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Novel immunological strategies for islet transplantation
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Review
Novel immunological strategies for islet transplantation Sara Tezza a,b,e , Moufida Ben Nasr a,b , Andrea Vergani b,c , Alessandro Valderrama Vasquez b , Anna Maestroni b , Reza Abdi a , Antonio Secchi b,d , Paolo Fiorina a,b,∗ a
Nephrology Division, Boston Children’s Hospital, Harvard Medical School, Boston, MA, USA Transplant Medicine, IRCCS Ospedale San Raffaele, Milano, Italy Dompé Inc. Research and Development Department, Diabetes and Transplantation Unit, New York, NY, USA d Universita’ Vita-Salute San Raffaele, Milan, Italy e Univerista’ degli Studi di Roma “Tor Vergata”, Rome, Italy b c
a r t i c l e
i n f o
Article history: Received 11 June 2014 Received in revised form 27 June 2014 Accepted 30 June 2014 Available online xxx Keywords: Islet transplantation Type 1 diabetes Immune-therapies Immunosuppression Encapsulation Xenograft Costimulatory molecules
a b s t r a c t Islet transplantation has been demonstrated to improve glycometabolic control, to reduce hypoglycemic episodes and to halt the progression of diabetic complications. However, the exhaustion of islet function and the side effects related to chronic immunosuppression limit the spread of this technique. Consequently, new immunoregulatory protocols have been developed, with the aim to avoid the use of a life-time immunosuppression. Several approaches have been tested in preclinical models, and some are now under clinical evaluation. The development of new small molecules and new monoclonal or polyclonal antibodies is continuous and raises the possibility of targeting new costimulatory pathways or depleting particular cell types. The use of stem cells and regulatory T cells is underway to take advantage of their immunological properties and to induce tolerance. Xenograft islet transplantation, although having severe problems in terms of immunological compatibility, could theoretically provide an unlimited source of donors; using pigs carrying human immune antigens has showed indeed promising results. A completely different approach, the use of encapsulated islets, has been developed; synthetic structures are used to hide islet alloantigen from the immune system, thus preserving islet endocrine function. Once one of these strategies is demonstrated safe and effective, it will be possible to establish clinical islet transplantation as a treatment for patients with type 1 diabetes long before the onset of diabetic-related complications. © 2014 Elsevier Ltd. All rights reserved.
Contents Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Outcomes . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Islet xenografts . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Encapsulated islets . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . New immunological strategies . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Hematopoietic stem cells . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Anti-TNF-␣ strategy . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Alemtuzumab . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Anti-CD3-specific antibody . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Anti-thymoglobulin . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Costimulation blockade . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . IL-8 signaling blockade . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
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∗ Corresponding author at: Nephrology Division, Enders Building, 5th Floor, Room En511, Boston Children’s Hospital, Harvard Medical School, Longwood Ave., Boston, MA, USA. Tel.: +1 617 919 2624; fax: +1 617 732 5254. E-mail address: paolo.fi[email protected] (P. Fiorina). http://dx.doi.org/10.1016/j.phrs.2014.06.016 1043-6618/© 2014 Elsevier Ltd. All rights reserved.
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Induction of T-regs . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Targeting dendritic cells . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Conclusion . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Acknowledgments . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Appendix A. Supplementary data . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
Introduction The major treatment for patients with type 1 diabetes mellitus (T1D) is insulin therapy. Unfortunately, insulin treatment cannot fully prevent chronic complications related to T1D, even with intensive insulin treatment [1,2], and exposes patients, when tight control is searched, to the risk of dangerous hypoglycemia. Different clinical trials [3–5], showed that islet transplantation lead to long-term insulin independence and provide metabolic stability for patients with T1D, improve or stabilize diabetesrelated complications, normalize glucose homeostasis and reduce hypoglycemic episodes [3–5]. Islet transplantation is currently performed through percutaneous intraportal injection of purified pancreatic islets in local anesthesia with a relatively safe and low invasive procedure compared with pancreas transplantation [6], suggesting the absence of major procedural obstacles to the spread of the technique. Outcomes More than 700 islet transplantation procedures have been performed worldwide (Fig. 1). Historical data from the islet transplant registry headed by the Giessen group showed rates of insulin independence of less than 20% at one year [7]. Clinical outcomes have changed in recent years with the introduction of safer and less toxic immunosuppressive protocols. As of 2000, this rate was increased by the introduction of a steroid-free protocol by the Edmonton group whose success was confirmed by a report in the New England Journal of Medicine [4]. Following the publication of the Edmonton protocol the interest in islet transplantation increased substantially and has received research support from the NIH and JDRF. A more recent publication of the Collaborative Islet Transplantation Registry (CITR) reported an improvement of insulin independence at three years after transplantation from a 27% (1999–2002) to 44% (2007–2010) [8]. In selected protocols insulin independence was observed in 50% of patients [8,9]. Shapiro and colleagues for instance reported 100% of insulin independence in 7 patients with type 1 diabetes and life-threatening hypoglycemia [3]. When compared to whole pancreas transplantation, islet cells transplantation shows reduced number of adverse effects [6], proving the potential for further expansion in these therapeutic area [9]. Islet transplantation is associated with better glycometabolic control if compared to intensive medical therapy [10], and slows the progression of advanced diabetic complications and improves the quality-of-life in the transplanted patients [10]. However, multiple islet infusions are required to sustain insulin independence and islet graft survival rates remain far below those of other grafts [6]. In the long term, while a partial islet function is often maintained for a long period of time, the insulin-free survival rate falls to 25–50% at 5 years, narrowing the window of clinical benefit (Fig. 2) [6,11–13]. Considering the potential advantages of islet transplantation on diabetic complications and the relatively low invasiveness of the procedure, much research has focused to make islet cell transplantation as successful as other solid organ transplantation [14]. In parallel with the development of new immunosuppressive regimen combinations, research has also concentrated on the development of tolerogenic protocols to obtain indefinite graft acceptance without
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immunosuppression. Indeed tolerance induction in islet transplantation is particularly challenging because the transplanted islet are subjected to both allo- and autoimmune response [15,16]. Moreover, chronic immune suppression in individuals with T1D is unacceptable because of the associated burden of malignancies, infections and nephrotoxicity. Islet xenografts Widespread application of -cell replacement therapy for T1D requires a readily accessible source of insulin-producing cells. Xenotransplantation from porcine donors represents an attractive solution to the overwhelming problem of limited availability of human donors, but also allows for less variability in graft quality and manufacturing outcome. The achievement of graft acceptance across xenogenic barriers is challenging, but recent papers have contributed to dramatically improve this field [17,18]. One of the major obstacles to tolerance in xenobiology is the galactose ␣-1,3galactose (Gal) epitope. Humans and nonhuman primates (NHP) have natural preformed antibodies directed against the Gal epitope as well as against non-Gal antigens that can cause hyperacute or acute humoral rejection [19,20]. Elimination of the Gal epitope prevented hyperacute rejection of pigs to NHP in a model of heart xenografts [21]. Unfortunately, the success has been less obvious with nonvascularized grafts (e.g., islets). Islet endocrine cells expressed Gal epitope to a lesser extent compared with other tissues (approximately ∼5% of adult pig islet endocrine cells expressed Gal) [22]. Consequently, cultured xenoislets from genetically wild-type pigs transplanted intraportally into NHP seemed to undergo primarily cellular rejection [23]. Hering et al. reported in 2006 [17] the reversal of diabetes for more than 100 days in cynomolgus macaques after intraportal transplantation of islets from genetically unmodified pigs without Gal-specific antibody manipulation. Immunotherapy was based on anti-monoclonal antibodies to CD25 and CD154 plus a combination of FTY720 (or tacrolimus), everolimus, and leflunomide [17]. Graham et al. interestingly evaluated the data on long-term porcine islet xenograft survival in diabetic macaque, revealing some limitations such as chronic-mild hyperglycemia or absence of body weight gain and progressive body weight loss [24]. Another approach was proposed by Cardona et al. [18], who used a combination of antiinterleukin 2 receptor and anti-CD154 antibodies and maintenance with sirolimus and belatacept, a second-generation high-affinity derivative of CTLA4-Ig. Interestingly, this immunosuppressive protocol and the infusion of neonatal porcine islets into NHP resulted in sustained normoglycemia [18]. Encapsulated islets The idea behind encapsulated islets is primarily to avoid antigen recognition and to protect islets from the immune response. Different groups have recently reported interesting data regarding the use of agarose- and alginate-encapsulated islets [25–27]. The passage of small molecules (such as insulin and glucose), but not of antibodies or large cells, is one of the promises held by the use of semipermeable membranes in islet encapsulation. This would effectively inhibit humoral- and T cell-mediated immunity to exert
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Fig. 1. List of the most relevant islet transplant sites. More than 700 islet transplantation procedures have been performed in more than 30 active sites worldwide.
their deleterious effects on islet graft. Three major systems of membranes have been proposed: perifusion intravascular chambers (connected to the bloodstream), diffusion chambers (implantable intraperitoneally or subcutaneously), and small glomerular membrane [28]. The major limitations to the success of encapsulation for islet transplantation are good biocompatibility of the membranes, the absence of obstacles to oxygen diffusion, and adequate immunoprotection. Recent data in NOD mice seem to confirm that agarosemicroencapsulated islets can protect against the autoimmune response. Islets were isolated from prediabetic male NOD mice and microencapsulated in a 5% agarose hydrogel [26]. Microencapsulated or non-encapsulated islets were transplanted into the omental pouch of spontaneously diabetic NOD mice [26]. Although the diabetic mice that received non-encapsulated islets experienced a temporary reversal of their hyperglycemic condition, all 10 became hyperglycemic within 3 weeks [26]. In contrast,
% of cpep positive or insulin independent patients
C pep positive insulin independence 100 80 60 40 20 0
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9 of 10 mice that received microencapsulated islets maintained normoglycemia for more than 100 days [26]. A recent study compared the metabolic outcome of free and alginate-encapsulated human beta cells preparations in the kidney subcapsular space and the peritoneal cavity of diabetic immunodeficient mice [29]. Alginate-encapsulated beta cells exhibited a potent glucose responsiveness and a better metabolic effect [29]. As far as human data, two patients with T1D in Perugia, Italy, recently have been transplanted with encapsulated islets [30]. The procedure was safe and painless for patients, unfortunately, both patients remained on insulin therapy, but the improvement in glycated hemoglobin and the elimination of hypoglycemia suggested that this is a path in need of further exploration [30]. In another study, Tuch et al. investigated if the transplantation of islets microcapsules was overcoming the need for immunosuppressive therapy [31]. In all the four patients who received the transplant, C-peptide was detected at day 1 post-transplantation but became undetectable by 1–4 weeks, and cytotoxic antibodies as well as antibodies against GAD were detected [31]. More recently, four non-immunosuppressed patients with long-standing T1D received intraperitoneal transplant of microencapsulated islets [32]. All of them turned positive for serum C-peptide with reduction in blood glucose and glycated hemoglobin levels [32]. If the encapsulation technique can avoid its potential deleterious effects on islet secretory ability or the risk of portal vein thrombosis, it will become an important option for islet transplantation within the next few years (Fig. 3). A recent paper published in PNAS suggested that large encapsulated islets placed in the omentum may preserve the graft from immune attack and improve glycometabolic control [33]. These date prove the potential of this technique as a safe approach for successful islet transplantation. New immunological strategies
years after tx Fig. 2. Islet function declines in the middle term soon after transplantation. Insulin independence, although frequent after the procedure, is present in one-quarter of the patients after 5 years. However, in most of the patients C-peptide secretion is still evident. Abbreviations: C-peptide (C pep).
Hematopoietic stem cells The use of hematopoietic stem cells (CD34+ cells) has been proposed for islet transplant for the potential of inducing
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T cells Soluble factors
T reg
T cells
Dendritic Cells
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d
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a CD34+
Human antigens
T cells
T reg
Intraportal islet tx
T eff
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Synthetic capsule
Xenogenic islet
Dendritic Cells
Fig. 3. Different immunological approaches are being attempted to improve islet function. (a) Donor CD34+ cells and islet infusion. (b) Use of new monoclonal antibodies to target specific donor T cells or soluble factors. (c) T-regs induction. (d) Targeting of costimulation pathways to inhibit dendritic cells–T cells interaction. (e) Tipping the balance between regulatory and effector cells. (f) Targeting of donor dendritic cells. (g) Synthetic encapsulation of the islet. (h) Generation of humanized animals with introduction of strategic immune relevant antigens of islet cells. Abbreviations: Regulatory T cells (T-regs).
chimerism, when used allogeneic with the recipients, and for their immunosuppressive properties. However a recent trial at the University of Miami based on Campath 1-H and infusion of donor hematopoietic stem cells (CD34+ cells) (ClinicalTrials.gov Identifier: NCT00315614) failed to provide any benefits [34]. After the engraftment of donor-derived haematopoietic stem cells in the bone marrow, donor-descendant cells can migrate to the thymus, where they can promote central tolerance to donor-derived antigens [34]. The level of chimerism sufficient to protect the graft varies among models [34]; notably, a mixed chimerism of more than 30% was necessary for inducing tolerance in islet transplantation in NOD mice [35]. Such a high level of chimerism can be obtained only with an aggressive induction treatment to permit donor bone marrow engraftment, which cannot be proposed in islet transplantation. Several efforts have been made to facilitate bone marrow engraftment while maintaining low toxicity. T cell depleting agents and costimulation blockade molecules, by protecting transferred bone marrow cells from rejection, were shown to be effective in promoting a high level of chimerism without a myeloablative regimen and permitting long-term function of allogenic islets in NOD mice [36,37] (Fig. 3). Furthermore, hematopoietic stem cells have been shown to have potent immunosuppressive properties and can theoretically per se protect the islet graft from recipient’s cytotoxic T cells, thus prolonging islet graft survival [38–40]. The study was designed to discontinue immunosuppressive therapy after 1 year and has not been completed yet (Fig. 3). Based on these evidences, the use of hematopoietic stem cells to induce tolerance toward the islet graft transplant and potentially for T1D [41] represents an interesting tool.
Anti-TNF-˛ strategy TNF-␣ has been shown to be detrimental to islet engraftment [42], and thus etanercept and infliximab, which inhibit the action of TNF-␣, acting respectively as a soluble receptor and a blocking antibody [42], have been proposed [43,44]. These drugs have been tested along with the standard immunosuppressive regimen (daclizumab, sirolimus, and tacrolimus) in islet transplantation protocols at the University of Miami and the University of Minnesota (ClinicalTrials.gov Identifier: NCT00434811) [45]. The Edmonton group evaluated the impact of infliximab in 10 consecutive islets recipients and did not find evidence of positive impact on engraftment compared with controls [46] (Fig. 3). The use of TNF␣ inhibitors in islet transplantation represents the gold standard therapy. Alemtuzumab Alemtuzumab (Campath-1) is a monoclonal antibody to CD52 that is being used extensively in solid organ transplantation, especially kidney transplantation [47]. Its primary use has been as an induction agent at the time of transplantation, with the aim of providing steroid/calcineurin-free maintenance immunosuppression; moreover, it has had some limited use for treating steroid-resistant rejection [47]. Although there is a profound and long-lasting T cell lymphopenia after administration of alemtuzumab, there is no apparent increase in infections or post-transplantation lymphoproliferative disorders [47]. A study at the University of Alberta assessed the efficacy of alemtuzumab and compared it with other induction treatments for enhancing the survival of islet allografts.
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Data suggested that alemtuzumab improves islet engraftment and the rate of insulin independence in single donors, but only when used in conjunction with high doses of tacrolimus (10 ng/ml trough levels) and MMF (James Shapiro, personal communication) (Fig. 3) [45]. The efficacy of alemtuzumab in the long-term islet graft tolerance remains yet to be determined. Anti-CD3-specific antibody The use of anti-CD3 has been shown to induce tolerance in some non-autoimmune models of allograft transplantation [48], to reverse autoimmunity in NOD mice [49], and to slow the progression to permanent diabetes in humans with recent-onset diabetes [50]. Treatment with anti-CD3 efficiently depletes effector T cells (T-effs) and preferentially drives the remaining T cells to a Th2 response (less active in promoting graft rejection compared with Th1 cells). Moreover, the expansion of the regulatory T cell (Tregs) compartment during treatment with anti-CD3 may explain the long-term effect on transplantation tolerance [48,51]. However, although treatment with anti-CD3 is efficient in non-autoimmune models, it has not been reported to enable long-term engraftment of allogenic islets in diabetic NOD mice. A new, humanized nonmitogenic version of OKT3 (HuOKT3␥1 Ala-Ala), which does not promote significant cytokines release, has had promising results [52]. The University of Minnesota is testing the effect of treatment with HuOKT3␥1 induction combined with tacrolimus and sirolimus in islet transplantation (Fig. 3). Lastly another concern regarding the use of anti-CD3 is associated with its very strong adverse effects. Anti-thymoglobulin Anti-thymoglobulin represent the purified IgG fraction of sera from rabbits, horses or goats immunized with human T cells lines or thymocytes [53]. And has been on the market for at least 15 years. Its immunosuppresive activity has been associated primarily with the depletion of peripheral lymphocytes through complement-dependent lysis, apoptosis, the modulation of surface adhesion molecules or chemokine receptor expression [54–56]. Anti-thymoglobulin has generated new interest now that a new mechanism of action has been discovered: the ability to expand antigen-specific regulatory T cells [51,57]. A European Consortium on Islet Transplantation (ECIT) has been created to explore new immunosuppressive strategies in islet transplantation. The first protocol was based on anti-thymoglobulin induction in a calcineurin inhibitor–free regimen (Fig. 3). A clinically relevant immunoregulatory strategy based on the Thymoglobulin mATG Genzyme and CTLA4-Ig treatment in NOD mice has been shown to prevent allo- and autoimmune activation in model of islet transplantation and diabetes reversal [58]. The use of antithymoglobulin with CTLA4-Ig possibly represents the strongest immunosuppressive combination demonstrated at the present time. Costimulation blockade The activation of naive T cells into effector T cells requires the interaction of naive T cells with activated antigen-presenting cells (APCs). However, the presentation of MHC-peptide complex in the absence of such costimulatory signals results in apoptosis/anergy of T-effs or in the generation of T-regs [59]. The dependence on a costimulation pathway for activation of naive T cells has been widely explored in several models of allogenic transplantation [60]. The costimulatory pathways most thoroughly investigated and perhaps most important for the activation of naive T cells are B7.1/2-CD28 and CD40-CD40L. It is notable, in fact, that short-term blockade of B7.1/2-CD28 and CD40-CD40L pathways results in transplant
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tolerance in most non-autoimmune models [61], but does not enable long-term engraftment of allogenic islets in NOD mice [62]. The reason for this difference is unclear, and an intrinsic resistance to tolerance induction has been well described in NOD mice [63]. The targeting of new costimulatory molecules has also been tested, and consistent data were obtained by the blockage of ICOS and OX40 pathways; however, none of these approaches resulted in tolerance induction in an autoimmune background [64–66] (Fig. 3). The programmed death-1 receptor and its ligand (PDL-1) have been shown to play a critical role in auto and alloimmune responses [67,68]. Understanding the inhibitory T cell costimulatory pathways in alloimmunity and transplantation tolerance may provide a novel approach in combination with the blockade of positive costimulatory pathways.
IL-8 signaling blockade Another important pathway that has been successfully targeted in islet transplantation is the IL-8/CXCR1-CXCR2 axis [69]. IL-8 has been shown to be involved in the post-transplant inflammatory events and blocking its signaling through the 2 known IL-8 receptors (CXCR1 and CXCR2), improved the survival of transplanted islets [69]. Piemonti et al. have recently published the results of a clinical study based on the use of CXCR1/2 allosteric inhibitor named Reparixin [69]. In Reparixin-treated individuals there was an improvement of glycemic control, a decreased in insulin requirement and higher levels of C-peptide as compared to untreated control group [69]. These findings suggest that targeting IL-8 signaling may be an important option to improve islet transplant outcomes.
Induction of T-regs T-regs are fundamental for maintaining immune system homeostasis, preventing the activation of autoreactive cells. Although several cells have been shown to have regulatory characteristics, interest has focused on CD4+ CD25+ Foxp3+ and CD4+ CD25− IL10+ T cells [70]. Although the development of T-regs might help explain the efficiency of several protocols that induce transplantation tolerance [71], some protocols are designed to elicit a specific, direct expansion of the T-regs compartment. Of particular interest is the combination of rapamycin and IL-10, which was shown to selectively expand T-regs in vitro and in models of diabetes or transplantation [72]. However, to date these results have been confined to a non-autoimmune background (Fig. 3). In a number of papers, the stability of Foxp3 expression by T-regs has been argument of discussion in the context of autoimmunity and inflammation [73]. The coexpression of CD49b and LAG-3 has been recently described to identify murine and human type 1 Tregs [74], and these new markers can provide new insights in the characterization of T-regs functions.
Targeting dendritic cells Dendritic cells (DCs) are the main actors in the context of rejection, at least for the activation of naive T cells. Both donor and recipient DCs have been well characterized for their ability to prime the immune response through direct and indirect presentation of alloantigens [75]. The targeting of donor DCs in islet transplantation is absolutely safe and the results obtained with islet depletion of donor DCs seem interesting [76,77] (Fig. 3). More clinically relevant studies are required in the field.
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Conclusion The potential impact of islet transplantation on glycometabolic control and on diabetic-related complications is enormous [12,14,78]. Alternative and novel immunological pathways have been discovered and can be targeted to improve islet transplantation outcomes [79–82]. Once a safe and effective protocol will be established, islet transplantation promises to become a valid treatment for patients with T1D. Acknowledgments Paolo Fiorina is the recipient of a JDRF Career Development Award, an ASN Career Development Award, and an ADA Mentorbased Fellowship grant. P.F. is also supported by a Translational Research Program (TRP) grant from Boston Children’s Hospital, Harvard Stem Cell Institute grant (“Diabetes Program” DP-012312-00), American Heart Association (AHA) Grant-in-Aid and Italian Ministry of Health grant (RF-2010-2303119, RF-2010-2314794, and RF-FSR-2008-1213704).
[16] [17]
[18]
[19]
[20]
[21]
[22]
[23]
[24]
Appendix A. Supplementary data [25]
Supplementary material related to this article can be found, in the online version, at http://dx.doi.org/10.1016/j.phrs.2014.06.016. [26]
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Contents lists available at ScienceDirect
Pharmacological Research journal homepage: www.elsevier.com/locate/yphrs
Review
Novel immunological strategies for islet transplantation Sara Tezza a,b,e , Moufida Ben Nasr a,b , Andrea Vergani b,c , Alessandro Valderrama Vasquez b , Anna Maestroni b , Reza Abdi a , Antonio Secchi b,d , Paolo Fiorina a,b,∗ a
Nephrology Division, Boston Children’s Hospital, Harvard Medical School, Boston, MA, USA Transplant Medicine, IRCCS Ospedale San Raffaele, Milano, Italy Dompé Inc. Research and Development Department, Diabetes and Transplantation Unit, New York, NY, USA d Universita’ Vita-Salute San Raffaele, Milan, Italy e Univerista’ degli Studi di Roma “Tor Vergata”, Rome, Italy b c
a r t i c l e
i n f o
Article history: Received 11 June 2014 Received in revised form 27 June 2014 Accepted 30 June 2014 Available online xxx Keywords: Islet transplantation Type 1 diabetes Immune-therapies Immunosuppression Encapsulation Xenograft Costimulatory molecules
a b s t r a c t Islet transplantation has been demonstrated to improve glycometabolic control, to reduce hypoglycemic episodes and to halt the progression of diabetic complications. However, the exhaustion of islet function and the side effects related to chronic immunosuppression limit the spread of this technique. Consequently, new immunoregulatory protocols have been developed, with the aim to avoid the use of a life-time immunosuppression. Several approaches have been tested in preclinical models, and some are now under clinical evaluation. The development of new small molecules and new monoclonal or polyclonal antibodies is continuous and raises the possibility of targeting new costimulatory pathways or depleting particular cell types. The use of stem cells and regulatory T cells is underway to take advantage of their immunological properties and to induce tolerance. Xenograft islet transplantation, although having severe problems in terms of immunological compatibility, could theoretically provide an unlimited source of donors; using pigs carrying human immune antigens has showed indeed promising results. A completely different approach, the use of encapsulated islets, has been developed; synthetic structures are used to hide islet alloantigen from the immune system, thus preserving islet endocrine function. Once one of these strategies is demonstrated safe and effective, it will be possible to establish clinical islet transplantation as a treatment for patients with type 1 diabetes long before the onset of diabetic-related complications. © 2014 Elsevier Ltd. All rights reserved.
Contents Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Outcomes . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Islet xenografts . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Encapsulated islets . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . New immunological strategies . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Hematopoietic stem cells . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Anti-TNF-␣ strategy . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Alemtuzumab . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Anti-CD3-specific antibody . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Anti-thymoglobulin . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Costimulation blockade . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . IL-8 signaling blockade . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
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∗ Corresponding author at: Nephrology Division, Enders Building, 5th Floor, Room En511, Boston Children’s Hospital, Harvard Medical School, Longwood Ave., Boston, MA, USA. Tel.: +1 617 919 2624; fax: +1 617 732 5254. E-mail address: paolo.fi[email protected] (P. Fiorina). http://dx.doi.org/10.1016/j.phrs.2014.06.016 1043-6618/© 2014 Elsevier Ltd. All rights reserved.
Please cite this article in press as: Tezza S, et al. Novel immunological strategies for islet transplantation. Pharmacol Res (2014), http://dx.doi.org/10.1016/j.phrs.2014.06.016
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Induction of T-regs . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Targeting dendritic cells . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Conclusion . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Acknowledgments . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Appendix A. Supplementary data . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
Introduction The major treatment for patients with type 1 diabetes mellitus (T1D) is insulin therapy. Unfortunately, insulin treatment cannot fully prevent chronic complications related to T1D, even with intensive insulin treatment [1,2], and exposes patients, when tight control is searched, to the risk of dangerous hypoglycemia. Different clinical trials [3–5], showed that islet transplantation lead to long-term insulin independence and provide metabolic stability for patients with T1D, improve or stabilize diabetesrelated complications, normalize glucose homeostasis and reduce hypoglycemic episodes [3–5]. Islet transplantation is currently performed through percutaneous intraportal injection of purified pancreatic islets in local anesthesia with a relatively safe and low invasive procedure compared with pancreas transplantation [6], suggesting the absence of major procedural obstacles to the spread of the technique. Outcomes More than 700 islet transplantation procedures have been performed worldwide (Fig. 1). Historical data from the islet transplant registry headed by the Giessen group showed rates of insulin independence of less than 20% at one year [7]. Clinical outcomes have changed in recent years with the introduction of safer and less toxic immunosuppressive protocols. As of 2000, this rate was increased by the introduction of a steroid-free protocol by the Edmonton group whose success was confirmed by a report in the New England Journal of Medicine [4]. Following the publication of the Edmonton protocol the interest in islet transplantation increased substantially and has received research support from the NIH and JDRF. A more recent publication of the Collaborative Islet Transplantation Registry (CITR) reported an improvement of insulin independence at three years after transplantation from a 27% (1999–2002) to 44% (2007–2010) [8]. In selected protocols insulin independence was observed in 50% of patients [8,9]. Shapiro and colleagues for instance reported 100% of insulin independence in 7 patients with type 1 diabetes and life-threatening hypoglycemia [3]. When compared to whole pancreas transplantation, islet cells transplantation shows reduced number of adverse effects [6], proving the potential for further expansion in these therapeutic area [9]. Islet transplantation is associated with better glycometabolic control if compared to intensive medical therapy [10], and slows the progression of advanced diabetic complications and improves the quality-of-life in the transplanted patients [10]. However, multiple islet infusions are required to sustain insulin independence and islet graft survival rates remain far below those of other grafts [6]. In the long term, while a partial islet function is often maintained for a long period of time, the insulin-free survival rate falls to 25–50% at 5 years, narrowing the window of clinical benefit (Fig. 2) [6,11–13]. Considering the potential advantages of islet transplantation on diabetic complications and the relatively low invasiveness of the procedure, much research has focused to make islet cell transplantation as successful as other solid organ transplantation [14]. In parallel with the development of new immunosuppressive regimen combinations, research has also concentrated on the development of tolerogenic protocols to obtain indefinite graft acceptance without
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immunosuppression. Indeed tolerance induction in islet transplantation is particularly challenging because the transplanted islet are subjected to both allo- and autoimmune response [15,16]. Moreover, chronic immune suppression in individuals with T1D is unacceptable because of the associated burden of malignancies, infections and nephrotoxicity. Islet xenografts Widespread application of -cell replacement therapy for T1D requires a readily accessible source of insulin-producing cells. Xenotransplantation from porcine donors represents an attractive solution to the overwhelming problem of limited availability of human donors, but also allows for less variability in graft quality and manufacturing outcome. The achievement of graft acceptance across xenogenic barriers is challenging, but recent papers have contributed to dramatically improve this field [17,18]. One of the major obstacles to tolerance in xenobiology is the galactose ␣-1,3galactose (Gal) epitope. Humans and nonhuman primates (NHP) have natural preformed antibodies directed against the Gal epitope as well as against non-Gal antigens that can cause hyperacute or acute humoral rejection [19,20]. Elimination of the Gal epitope prevented hyperacute rejection of pigs to NHP in a model of heart xenografts [21]. Unfortunately, the success has been less obvious with nonvascularized grafts (e.g., islets). Islet endocrine cells expressed Gal epitope to a lesser extent compared with other tissues (approximately ∼5% of adult pig islet endocrine cells expressed Gal) [22]. Consequently, cultured xenoislets from genetically wild-type pigs transplanted intraportally into NHP seemed to undergo primarily cellular rejection [23]. Hering et al. reported in 2006 [17] the reversal of diabetes for more than 100 days in cynomolgus macaques after intraportal transplantation of islets from genetically unmodified pigs without Gal-specific antibody manipulation. Immunotherapy was based on anti-monoclonal antibodies to CD25 and CD154 plus a combination of FTY720 (or tacrolimus), everolimus, and leflunomide [17]. Graham et al. interestingly evaluated the data on long-term porcine islet xenograft survival in diabetic macaque, revealing some limitations such as chronic-mild hyperglycemia or absence of body weight gain and progressive body weight loss [24]. Another approach was proposed by Cardona et al. [18], who used a combination of antiinterleukin 2 receptor and anti-CD154 antibodies and maintenance with sirolimus and belatacept, a second-generation high-affinity derivative of CTLA4-Ig. Interestingly, this immunosuppressive protocol and the infusion of neonatal porcine islets into NHP resulted in sustained normoglycemia [18]. Encapsulated islets The idea behind encapsulated islets is primarily to avoid antigen recognition and to protect islets from the immune response. Different groups have recently reported interesting data regarding the use of agarose- and alginate-encapsulated islets [25–27]. The passage of small molecules (such as insulin and glucose), but not of antibodies or large cells, is one of the promises held by the use of semipermeable membranes in islet encapsulation. This would effectively inhibit humoral- and T cell-mediated immunity to exert
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Fig. 1. List of the most relevant islet transplant sites. More than 700 islet transplantation procedures have been performed in more than 30 active sites worldwide.
their deleterious effects on islet graft. Three major systems of membranes have been proposed: perifusion intravascular chambers (connected to the bloodstream), diffusion chambers (implantable intraperitoneally or subcutaneously), and small glomerular membrane [28]. The major limitations to the success of encapsulation for islet transplantation are good biocompatibility of the membranes, the absence of obstacles to oxygen diffusion, and adequate immunoprotection. Recent data in NOD mice seem to confirm that agarosemicroencapsulated islets can protect against the autoimmune response. Islets were isolated from prediabetic male NOD mice and microencapsulated in a 5% agarose hydrogel [26]. Microencapsulated or non-encapsulated islets were transplanted into the omental pouch of spontaneously diabetic NOD mice [26]. Although the diabetic mice that received non-encapsulated islets experienced a temporary reversal of their hyperglycemic condition, all 10 became hyperglycemic within 3 weeks [26]. In contrast,
% of cpep positive or insulin independent patients
C pep positive insulin independence 100 80 60 40 20 0
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9 of 10 mice that received microencapsulated islets maintained normoglycemia for more than 100 days [26]. A recent study compared the metabolic outcome of free and alginate-encapsulated human beta cells preparations in the kidney subcapsular space and the peritoneal cavity of diabetic immunodeficient mice [29]. Alginate-encapsulated beta cells exhibited a potent glucose responsiveness and a better metabolic effect [29]. As far as human data, two patients with T1D in Perugia, Italy, recently have been transplanted with encapsulated islets [30]. The procedure was safe and painless for patients, unfortunately, both patients remained on insulin therapy, but the improvement in glycated hemoglobin and the elimination of hypoglycemia suggested that this is a path in need of further exploration [30]. In another study, Tuch et al. investigated if the transplantation of islets microcapsules was overcoming the need for immunosuppressive therapy [31]. In all the four patients who received the transplant, C-peptide was detected at day 1 post-transplantation but became undetectable by 1–4 weeks, and cytotoxic antibodies as well as antibodies against GAD were detected [31]. More recently, four non-immunosuppressed patients with long-standing T1D received intraperitoneal transplant of microencapsulated islets [32]. All of them turned positive for serum C-peptide with reduction in blood glucose and glycated hemoglobin levels [32]. If the encapsulation technique can avoid its potential deleterious effects on islet secretory ability or the risk of portal vein thrombosis, it will become an important option for islet transplantation within the next few years (Fig. 3). A recent paper published in PNAS suggested that large encapsulated islets placed in the omentum may preserve the graft from immune attack and improve glycometabolic control [33]. These date prove the potential of this technique as a safe approach for successful islet transplantation. New immunological strategies
years after tx Fig. 2. Islet function declines in the middle term soon after transplantation. Insulin independence, although frequent after the procedure, is present in one-quarter of the patients after 5 years. However, in most of the patients C-peptide secretion is still evident. Abbreviations: C-peptide (C pep).
Hematopoietic stem cells The use of hematopoietic stem cells (CD34+ cells) has been proposed for islet transplant for the potential of inducing
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T cells Soluble factors
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Human antigens
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Fig. 3. Different immunological approaches are being attempted to improve islet function. (a) Donor CD34+ cells and islet infusion. (b) Use of new monoclonal antibodies to target specific donor T cells or soluble factors. (c) T-regs induction. (d) Targeting of costimulation pathways to inhibit dendritic cells–T cells interaction. (e) Tipping the balance between regulatory and effector cells. (f) Targeting of donor dendritic cells. (g) Synthetic encapsulation of the islet. (h) Generation of humanized animals with introduction of strategic immune relevant antigens of islet cells. Abbreviations: Regulatory T cells (T-regs).
chimerism, when used allogeneic with the recipients, and for their immunosuppressive properties. However a recent trial at the University of Miami based on Campath 1-H and infusion of donor hematopoietic stem cells (CD34+ cells) (ClinicalTrials.gov Identifier: NCT00315614) failed to provide any benefits [34]. After the engraftment of donor-derived haematopoietic stem cells in the bone marrow, donor-descendant cells can migrate to the thymus, where they can promote central tolerance to donor-derived antigens [34]. The level of chimerism sufficient to protect the graft varies among models [34]; notably, a mixed chimerism of more than 30% was necessary for inducing tolerance in islet transplantation in NOD mice [35]. Such a high level of chimerism can be obtained only with an aggressive induction treatment to permit donor bone marrow engraftment, which cannot be proposed in islet transplantation. Several efforts have been made to facilitate bone marrow engraftment while maintaining low toxicity. T cell depleting agents and costimulation blockade molecules, by protecting transferred bone marrow cells from rejection, were shown to be effective in promoting a high level of chimerism without a myeloablative regimen and permitting long-term function of allogenic islets in NOD mice [36,37] (Fig. 3). Furthermore, hematopoietic stem cells have been shown to have potent immunosuppressive properties and can theoretically per se protect the islet graft from recipient’s cytotoxic T cells, thus prolonging islet graft survival [38–40]. The study was designed to discontinue immunosuppressive therapy after 1 year and has not been completed yet (Fig. 3). Based on these evidences, the use of hematopoietic stem cells to induce tolerance toward the islet graft transplant and potentially for T1D [41] represents an interesting tool.
Anti-TNF-˛ strategy TNF-␣ has been shown to be detrimental to islet engraftment [42], and thus etanercept and infliximab, which inhibit the action of TNF-␣, acting respectively as a soluble receptor and a blocking antibody [42], have been proposed [43,44]. These drugs have been tested along with the standard immunosuppressive regimen (daclizumab, sirolimus, and tacrolimus) in islet transplantation protocols at the University of Miami and the University of Minnesota (ClinicalTrials.gov Identifier: NCT00434811) [45]. The Edmonton group evaluated the impact of infliximab in 10 consecutive islets recipients and did not find evidence of positive impact on engraftment compared with controls [46] (Fig. 3). The use of TNF␣ inhibitors in islet transplantation represents the gold standard therapy. Alemtuzumab Alemtuzumab (Campath-1) is a monoclonal antibody to CD52 that is being used extensively in solid organ transplantation, especially kidney transplantation [47]. Its primary use has been as an induction agent at the time of transplantation, with the aim of providing steroid/calcineurin-free maintenance immunosuppression; moreover, it has had some limited use for treating steroid-resistant rejection [47]. Although there is a profound and long-lasting T cell lymphopenia after administration of alemtuzumab, there is no apparent increase in infections or post-transplantation lymphoproliferative disorders [47]. A study at the University of Alberta assessed the efficacy of alemtuzumab and compared it with other induction treatments for enhancing the survival of islet allografts.
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Data suggested that alemtuzumab improves islet engraftment and the rate of insulin independence in single donors, but only when used in conjunction with high doses of tacrolimus (10 ng/ml trough levels) and MMF (James Shapiro, personal communication) (Fig. 3) [45]. The efficacy of alemtuzumab in the long-term islet graft tolerance remains yet to be determined. Anti-CD3-specific antibody The use of anti-CD3 has been shown to induce tolerance in some non-autoimmune models of allograft transplantation [48], to reverse autoimmunity in NOD mice [49], and to slow the progression to permanent diabetes in humans with recent-onset diabetes [50]. Treatment with anti-CD3 efficiently depletes effector T cells (T-effs) and preferentially drives the remaining T cells to a Th2 response (less active in promoting graft rejection compared with Th1 cells). Moreover, the expansion of the regulatory T cell (Tregs) compartment during treatment with anti-CD3 may explain the long-term effect on transplantation tolerance [48,51]. However, although treatment with anti-CD3 is efficient in non-autoimmune models, it has not been reported to enable long-term engraftment of allogenic islets in diabetic NOD mice. A new, humanized nonmitogenic version of OKT3 (HuOKT3␥1 Ala-Ala), which does not promote significant cytokines release, has had promising results [52]. The University of Minnesota is testing the effect of treatment with HuOKT3␥1 induction combined with tacrolimus and sirolimus in islet transplantation (Fig. 3). Lastly another concern regarding the use of anti-CD3 is associated with its very strong adverse effects. Anti-thymoglobulin Anti-thymoglobulin represent the purified IgG fraction of sera from rabbits, horses or goats immunized with human T cells lines or thymocytes [53]. And has been on the market for at least 15 years. Its immunosuppresive activity has been associated primarily with the depletion of peripheral lymphocytes through complement-dependent lysis, apoptosis, the modulation of surface adhesion molecules or chemokine receptor expression [54–56]. Anti-thymoglobulin has generated new interest now that a new mechanism of action has been discovered: the ability to expand antigen-specific regulatory T cells [51,57]. A European Consortium on Islet Transplantation (ECIT) has been created to explore new immunosuppressive strategies in islet transplantation. The first protocol was based on anti-thymoglobulin induction in a calcineurin inhibitor–free regimen (Fig. 3). A clinically relevant immunoregulatory strategy based on the Thymoglobulin mATG Genzyme and CTLA4-Ig treatment in NOD mice has been shown to prevent allo- and autoimmune activation in model of islet transplantation and diabetes reversal [58]. The use of antithymoglobulin with CTLA4-Ig possibly represents the strongest immunosuppressive combination demonstrated at the present time. Costimulation blockade The activation of naive T cells into effector T cells requires the interaction of naive T cells with activated antigen-presenting cells (APCs). However, the presentation of MHC-peptide complex in the absence of such costimulatory signals results in apoptosis/anergy of T-effs or in the generation of T-regs [59]. The dependence on a costimulation pathway for activation of naive T cells has been widely explored in several models of allogenic transplantation [60]. The costimulatory pathways most thoroughly investigated and perhaps most important for the activation of naive T cells are B7.1/2-CD28 and CD40-CD40L. It is notable, in fact, that short-term blockade of B7.1/2-CD28 and CD40-CD40L pathways results in transplant
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tolerance in most non-autoimmune models [61], but does not enable long-term engraftment of allogenic islets in NOD mice [62]. The reason for this difference is unclear, and an intrinsic resistance to tolerance induction has been well described in NOD mice [63]. The targeting of new costimulatory molecules has also been tested, and consistent data were obtained by the blockage of ICOS and OX40 pathways; however, none of these approaches resulted in tolerance induction in an autoimmune background [64–66] (Fig. 3). The programmed death-1 receptor and its ligand (PDL-1) have been shown to play a critical role in auto and alloimmune responses [67,68]. Understanding the inhibitory T cell costimulatory pathways in alloimmunity and transplantation tolerance may provide a novel approach in combination with the blockade of positive costimulatory pathways.
IL-8 signaling blockade Another important pathway that has been successfully targeted in islet transplantation is the IL-8/CXCR1-CXCR2 axis [69]. IL-8 has been shown to be involved in the post-transplant inflammatory events and blocking its signaling through the 2 known IL-8 receptors (CXCR1 and CXCR2), improved the survival of transplanted islets [69]. Piemonti et al. have recently published the results of a clinical study based on the use of CXCR1/2 allosteric inhibitor named Reparixin [69]. In Reparixin-treated individuals there was an improvement of glycemic control, a decreased in insulin requirement and higher levels of C-peptide as compared to untreated control group [69]. These findings suggest that targeting IL-8 signaling may be an important option to improve islet transplant outcomes.
Induction of T-regs T-regs are fundamental for maintaining immune system homeostasis, preventing the activation of autoreactive cells. Although several cells have been shown to have regulatory characteristics, interest has focused on CD4+ CD25+ Foxp3+ and CD4+ CD25− IL10+ T cells [70]. Although the development of T-regs might help explain the efficiency of several protocols that induce transplantation tolerance [71], some protocols are designed to elicit a specific, direct expansion of the T-regs compartment. Of particular interest is the combination of rapamycin and IL-10, which was shown to selectively expand T-regs in vitro and in models of diabetes or transplantation [72]. However, to date these results have been confined to a non-autoimmune background (Fig. 3). In a number of papers, the stability of Foxp3 expression by T-regs has been argument of discussion in the context of autoimmunity and inflammation [73]. The coexpression of CD49b and LAG-3 has been recently described to identify murine and human type 1 Tregs [74], and these new markers can provide new insights in the characterization of T-regs functions.
Targeting dendritic cells Dendritic cells (DCs) are the main actors in the context of rejection, at least for the activation of naive T cells. Both donor and recipient DCs have been well characterized for their ability to prime the immune response through direct and indirect presentation of alloantigens [75]. The targeting of donor DCs in islet transplantation is absolutely safe and the results obtained with islet depletion of donor DCs seem interesting [76,77] (Fig. 3). More clinically relevant studies are required in the field.
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Conclusion The potential impact of islet transplantation on glycometabolic control and on diabetic-related complications is enormous [12,14,78]. Alternative and novel immunological pathways have been discovered and can be targeted to improve islet transplantation outcomes [79–82]. Once a safe and effective protocol will be established, islet transplantation promises to become a valid treatment for patients with T1D. Acknowledgments Paolo Fiorina is the recipient of a JDRF Career Development Award, an ASN Career Development Award, and an ADA Mentorbased Fellowship grant. P.F. is also supported by a Translational Research Program (TRP) grant from Boston Children’s Hospital, Harvard Stem Cell Institute grant (“Diabetes Program” DP-012312-00), American Heart Association (AHA) Grant-in-Aid and Italian Ministry of Health grant (RF-2010-2303119, RF-2010-2314794, and RF-FSR-2008-1213704).
[16] [17]
[18]
[19]
[20]
[21]
[22]
[23]
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Appendix A. Supplementary data [25]
Supplementary material related to this article can be found, in the online version, at http://dx.doi.org/10.1016/j.phrs.2014.06.016. [26]
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Please cite this article in press as: Tezza S, et al. Novel immunological strategies for islet transplantation. Pharmacol Res (2014), http://dx.doi.org/10.1016/j.phrs.2014.06.016