit the differentiation and migration of Th17 cells to the CNS, ameliorating EAE symptoms [41,105].
\nAfter the first demonstration that VitD leads to induction of CD4+CD25+Foxp3+ cells with suppressive activity
Emphasis has been given to specific therapies, that is, to procedures that target CNS antigen and that would be, therefore, more efficient and devoid of side effects. In this context, MOG administration by different routes as intravenous [113], oral [114] or nasal [115], was able to suppress EAE symptoms. Various formulations containing myelin antigens were tested to control EAE. MOG conjugated with nanoparticles [116], mannan, [117] or inserted into a plasmid DNA [118] reduced EAE symptoms through induction of Foxp3+ Treg cells and dowmodulation of Th17 and Th1 cells. Our research group has been working in this context. Considering that an antigen from the CNS can provide the required specificity and that VitD is endowed with a strong downmodulatory potential, we anticipated that VitD could work as a tolerogenic adjuvant. Differently from the conventional immunogenic adjuvants that reinforce the immune response, the denominated tolerogenic adjuvants have the ability to downmodulate or modify the specific immune response when associated with specific antigens. Confirming this hypothesis, we recently demonstrated that a combined therapy with MOG + VitD blocked EAE development. This elevated efficacy was correlated with reduced production of IL-6 and IL-17 by spleen and CNS cell cultures stimulated with MOG, reduced splenic DC maturation, and also a striking decline in CNS inflammation [119] (Figure 2).
MOG + active vitamin D3 association strategy for EAE prophylaxis and treatment. C57BL/6 mice were vaccinated or treated with this association and the effect on EAE was evaluated in the acute EAE phase. Both strategies decreased production of inflammatory cytokines by CNS mononuclear cells, frequency of CD4+CD25+Foxp3+ Treg cells, and inflammation in the CNS.
Prophylactic strategies in EAE, and also in other autoimmune pathologies, are based in the concept of "inverse vaccination.” This procedure refers to the use of an immunization protocol that, differently from classical vaccination, aims to achieve an antigen-specific tolerogenic state [120]. Even though the term “inverse vaccination” could also be used as a therapeutical strategy, in this text we applied it only in the context of prophylactic vaccination. The majority of the prophylactic strategies in EAE have been done by administration of a diversity of MOG formulations delivered by distinct routes. A few examples of these procedures and the main histological and immunological findings are illustrated in Table 1.
\nThe prophylactic potential of VitD (or analogs) alone or associated with other pharmaceuticals has been tested in EAE. The adopted experimental protocols are not standardized and therefore, different amounts of VitD are administered by distinct routes. Time periods chosen for VitD administration in relation to EAE induction are also variable and some procedures consist in prolonged administration periods, even reaching the disease clinical phase. However, a general consensus is that VitD is able to improve clinical disease manifestation and also to trigger evident effects on the CNS and the immune system. Some of the effects observed in mice with EAE that were previously injected with VitD are exemplified in Table 2.
\nPeptide formulation | \nAnimal model | \nEffects | \nReferences | \n
---|---|---|---|
Plasmid DNA vaccines encoding MOG35–55 | \nC57BL6/J mice | \n↓Microglia/macrophage activation, astrogliosis, and axonal damage ↑CD4+CD25+Foxp3+ Treg | \nFissolo et al. [118] | \n
MOG35–55 conjugated to mannan, intradermally | \nC57BL/6 and SJL/J mice | \n↓Demyelination ↓Inflammatory infiltrates | \nTseveleki et al. [117] | \n
Tolerogenic DC pulsed with MOG40–55 | \nC57BL/6 mice | \n↑IL-10 production by MOG-stimulated splenocytes ↑CD3+CD4+CD25+FoxP3+ cells | \nMansilla et al. [121] | \n
MOG35–55-PLGA + IL-10-PLGA, subcutaneously | \nC57Bl/6 mice | \n↓IL-17 and IFN-α production by splenocytes↓Demyelination score | \nCappellano et al. [122] | \n
MOG prophylactic procedures in EAE.
Route | \nAnimal model | \nEffects | \nReferences | \n
---|---|---|---|
Diet | \nCD8+ −/− mice | \nProtection independent of TCD8+ cells | \nMeehan and DeLuca [101] | \n
Intraperitoneally | \nC57BL/6 mice | \n↓MyD88, IRF-4, IRF-7 and NF-kB expression ↓Several TLRs | \nLi et al. [123] | \n
Oral, gavage | \nC57BL/6 mice | \nIntact blood–CNS barrier ↓Inflammatory infiltrates in the CNS | \nGrishkan et al. [124] | \n
Intraperitoneally | \nC57BL/6 mice | \n↓Demyelination ↑Beclin-1 expression in neurons | \nZhen et al. [111] | \n
Vitamin D3 prophylactic procedures in EAE.
The combination of VitD with other substances as calcitonin [125], IFN-β [126], bisphosphonate [127], rapamycin [128], and cyclosporine [129] has determined cooperative effects over EAE control. We recently tested the association of VitD with MOG as a prophylactic approach to control EAE development. Again, in this procedure, we explored the concept of VitD as a tolerogenic adjuvant. This concept and its potential application to trigger self-tolerance in autoimmune diseases were conceived by Kang et al. [130]. These authors validated this hypothesis by demonstrating that FK506 (tacrolimus) associated with MOG was prophylactic in encephalomyelitis [131]. In this context, we hypothesized that active VitD could also behave as a tolerogenic adjuvant if associated with a CNS-specific antigen. Vaccination with MOG associated with VitD, before EAE induction in C57BL/6 female mice, determined a significant clinical improvement characterized by absence of clinical score and no body weight loss. An impressive reduction in CNS inflammation, DC maturation and also cytokine production by CNS and spleen cell cultures was detected in these vaccinated animals [132]. As described in Section 6 of this chapter, this combination of MOG with VitD was also very efficient as a therapeutic procedure in the EAE model. This prophylactic and therapeutic potential of the MOG/VitD association in EAE is illustrated in Figure 2. The possible use of VitD as a tolerogenic adjuvant in association with other self-antigens, as a strategy to control autoimmune pathologies, warrants future investigation. In our opinion, the fact that VitD is already accepted for human supplementation will facilitate its adoption for MS treatments based on its association with neuronal self-antigens.
\nThe authors are thankful for the financial support from São Paulo State Foundation (FAPESP)—Grant #2013/26257-8, Conselho Nacional de Desenvolvimento Científico e Tecnológico (CNPq)—Grant #302710/2013-2 and also Pró-Reitoria de Pesquisa—Universidade Estadual Paulista (PROPe—UNESP). Special thanks are given to Danilo Sanches Moreno for his substantial contribution to the art of drawing and figures.
\nThe Building Information Modeling (BIM) methodology is currently the main digital support to the elaboration of diverse construction activities. A BIM project is developed over a technological platform, in which all experts create, manipulate and add the information that is required and generated in the context of the work of each professional involved [1]. In this process, the methodology supports the development of different components of the project, allows adequate interoperability between specific systems related to various types of analysis or simulation, facilitates the tasks of budgeting, construction, maintenance and management and controls the procedure for a possible demolition [2].
The BIM concept began to be implemented in the construction industry at the present century as an immersive innovation in the sector supported in advanced technology. Its benefits were quickly recognized, reflected in the quality of the developed projects, based on effective process integration and clear collaboration between partners related to the different specialties intrinsic to construction [3]. BIM computational tools are a strong support for the improvement of different disciplines in a project, enabling their parametric modeling and easy access to all the information concentrated in the BIM model, created along the elaboration of a project.
In all areas of the construction activity, the construction owner, designers, builders and managers have verified the benefits of adopting BIM methodology. This fact has led to its growing acceptance, at a global level and in an exponential way, leading government entities to establish rules of action and mandatory implementation dates in public construction [4]. In addition, the school has the mission, essential in society, to train future engineers with the fundamental teachings related to different issues in the field of construction, and should also be focused on the technological innovations that can be applied in the sector. Naturally, construction-related companies follow this perspective, encouraging professionals to seek training actions that can add to professionals the BIM knowledge required in a globalized industrial world, increasingly competitive.
To stay up-to-day in business, companies are urged to recruit professionals that demand brand new knowledge and skillsets. BIM education learning regarding the concept, range of application and tools available is required in the activity. This necessity has led, recently, technical universities to introduce this innovative subject using emerging technologies in the graduate curricula and in complementary programmes aimed at construction professionals [5]. The great interest in teaching BIM within technical academies has been noted in the organization of specialization courses and workshops, aimed at professionals of the architecture and engineering sectors. The applicability range of BIM interferes with several disciplines, in Civil Engineering degree, from technical drawing and modeling issues to structural analyses and construction planning. So BIM topic must be understood by all teachers in order to ability each one to teach their specific sciences using some capacities of the available BIM tools. The main objective of the course is essentially to empower training and knowledge participants that are useful to them in their activity. The professionals feel the necessity to update their skills in BIM, and the present course contributes in a positive way to this training.
A short course, presented in March of 2022, includes the methodological concepts and a wide range of the applicability in all sectors inherent to the development of projects using BIM platforms. The text includes the contents of the course and its main objectives. The organizational structure of the course introduces the underlying fundaments of the methodology, such as parametric modeling and interoperability, and presents the scope of the applicability of BIM. The most recent research achievement in BIM applications was resumed and presented to the professional course participants.
Currently, the attention of Civil Engineering education is oriented to BIM, and it is up to the school, as the main trainer of the future engineer, to introduce this theme, as a concept that should be transmitted, contributing to support all new subjects, included in the curriculum, on a BIM-based digital support. The requirement of BIM skills in the sector has imposed an educational maturity of alert in relation to its need in society, which has led to a progressive adaptation of the curricula taught [6].
The most recent demonstration of the benefit inherent to the use of the BIM methodology has been registered in the various sectors, motivating designers and managers to acquire knowledge related to the concept and scope of its applicability. Professionals from all sectors are interested in knowing the BIM concept and the scope of its applicability, and technical schools organize BIM training activities to help to add knowledge and competitiveness to industry professionals.
The schools have been contributing positively to the update of knowledge of professionals in the sector, through the organization of BIM training courses, in accordance with the interest and expectation expressed by the offices and public entities. Industry and the school are partners in finding the best strategy for establishing effective ways of teaching useful to the community. In Europe, BIM training has been essentially introduced into postgraduate studies as curricular modules, disciplines or specialization courses. In Ref. universities, in Spain, Switzerland, Portugal and Italy, the curricular research points to a relatively rapid assimilation in engineering training:
The
At the
At the
The curriculum, of the
BIM is one of the most advanced methodologies applied in architecture and civil engineering in recent years; therefore, it becomes important to promote its integration into university education. The construction industry has been demanded from schools an offer aimed the construction professions, requiring different perspectives of training. Engineers and architects recognize that in a globalized world, to perform with quality and competence their activity, the use of BIM platforms is a priority. The adoption of BIM in the sector leads to the achievement of better products and the establishment of more competitive projects. Following this, several modules, workshops and short courses have been offered to the professionals:
Huang [8] introduced a
A 3-day
A BIM course, structured as a
As the students present different technological abilities and skills, this can introduce some
A 1-day live
The Architectural Technology and Construction
The
Taylor
The professional course,
The introduction of the main fundamentals of BIM concerns the concept, the range of applicability in a global perspective and the state of the art of its implementation (Figure 1). The central BIM notion is the generation of a centralized digital model formed with all construction-related information. The BIM model is frequently defined as a digital representation of the building or infrastructure, strongly supported by parametric modeling and standard format of data. The model assists the elaboration of collaborative projects that can be performed over the model, requiring the use of advanced technologies and a high level of interoperability.
Slides of the professional course [author].
A practical lesson concerning the use of BIM-based tool introduces the concept of parametric modeling, essential to the understanding of the development of multitasking. In the modeling process, the first step is to define the base settings (work units, elevation levels and alignments), followed by the selection and adaptation of parametric objects, associated to physical properties [16]. As an example of how to handling with a BIM-based tools, a structural BIM model was created, beginning with columns and beams (Figure 2) and foundations (Figure 3). After, there were obtained several tables of take-off of materials and elements from the generated BIM model (Figure 4).
Modeling columns and beams [author].
Modeling foundations [author].
Interface with selection of a new schedule and table of columns extracted from the model [author].
An analysis of conflicts detection between distinct projects was also exposed to the audience. The BIM modeling tools allow the overlap of three disciplines (architecture, structures and mechanic) and support the definition of each component by direct analysis of conflicts, identified by the system with the presentation of inconsistency messages [17]. There are several software with conflict analysis-oriented capability, namely Tekla BIMsight, Navisworks and Solibri Model Checker tools. After running any of these systems, the modeler adjusts each conflict situation over the BIM model. In the study case shown in the course, the models of water system and structures were overlapped and an analysis of inconsistency was applied (Figure 5) [18].
Analyses of conflicts between structures and mechanic models [
In addition, a foundation case was analyzed concerning conflicts between structural elements and piping components (Figure 6) [19]. Using Navisworks and Tekla BIMsight, a set of conflicts were listed and visualized. The conflicts detected were after adjusted accordingly, in the modeling system, in order to obtain correct situations (Figure 7) [18].
Analyses of conflicts in the foundation level [
Changes were performed in a BIM modeler software [
The course also illustrates how to generate a 4D BIM model, relating to the construction process of a buildings. First, the complete 3D BIM model of the structural project must be defined and after the constructive sequence planning (phases and periods of implementation or placement) and allocated human resources must be established in the form of a Gant map (Figure 8) [20].
Structural BIM model and the Gant map of its construction [
The 4D model is then created in the Navisworks software, a BIM viewer. The BIM model, representing the structural project, is exported from the modeling system to the BIM viewer, performed in the native format of data, allowing a height level of interoperability. In addition, the construction-planning file (Gantt map) is transferred from the Ms. Project system to the Navisworks. Next, it is necessary to associate the elements of the imported model, forming groups (sets), according to the activities of the schedule (Figure 9) [21].
Association of sets to activities [
Obtaining the correct and detailed 4D model, the simulation of the construction can be visualized (Figure 10).
Elements must be modeled by
Consider the modeling of
The elements shall contain information, in their
BIM 4D model generation and visual simulation [
The 4D model allows visual representation of the planned construction process. The Simulate tab of the Timeliner the Play option should be selected in order to initialize the construction simulation animation (Figure 11).
Simulation of the construction process in Naviswork [
The simulation can be exported through the Animation command on the Output tab and allow to monetarize the real work in the site. It is also possibility to do a virtual navigation inside the model with the insertion of an avatar (Figure 12). A comparison of the evolution of construction can be represented (Figure 12): executed (gray), progressing (green), early (yellow) and backward (red). The ability of the BIM 4D model to be transportable to the construction site supports the control of the real construction.
Virtual walking inside the construction and the representation of elements built and in progress [
Along the development of a project and later construction and use, several processes demanding the transfer of data between software are normally performed, and for that, a high level of interoperability is required. In a structural design, the transposition of models between BIM modeling and structural analysis tools is essential. Concerning the structural design, the interoperability capacity, the transfer and verification of consistencies and the centralization of information and graphic documentation were presented in the training [22].
The process of transposition of structural models between modeling and calculation systems (two-way flow) was analyzed in several situations involving ArchiCAD, Revit and AECOsim modeling tools and SAP [18, 23], Robot [24] and ETABS [25] structural dimensioning tools. The transposition of models between systems is supported in native format of data, when the software belong to the same manufacturer or by the recourse to the universal data transfer standard, the Industry Foundation Classes (IFC) format.
The interoperability capability analysis, verified in each model transposition process, is evaluated over several case studies of distinct volume and use. The architectural component was also modeled in order to illustrate the vantages of engineers and architects collaborate over a single and centralized model (Figure 13).
Architectural and structural BIM models of distinct buildings (a) [
First, the BIM models were transferred from the modeler system to the analyses software and the geometric consistency was evaluated. Several inconsistencies were detected (Figure 14).
The
The
The analytical
Structural BIM models transferred to the analyses software (a) [
However, the structural elements (columns, beams and slabs), grids and material, concrete C30/37 and A500 NR SD steel were correctly transposed (Figure 15).
Structural elements transferred with accuracy (a) [
After the structural analysis was performed for each case:
All
The
Calculation systems allow a high automation capacity of detail
Next, as required by the BIM centralization concept, the calculation result should be transferred to the initial BIM model. Also, the reinforcements were defined in the dimensioning software and after transferred to the initial structural model (Figure 16) [24]:
The model database should be
However, the reverse transfer process has a much higher volume of
Inaccuracies detect with the reinforcements elements after transposition of models [
The limitation detected in the interoperability performance of the software is frequently the main reason to justify the resistance of the implementation of BIM in the design of structures. The main remarks concerning the level of interoperability between BIM-based modeling and calculation systems were assessed and transmitted to the assistance of the course:
There are advantages of using
The
The advantages are essentially related to the
It is appropriate to perform the
A recent implementation perspective, the Historic or Heritage Building Information Modeling (HBIM) is directed towards properties of historical value or heritage relevance. Recent research related to HBIM addresses [26]:
The standardization of architectural configurations and creation
The analysis of
The
It is required to understand geometric rules, in parametric terms, from the books of architectural patterns to the HBIM modeling process. Sets of specific parametric objects must be generated to allow the generation of old buildings with accuracy (Figure 17).
Architectural configurations (a) [
The registered documentary information provides data concerning the characterization of the construction (historical epoch and traditional construction systems), the registration of refurbishing interventions and local inspection reports. In addition, the documentary collection, along with municipal archives, composed of drawings of plants, elevations and cut, referring to different dates and with yellows and reds, brings a complete description of the old building.
The stratigraphic analysis covers the study of the constructive steps, which are represented through different colors, leading to a clear visual perception. In an HBIM process, it is also frequently necessary to establish a station of laser devices, properly positioned, so that, later, the points obtained can be unified, in a single cloud of space points (Figure 18).
Antique drawings of building (a) [
A practical case of reconversion of a building of heritage value was presented [32, 33]. A proposal for the adaptation of an old building, located in Lisbon, requiring the reorganization of internal compartmentalization, but preserving their architectural characteristics, illustrated an application of HBIM (Figure 19).
Building of heritage value, old drawing and BIM model of the proposal [
Although the BIM base tools, of current use, are more dedicated to the new construction, adapted to the geometry of the current architecture, the growing interest in the rehabilitation sector has led to the incursion of the application of BIM in the support of the conservation of historic buildings. Old constructive solutions require adequacy libraries of parametric object, to enable the implementation of BIM, also in the recovery of heritage-value buildings.
Within HBIM, the creation of families of specific parametric objects is normally required for the rigorous representation of buildings of patrimonial value. In the context of study case, as a basis for modeling, it was required to collect the existing documentation in the Municipal Archive of Lisbon, to obtain photographs from outside and inside of the building and the registration of detailed sketches. In addition, to allow a correct geometry represented in the form of parametric objects, it was necessary to add the material type and adjust the physical and mechanical properties, in order to respect the ancestral techniques of construction. The work contributes to empower the HBIM library of parametric objects of old building components. Namely, concerning a new library of doors (Figure 20) and windows (Figure 21).
New parametric objects representing doors [
Image, sketch and sequence of the modeling process of a window [
The demonstration of the benefits inherent in the use of methodology for BIM in the construction industry, in the development of various activities based on the project, at a global level, motivates the great interest, which has recently verified by designers and managers to meet the BIM concept and the scope of its application. The course aims to contribute to the dissemination of the potential implementation of BIM methodology in sectors such as infrastructure, construction planning, conflict analysis, structural dimensioning or HBIM.
The course was oriented to various levels and sectors of the construction industry. The degree of satisfaction of the attendees is evaluated in Table 2. Some comments and recommendation were also expressed. The comments of the participants to the course were oriented to a general and specific appreciation:
The course exceeded expectations taking into account the time available, allowing an
Important insertion of
The
The
Topic | Contents |
---|---|
Building Information Modeling (BIM) | Concept, applicability and implementation; Parametric modeling, interoperability and centralization; BIM tool practice in generating model structures. |
BIM in the construction | Conflict analysis; Adding parameters to objects; Construction planning; Quantification of materials. |
BIM in structural design | Interoperability; Transfer and consistency check; Graphic documentation and information centralization. |
Heritage Building Information Modeling (HBIM) | Concept and collection of information; Digital capture of images (photogrammetry, scanner and drones); Generation of specific families of parametric objects; Documentation file (as-built); Practical case: heritage building reconversion. |
Professional course BIM methodology: construction, structures and HBIM.
Professional course BIM methodology: construction, structures and HBIM.
Other topics were suggested that could be included in future BIM short courses:
More
BIM applied to
Exploring BIM in
Training on
Generation and use of BIM
Currently, there is an immediate market need for professional to be more up to speed with BIM and universities are developing BIM guidance, training and BIM certification schemes, and so collaboration in learning and even support between individuals are needed to achieve a common goal. To enhance better and fruitful contributions to the construction industry, a collaborative approach between industry and academia should be instigated. It was found that in order to fulfil the industry requirements, the academia capacities should be oriented in that perspective, contributing to the society, as it is the most important role of a University. Schools should become leaders of the necessary partnerships with industry.
A 1-day course,
The course was presented in a 1-day session. A practical component was included supporting an adequate base of understanding of the BIM multi-application, in order to meet the various interests of the participants. The participants were composed of professionals of different engineering sectors: civil, mechanical, electrical and informatics, as well as designers, architects and managers. The course initialized with an introduction to the innovative topic and covered a wide range of the applicability of BIM in the sector. Participants showed great interest in all the topics presented, often questioning the trainers, with a perspective of clarifying some doubts of their particular activity, depending on if the background is construction, structures or heritage.
The main purpose of the course was to transmit the main concepts, the strategies of working in each type of BIM application and the reference to the main benefits and limitations. All parts of the course, including practice, construction, structures and HBIM, were essentially illustrated with study cases selected in accordance with the audience. As so, the proposed programme covers diverse sectors of the construction industry, namely, conflict analysis in projects, construction planning, materials take-off, project of structures with the focus on the interoperability capacity of the available software and the activity related with HBIM domain.
The course main goal is to contribute to the dissemination of the potential of BIM in the areas of designing, construction and preservation or renovating of historical buildings. By analyzing the surveys collected, the course was recognized with a good overall classification, and all topics were well classified. Industry professionals feel the need to update themselves in the BIM context, and the course contributes in a positive way to this learning. The school and the industry collaborated in order to establish an interesting and useful programme.
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