Emerging immune therapies in type 1 diabetes and pancreatic islet transplantation

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1 Emerging immune therapies in type 1 diabetes and pancreatic islet transplantation D. A. Schneider, A. M. Kretowicz & M. G. von Herrath Developmental Immunology, La Jolla Institute for Allergy and Immunology, La Jolla, CA, USA Diabetes, Obesity and Metabolism 15: , Blackwell Publishing Ltd review article In type 1 diabetes (T1D) the immune system attacks insulin-producing pancreatic β-cells. Unfortunately, our ability to curb this pathogenic autoimmune response in a disease- and organ-specific manner is still very limited due to the inchoate understanding of the exact nature and the kinetics of the immunological pathomechanisms that lead to T1D. None of the clinical immune interventions thus far, which focused primarily on new-onset disease, were successful in producing lasting remission or curbing recurrent autoimmunity. However, these studies do provide us access to a tremendous amount of clinical data and specimens, which will aid us in revising our therapeutical approaches and defining the highly needed paradigm shift in T1D immunotherapy. Analysing the foundation and the results of the most current T1D immunotherapeutic trials, this article gives an outlook for future directions of the field. Keywords: beta cell, clinical trial, diabetes mellitus, islets, transplantation, type 1 diabetes Date submitted 2 July 2012; date of first decision 14 August 2012; date of final acceptance 18 November 2012 Introduction Pathogenesis of Type 1 Diabetes (T1D) T1D results from the specific immune-mediated destruction of the insulin-producing β-cells of the pancreas (figure 1). In genetically susceptible individuals [1,2], a still undetermined initiating event causes auto-reactive CD8 T-cells to infiltrate the pancreatic islets [3], this invasion leads to the destruction of β-cells. To a lesser extent, CD20+ B cells, CD4+ cells, macrophages and natural killer (NK) cells are also involved in such insulitic infiltrates. Studies in animal models have revealed that pro-inflammatory cytokines secreted by local antigen-presenting cells (APC), NK and T-cells lead to further recruitment and activation of immune cells, consequently enforcing this autoimmune assault on the β-cells. In humans, CD4+ T-cells are found in very low numbers throughout all of the stages of β-cell loss, which suggests that the absence of CD4+ regulatory T-cells (T-regs) [4,5] may permit the propagation of insulitis. Thus, T1D might possibly result from a disruption in the balance between self-reactive T-eff and protective T-reg cells. Today, our ability to predict the likelihood and timing of a patient s development of T1D is good, because the contraction of T1D correlates with the expression of autoantibodies and with the burden of susceptibility genes. Combining metabolic and autoantibody tests allows us to predict the 6-years risk of developing T1D in individuals with T1D relatives with 90% certainty [6 8]. Correspondence to : Matthias G. von Herrath, Developmental Immunology, La Jolla Institute for Allergy and Immunology, 9420 Athena Circle, La Jolla, CA, USA. There is usually a gap of up to several years between the presence of autoantibodies and the clinical diagnosis of T1D. During this prediabetic phase, a variable interplay between destructive and regulatory immune responses can occur and ultimately the destruction overtakes any attempts the β-cells make to regenerate or proliferate [9,10] (figure 2). In humans, this β-cell failure occurs in a lobular fashion [11]. Once the β-cells have been destroyed, the autoimmune attack resolves, but insulin-containing β-cells, combined with insulitis, can persist in some patients up to 50 years postdiagnosis [12,13]. Immunotherapeutic Strategies Therapeutic approaches either try to inhibit the activation of pathogenic cells or to augment the pathways that suppress them (figure 1): 1 Non-antigen-specific immunomodulators either inhibit lymphocyte proliferation or target pathogenic T and B lymphocytes, co-stimulatory molecules, and cytokines involved in β-cell destruction, thus also altering the normal function of the immune system. 2 (Islet)-antigen-specific immunomodulators reintroduce the culprit auto-antigen into the system, which aims to induce β-cell specific regulatory T-cells and achieve/maintain long-term operational tolerance toward the auto-antigens by suppressing inflammation specifically in the pancreatic draining lymph nodes [14,15]. Levels of Intervention in T1D Immunotherapy Thus far, immunoprevention aims to either prevent the emergence of autoimmunity in healthy individuals at risk

2 DIABETES, OBESITY AND METABOLISM Figure 1. Timeline of type 1 diabetes (T1D) pathogenesis and levels of therapeutic intervention. β-cell mass or function in orange and the different immunological phases as columns with alphabetized tabs on top. Once the orange line of β-cell function falls into the red zone, the individual is clinically diagnosed with T1D. An unfortunate concurrence of genetic susceptibility and an environmental trigger sets the cornerstone for T1D. In the pancreas, β-cells upregulate interferon (IFN)-α and subsequently MHC class I. This exposes the β-cells to attack by autoreactive CD8 T cells with specificity for islet antigens. Consequently, the released β-cell antigens are picked up by resident antigen-presenting cells (APC) and transferred to PLN. Meanwhile in the periphery, the environmental trigger has caused a metabolomic switch creating a proinflammatory environment that favours effector T-cell responses over Treg function. β-cell antigens presented in this proinflammatory context and with CD4 help initiate conversion of B cells into plasma cells and the appearance of insulin autoantibodies (seroconversion). Also, autoreactive CD8 T cells are stimulated to proliferate and migrate into the pancreas. The stress induced by this second wave of β-cell killing, which involves perforin, interferon (IFN)-γ, and tumour necrosis factor (TNF)-α,causesβ-cell death and the release of new β-cell antigens that are picked up by APCs, including migrated B cells, and get shuttled to the PLN. This engages new specificities of CD4 and CD8 T cells and B cells in a process called epitope spreading. A subsequent wave of β-cell killing is therefore more severe and usually results in severe depletion of β-cell function and mass. Surprisingly, the autoimmune inflammation can also stimulate some β-cell proliferation, so that the β-cell mass temporarily resurrects. Also, Tregs can sometimes overpower and dampen the effector response. The fluctuation between destructive autoreactive responses and the alleviation by immune regulation and β-cell proliferation possibly creates a non-stop relapse-remitting profile of β-cell mass (orange line). (primary prevention), or reverse the autoimmune attack before the clinical onset of T1D (secondary prevention) (figure 2). Immunointervention aims to halt β-cell destruction and preserve the remaining β-cell mass after clinical diagnosis of T1D (tertiary prevention) (figure 2). Current Limitations in T1D Immunotherapy Lack of Suitable Biomarkers. At the time of clinical diagnosis, only 15 20% of the original β-cells remain, but this small remaining portion still has noticeable benefits [16]. In some cases, the process of β-cell destruction started more than three years before the first clinical symptoms appeared, and is therefore believed to be non-linear [17]. Also, 43 56% of children with T1D experience a honeymoonphase, characterized by a temporary amelioration of β-cell function, which can last up to 24 months or even longer [18]. Non-linear β-cell destruction and the honeymoon-phase suggest that the nature of the immune response toward β-cells potentially changes over time, yet the exact kinetics for these processes are unknown. It is also possible, that in humans, β-cell loss is a relapsing syndrome, in which possible subsiding immune attack periods separate the infiltration of different lobes of the pancreas. Hence, immunotherapeutic approaches should ideally be tailored to the status of an individual s disease, specifically his/her β-cell mass. However, one of the current limitations to such an approach is the lack of biomarkers available to assess the existing β-cell mass and immunoreactivities to β-cell antigens precisely, this being particularly important before exposing very young patients and/or prediabetic (clinically healthy) individuals to reagents developed to interfere with their immune system. Translation to Clinical Studies. The non-obese diabetic (NOD) mouse provides a suitable model to initially test therapies [19] 582 Schneider et al. Volume 15 No. 7 July 2013

3 DIABETES, OBESITY AND METABOLISM review article Figure 2. Pathogenesis of type 1 diabetes (T1D) and points of therapeutic interventions. In susceptible individuals, an unknown event leads to β-cell damage and release of β-cell antigens. These are engulfed by tissue-specific antigen-presenting cells (APC), which migrate to the PLN and present the antigen to CD4 or CD8 cells. Subsequently, the islets are infiltrated by activated antigen-specific CTL that destroy the β-cells via direct contact and via the release of toxic cytokines and chemokines. This leads to the release of new β-cell antigens and a new cycle of CTL mediated β-cell destruction. The numbers show current therapeutic options: anti-cd3 (1), anti-cd2 (2), ATG (3), IL-2 (4), CTLA4IgG (5), anti-cd20 (6), anti-il-1 (7), anti-tnf (8), DiaPep277 (9), anti-inflammatory substances (10), transfer of T-regs (11), B-cell regeneration (12), mab anti-mhc-ii/autoantigen/tcr (13), mab anti-cd4/anti-cd8 mab (14), β-cell encapsulation devices (15). and has also been an essential tool for studying the pathophysiology and genetics of T1D, given the scarcity of human pancreatic specimens from the prediabetic phase [19]. However, not all NOD studies have translated well to human trials, mainly because of the differences in their immune responses, their steps in the expression and contraction of T1D, their disease kinetics and the different biological properties of their β-cells. Since preclinical mouse studies are an important intermediary step in the examination of a potentially successful therapy, several laboratories are working on the development of mice bearing a humanized immune system, which might overcome the shortcomings of experimental models like the NOD. There are also other incompatibilities that hinder the execution of valuable concepts or therapies as they are translated from the NOD mouse to human application [20]. A few examples: The dose of oral insulin in the DPT-1 trial in humans was only sevenfold higher than in the mouse models that prompted the design of this trial. This dosage was much too low to reach the lower human gut when administered with a meal and to induce the desired T-reg response. The use of Alum as an adjuvant in Diamyd s recent trial to prevent diabetes, effected little, if any, efficacy when coupled with GAD protein in mice. CTLA4-Ig had only limited benefit in humans after it showed no benefit in mice. Lastly, the stages of disease, reached end points, and drug dosages required are often not well translated from mice to human trials. These conversion obstacles became evident in the last two phase 3 trials with anti-cd3. While some of these issues are driven by clinical needs rather than rationale (e.g. the need to avoid high oral insulin or systemic anti-cd3 dosages or the urge to try certain drugs because they have been proven to be effective in other diseases), we could significantly improve this translational process. Type, Dose and Route of Administration for Antigen-specific Approaches. The antigen-specific prevention of T1D, mediated by CD4+ T-regs in many mouse studies, can be achieved by means of DNA-vaccines, peptide or full-length protein antigens when given in a tolerogenic fashion. Because the induced T-regs become activated only at the sites where β-cell antigens are presented, antigen-specific therapies are site-specific and have (almost) no systemic side effects. However, we still have some inquiries that are limiting our use of this therapy, such as: Which islet antigens are most suitable for protection? Is it conceivable that immunization with an auto-antigen might accelerate the immune process, as reported in multiple sclerosis [21], or might induce life-threatening hypersensitivity [22] or off-target autoimmunity [23]? Which dose should be given and at which frequency and route? Volume 15 No. 7 July 2013 doi: /dom

4 Again, all these concerns will be easier to address once we have suitable biomarkers for immune activity toward β-cells or for correlation with the successful induction of a protective immune response following antigen-specific therapy (vaccination). Combination Therapies: Requirements and Components It is improbable that single agent therapies will be successful in T1D, as they usually target only one arm of the immune process, have lower efficacy thus higher dose requirements and, subsequently, higher side effects. A reasonable combination therapy, that will be both supported by industry and approved by the regulatory authorities, should comprise substances that have already been tested in T1D or other autoimmune diseases and that have independent/complementary mechanisms, that include: 1 A component that depletes T effector cells, ideally given at times when islet specific effector responses are at their peak; 2 An anti-inflammatory component given for a short period of time at the induction of therapy; 3 A component that induces antigen-specific regulatory T- cells, ideally given at a time point when the number of the T-regs specific for β-cell antigens is declining; 4 A component that promotes β-cell regeneration, or, alternatively, the transplantation of β-cells. Unfortunately, there are many factors that currently limit the possible usage of these approaches in combination therapies. Two of these factors are: There are too few preclinical studies testing combinations of substances, especially since some but not all, exhibit synergy [24] however, the Immune Tolerance Network has recently implemented a testing consortium to prioritize combinations by testing them independently in four different laboratories. If drugs are given simultaneously, it is very difficult to predict, the extent to which side effects will potentiate, and to differentiate between the individual contribution of each of the combination partners. Therefore, especially when utilizing systemically acting immune modulators, sequential therapies should be tested wherever possible, especially if more than two agents are being utilized. This is an important issue since different companies manufacture almost all substances tested thus far and these corporations will be reluctant to accept the side effects caused by their drug s combination with the substances of other manufacturers. Substances Tested in Immunointervention Non-antigen-Specific Approaches Systemic Immunosuppressants. Cyclosporine A, Azathioprine and prednisone induce immunoreversal and lower insulin requirements at T1D onset, but their intolerable side effects and limited efficacy, which was restricted to the duration of treatment, hampered their clinical application. DIABETES, OBESITY AND METABOLISM Immunomodulators Targeting T-cells. Anti-CD3. Anti-CD3 antibodies can target pathogenic T-cells and amplify regulatory T-cells in mouse studies. This strategy, initially demonstrated in NOD mice [25], has proven effectively to preserve C-peptide in two clinical trials in recent onset T1D research [16,26]. However, the drug failed in the phase 3 trials: 1 Otelixizumab: the Defend-1 study (tertiary prevention), most likely because of the dose reduction to 1/16th of the phase 2 trial dosage. 2 Teplizumab (AbATE): reproduced beneficial effects in terms of C-peptide responses, however, the retreatment with anti- CD3 failed to reproduce the initial beneficial results. 3 Teplizumab (Protégé) [27,28]: shortcomings in patient selection and an incorrect choice of endpoint are believed to have impeded teplizumab s efficacy in the phase 3 trial. However, secondary analyses demonstrated that children aged 8 11 years had a dramatic maintenance of C-peptide levels post treatment. In a recent pilot trial, therapy with anti-cd3 (Teplizumab) beneficially affected C-peptide preservation even when given 4 12 months after T1D onset. The drug made the greatest impact on participants who received Teplizumab earlier after diagnosis [29]. Due to its beneficial effects on β-cell preservation and its good safety profile, anti-cd3 remains an interesting drug for T1D and its potential should be exploited in combinations with islet autoantigen administrations and/or anti-inflammatory agents in order to promote synergy and improve the side-effect profile, especially in primary or secondary prevention studies. CD2 Blockade. Anti-CD2 prevented autoimmune diabetes in the DP rat threefold by depleting CD4+ T-cells, preventing the activation of T-effectors (T-eff), and blocking CD2/ligand interaction between effector and target T-cells [30]. Alefacept (Amevive ), a dimeric fusion protein that binds to the T-cell CD2 receptor and engages the NK-cell immunoglobulin receptor, Fcγ RIII, has shown significant efficacy in plaque psoriasis [31]. A phase 2 trial is currently enrolling patients to test CD2 blockade in β-cell preservation (NCT ) Antithymocyte Globulin (ATG). ATG modulates T-cell activating, homing and cytotoxic activities; reduces circulating effector memory T-cells (T-em) and induces an immunoregulatory shift from a Th1 to a Th2 cytokine profile [32]. ATG induced a lasting remission in the NOD mouse [33] and BB rat [34]. In humans, ATG Fresenius positively effected the preservation of β-cell function in 11 patients with established T1D [35]. Two other trials are ongoing and positive interim results have been reported. Equine ATG in newly onset T1D allegedly prolonged the honeymoon phase (START trial) and ATG (Thymo ) arrested β-cell destruction in a recently finalized phase 2 trial [36]. Moreover, combined with granulocyte colony stimulating factor and cyclophosphamide, ATG has shown robust effects in maintaining β-cell function (NCT ). A third trial phase 2 that formally examines whether Thymo can preserve β-cell mass in recent onset T1D of less than 3 months duration is currently enrolling participants (ITN028AI). 584 Schneider et al. 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5 DIABETES, OBESITY AND METABOLISM Interleukin-2 (IL-2). IL-2, a cytokine that promotes T-reg survival and function but also aids T-eff cells, has been shown to reverse diabetes in NOD mice, presumably by increasing the number of pancreatic T-regs and suppressing interferon (IFN)-γ production by pancreas-infiltrating T-cells [37]. In patients with HCV associated vasculitis, the administration of low-dose IL-2 was followed by an increase in the percentage of CD4+, CD25(high) T-regs [38,39]. A clinical trial testing for the dose-response curve of low dose IL-2 in patients with recent onset T1D (of less than 2 years duration) was finished in April 2012 and results are expected (NCT ). However, in conjunction with Rapamycin, IL-2 induced an enhanced NK and T-eff cell activity associated with a more rapid loss of C-peptide (see below). CTLA4-IgG. Abatacept (CTLA4-IgG) binds to CD80/86 molecules and inhibits their interaction with CD28, consequently hindering the co-stimulatory signal necessary to activate naïve T-cells [40]. While CTLA4-IgG was not effective in NOD mice when given after disease onset [41], in a clinical trial it temporarily slowed the reduction in β-cell function and preserved C-peptide [42]. Unfortunately, these favourable results were limited to the first 6 months of treatment, the interval when the drug was being administered, which argues against the feasibility of long-term therapy (NCT ). Immunomodulators Targeting B-cells Anti-CD20 (Rituximab). A recent trial with Rituximab in recent onset T1D has shown initial C-peptide preservation, which waned considerably after 3 months [43]. This decline confirms that B-cells do play a role in the pathogenesis of T1D, yet the question of how exactly B- cells contribute to the development of this disease is still unclear (possible role as antigen presenting cells?) We do believe that Rituximab could play a future role as part of a combination therapy in T1D treatment. Immunomodulators Targeting Pro-inflammatory Pathways. Inflammation plays a major part in β-cell dysfunction [44], and is thought to be a key component of T1D pathogenesis alongside MHC-I upregulation and subsequent CD8+ infiltration. Anti-IL-1 (Anakinra ). Children treated with Anakinra, a selective antagonist of the IL-1 receptor, for 28 days within 1 week of T1D diagnosis, had lower insulin requirements at 1 and 4 months after diagnosis than placebo treated controls but did not have any differences in HbA1c and MMTT responses [45]. Trials evaluating IL-1 blockade with either Anakinra (NCT ) or Canakinumab (NCT ), a monoclonal antibody (mab) against IL-1, that has been already evaluated in systemic juvenile idiopathic arthritis [46], are currently ongoing, as well as with Gevokizumab (XOMA-052), an IgG2 humanized mab against human IL-1β with a longer t 1/2, which allows for once-monthly dosing. Unfortunately, a very recent report showed that monotherapy with these substances failed to preserve β-cell mass [47]. α-1 Antitrypsin (Aralast NP). α-1 antitrypsin (AAT) is a serine proteinase inhibitor that deters the production of proinflammatory cytokines, complement activation and immune cell infiltrations [48]. AAT has the ability to reverse new review article onset T1D in NOD mice [49] and also has beneficial effects on islet transplantation in mice [50]. A current phase 2 trial (RETAIN) is investigating whether intravenous AAT can preserve β-cell mass in recent onset T1D (NCT ) [51], preliminary data shows C-peptide preservation at the early timepoint of 18 weeks [52]. In a very recent efficacy and safety study (NCT ), AAT was well tolerated and showed beneficial metabolic effects in patients with recent onset T1D [53]. Anti-tumour necrosis factor-α (TNF-α). Etanercept is a TNFα antagonist that has been used successfully in rheumatoid arthritis [54]. A pilot study involving 18 subjects with T1D (ages 7 18 years) produced beneficial effects [55]. However, there are concerns regarding the use of this drug, especially in younger children, due to the risk of tuberculosis and other infections [56,57]. Etanercept is a strong candidate for combination therapies. DiaPep277. DiaPep277 is a peptide of the heat shock protein HSP60, which activates TLR2 receptors on T-cells [58]. DiaPep277 promotes cell adhesion, inhibits migration and induces an immunoregulatory shift toward a Th2 cytokine profile in mice [59]. In a phase 2 trial, DiaPep277 produced promising results [60] and Andromeda stated that in phase 3 clinical trials the peptide significantly preserved C-peptide levels [61,62]. The trial is still ongoing (NCT ). Statins. Treatment with statins, the widely used inhibitors of cholesterol biosynthesis, attenuates inflammatory reactions and immune activation [63]. The administration of statins in several animal studies either preserved β-cell mass or improved regeneration [64]. In T1D studies, statins did not prevent diabetes in the NOD mouse, however, they had profound effects on islet CD8+ infiltration [65]. Furthermore, the randomized placebo-controlled diabetes and Atorvastatin (DIATOR) trial yielded β-cell preservation when given to patients with high basal C-peptide levels [51]. A follow-up trial is currently ongoing (NCT ). Combinations of Immunosuppressive and Anti-inflammatory Compounds. The co-administration of IL-2 and rapamycin to 10-weeks old NOD mice synergistically prevented diabetes development for 13 weeks post-therapy, and also protected syngeneic transplanted islets in NOD mice [66]. Based on these results, a phase 1 trial combining therapy with IL-2 (Proleukin ) and Rapamycin (Rapamune )insubjects with T1D was developed (NCT ). Unfortunately, the results of this trial were disappointing as C-peptide loss was actually accelerated. Though Rapamycin plus IL-2 combination promoted the expansion of T-regs, it also expanded both T-eff and NK cells along with increasing responsiveness to IL-2 in the T-reg, T-eff and NK populations [67]. Thus, without a reliable biomarker to define a suitable dose of IL-2, the application of IL-2 in humans is too risky. Antigen-specific Immunization (ASI) A key advantage of ASI is that the target autoantigens of the immune response can be utilized to delete specific Volume 15 No. 7 July 2013 doi: /dom

6 pathogenic T-cells and/or to expand and activate T-regs that are reacting with islet-autoantigens. Recent discoveries showed, that individuals generating autoantibodies to an islet antigen might also be more prone to make regulatory (Th2) responses to the same antigen facilitating the initiation of these therapies early in the disease s history [24,68]. ASI has a great safety profile and a high specificity in its mechanism of action. The use of ASI causes CD4+ T-cells to produce β-cell protective cytokines, causing these T-cells to function in a manner similar to T-regs [69,70]. ASI can control effector responses of various specificities (bystander suppression) through the modulation of APC, which results in a lack of anti-islet T-eff cell expansion. Unfortunately, the design of an effective drug development program and the translation of antigen-specific approaches into clinical trials has been hindered, mainly by a lack of adequate immunological biomarkers that could be used to distinguish responders from non-responders as well as to optimize the doses and the modalities of antigen delivery. Here, small clinical studies with an emphasis on mechanistic outcomes are needed, since in our opinion, ASI, which foster T-reg function and expansion, and immune modulators, which reduce the T-eff cell load [24], work well in combination. ProInsulin DNA Vaccine (BayHill BHT-3021). BHT-3021 is an injectable formulation of plasmid DNA, which contains the gene that encodes the proinsulin protein. Proinsulin peptide is transported to the lymphnode (LN) and presented to T-cells by APC, inducing insulin- and proinsulin-specific immune tolerance. In a recent phase 1 and 2 trial, the 1 mg dose was found to preserve C-peptide greater than the placebo at 15 weeks (p = 0.026) [71]. Bayhill underwent bankruptcy proceedings and the future of this promising strategy is currently uncertain. GAD65. GAD treatment inhibited stimulated C-peptide level decline in patients with recent onset T1D [72], but this suppression was only significantly achieved in a small subgroup, and the trial failed to meet its initial overall endpoint. Despite these results, Diamyd and TrialNet began a large-scale clinical trial. GAD failed to inhibit C-peptide decline in the Diamyd and the European sponsored TrialNet trials. The results of the US sponsored TrialNet trial have not yet been published. Notably, GAD treatment was associated with increased anti-gad antibodies, suggesting that GAD-alum is, indeed, capable of eliciting an immune response, but not necessarily a protective one. GAD is currently being evaluated in a secondary prevention setting. Insulin B-chain in IFA (IBC-VS01). IBC-VS01 in IFA was tested in a phase 1 clinical trial in 12 subjects with recently diagnosed T1D [73] (NCT ). Mixed meal stimulated C-peptide responses, measured every 6 months, showed no statistical differences between the therapeutic and placebo arm. However, all patients vaccinated with the autoantigen, but none with placebo, developed robust insulin-specific humoral and T-cell responses with measurable insulin B-chain-specific CD4+ T-cells (Tregs). Immunoprevention DIABETES, OBESITY AND METABOLISM Non-antigen-specific Approaches The only non-antigen-specific approach currently tested in a secondary prevention setting is Teplizumab (anti-cd3). This trial examines the approach on persons at risk of developing T1D: one relative with T1D and at least two measurable autoantibodies. The study is currently enrolling participants (NCT ). Antigen-specific Approaches GAD65. After the failure of GAD in the intervention setting, it is currently being evaluated in secondary prevention in participants at risk with ongoing autoimmunity (NCT ). Intranasal Insulin. In a phase 1 trial [74], application of intranasal insulin could not stop the decline in β-cell function. However, the insulin antibody response to injected insulin was significantly blunted sustainedly in the recipients of nasal insulin and the IL-γ response of blood T-cells to proinsulin was suppressed after nasal insulin. These results suggest that intranasal insulin can augment the immune response to proinsulin. Currently, intranasal insulin is being evaluated in a phase 2 trial (NCT ). Oral Insulin. There is ample evidence that administration of oral insulin can prevent autoimmune diabetes in animal models [75]. However, there has not been a single-dose study in humans. Moreover, the dose used in the DPT I/II trials was much too low and as a result the DPT I/II trials failed [76]. Posthoc analyses revealed that there is a certain level of protection in individuals with high levels of autoantibodies. A phase 3 trial currently enrols participants with high levels of autoantibodies to confirm these findings. Combination Therapies of Antigen-specific and Non-antigen-specific Substances Thus far, all therapeutic attempts using individual agents have been associated with an initial preservation or improvement in C-peptide, yet this effect waned after a short period, even with repeated doses of the substance. In our opinion, a much more effective approach for halting T1D progression would be to combine substances that address different arms of the autoimmune attack. Despite the fact, that several preclinical studies with combinations of antigen-specific and non-antigen-specific immunomodulatory approaches showed considerable beneficial effects, there have not been any clinical trials to test these combinations. As reasons, we would name: (i) the lack of biomarkers that could indicate the re-establishment of β-cell specific tolerance and (ii) the possibility of unforeseen drug interactions with deleterious effects of the combination. Thus, in order to promote combination therapies for T1D, these risks must be mitigated. The most feasible scenario hereto is to identify promising combinations from the limited list of already approved agents. 586 Schneider et al. Volume 15 No. 7 July 2013

7 DIABETES, OBESITY AND METABOLISM Anti-CD3 Plus Nasal Insulin Dampening the immune response with a systemic agent, such as anti-cd3, while also inducing T-regs with antigen-specific approaches seem promising. One of these combinations might be anti-cd3 and intranasal proinsulin, as it reversed recentonset diabetes in two murine diabetes models with much higher efficacy than monotherapy with anti-cd3 or antigen alone [24]. Anti-CD3 Plus Anti-IL-1 Hyperglycaemic NOD mice treated with anti-cd3 mab and an IL-1 receptor antagonist (IL-1RA) showed a more rapid rate of remission of diabetes than mice treated with solely anti-cd3 mab or IL-1RA [77,78]. Combination-treated mice had increased IL-5, IL-4 and IFN-γ levels in circulation and also reduced pathogenic NOD-relevant V7 peptide-v7+ T-cells in the pancreatic lymph nodes. The combination caused persistent remission from islet inflammation. Anti-CD3 Plus Exendin-4 Exendin-4, a glucagon-like peptide-1 receptor agonist, enhances remission of diabetes in NOD mice treated with anti-cd3 mab, most probably by enhancing residual islet recovery [79]. GLP-1 Plus Gastrin Combination therapy with GLP-1 and gastrin restored normoglycaemia in diabetic NOD mice [80] by increasing pancreatic insulin content, β-cell mass, and insulin-positive cells in pancreatic ducts, and by decreasing β-cell apoptosis. Insulin autoantibodies were reduced in GLP-1- and gastrintreated NOD mice, and splenocytes from these mice delayed adoptive transfer of diabetes in NOD-SCID mice. DPP-4 Plus a Proton Pump Inhibitor The combination of a DPP-4 inhibitor with a proton pump inhibitor, raises GLP-1 and gastrin levels, respectively, which reversed diabetes in the NOD mouse [81]. When tested on islet graft recipients with early graft dysfunction, Sitagliptin combined with Pantoprazole augmented β-cell function but failed to induce significant β-cell regeneration [82]. Cellular Therapy Transfer of CD4+ CD25+ Regulatory Cells (T-regs) The emergence of CD4+ CD25+ CD127lo FOXP3+ T-regs as an essential component of immune homeostasis provides a potential therapeutic opportunity for active immune regulation and long-term tolerance induction. Ten children with recent onset diabetes (less than 2 months after diagnosis) were given /kg autologous, ex vivo expanded T-regs and were still in remission after 6 months showing significantly higher C- peptide levels [83]. Currently, a phase 1 clinical trial is recruiting patients (T1D 3 24 months after diagnosis, at least one AAB+) review article for autologous T-reg transplantation (NCT ). Since the exact mechanism of T-reg function remains obscure, and there are concerns in regards to the stability of ex vivo expanded T-regs, we do not see this therapeutic approach being widely adopted in the near future. Transfer of Dendritic Cells with Downregulated Co-stimulation Capacity An overwhelming number of studies indicate that the administration of co-stimulation-impaired (or downregulated), functionally immature DC can prevent T1D [84 86]. Positive results in the NOD mouse [87] with DC maintained in a functionally immature state by treatment with antisense oligonucleotides to CD40, CD80 and CD86 (AS-ODN-DC) have prompted a first clinical safety study, were autologous DC, pretreated with AS-ODN, were injected subcutaneously at anatomical location close to the pancreas of patients with a T1D history of less than 5 years (NCT ). No adverse effects were seen thus far and a phase 2 trial is currently under development. Future Directions in T1D Immunotherapy Vaccination with High-affinity Binding Ligands Mimetopes that bind the MHC complex more effectively than the epitopes traditionally used in induction and that convert T- cells to T-regulatory cells much more effectively are believed to work better than currently used epitopes, as recently shown with Insb9-23 [88] that prevented diabetes in NOD mice. However, TCR transgenic mice were used, whereas in humans, the clonal complexity and TCR diversity of the individual antigenic T-cell specificities, targeted by specific APLs, cannot guarantee a tolerogenic outcome, as seen in MS trials, were APLs actually accelerated disease [89]. Moreover, a recent clinical trial with an altered peptide ligand (NBI-6024) from Neurocrine failed to preserve β-cell mass in patients with recent onset T1D [90]. Delivery of Multiple Epitopes from Multiple Antigens This approach is well known from the development of vaccines, like the induction of virus specific CTL through vaccination with a DNA plasmid expressing an artificial polyepitope or polytope protein comprising a series of contiguous minimal CTL epitopes from different antigens [91]. A similar strategy could be adopted for the induction of β-cell antigen-specific T-regs. Monoclonal Antibodies to Recognize MHC-II/Autoantigen/TCR Complexes The trimolecular complexes consisting of class II MHC molecules, autoantigenic peptides and specific TCR recognizing the MHC bound peptide are essential for β-cell specific targeting in T1D pathogenesis. These trimolecular complexes are being gradually deciphered [92], and the crystal structure of DQ8, the major genetical determinant of MHC molecule, with an insulin peptide (B9-23) exists already. Conceivable approaches could be small molecules that block autoantigen Volume 15 No. 7 July 2013 doi: /dom

8 presentation or TCR recognition of MHC-autoantigen complexes or monoclonal antibodies to recognize autoantigen peptide MHC complexes with the peptide in a defined register recognized by the TCR. However, the effects of blocking the whole MHC-II molecule are uncertain, and therapy with an antibody against MHC-II has been associated with CMV reactivation in a kidney transplantation model [93]. The Use of Soluble Monoclonal TCRs that Target Islet pmhc-i Antigens Engineered antibodies are rather poor at recognizing peptide- HLA and are largely limited to membrane-integral protein targets thus restricted to tissue-specific or lineage-expressed antigens. In contrast, TCRs specifically recognize endogenously processed peptides bound to pmhc antigens presented on the cell surface. Recent advances in the use of soluble monoclonal TCRs that target defines pmhc class I antigens in cancer therapy can be regarded as proof of principle for this concept. A similar approach using an islet-antigen-specific TCR fused to an anti-ctla4 Fab fragment might dampen local immunity. Retargeting T-regs Using MHC Class I-Restricted TCR Approaches that isolate CD4+ CD25+ T-cells by tetramer technology and expand these cells in culture conditions that favour the generation of T-regs are becoming more and more attractive, mainly because of the missing genotoxicity otherwise caused by the insertion of integrating vectors. However, besides issues related to functional exhaustion and uncertain stability in the face of viral infections, the difficulty in redirecting these T-regs to the tissue of interest is yet to be effectively overcome. MHC class I-restricted TCRs can be used efficiently for this purpose, especially because inflamed tissue is more likely to express MHC class I molecules than MHC class II [94,95]. Here we expect more reports in the near future. Nanoparticles to Harness Autoregulatory T-cell Memory for Treatment of Autoimmune Disease Activation of a naive T cell requires at least two different signals [96]: the engagement of the TCR and a co-stimulatory signal provided by molecules that are selectively expressed on the surface of professional APC. In memory T cells, in contrast, molecular changes acquired during memory T cell formation overcome the requirement for co-stimulation. Nanoparticles, coated with T1D-relevant peptide major histocompatibility complex molecules are unable to provide such co-stimulatory signals thus selectively trigger the activation and expansion of autoregulatory memory T cells [97]. This therapeutic approach enables the rational design of disease-specific nanovaccines capable of blunting autoimmunity without impairing systemic immunity. The Use of Non-depleting Anti-CD8 and Anti-CD4 Antibodies In a recent study, Yi and colleagues showed that a short course of non-depleting anti-cd4 and anti-cd8 antibodies DIABETES, OBESITY AND METABOLISM in recent-onset diabetic NOD mice selectively suppresses the diabetogenic response, efficiently reverses diabetes and establishes long-term β-cell-specific tolerance [98]. This information, correlated with the finding, that the cofactor CD4 is not mandatory for the correct function of T-regs might open a new avenue in the immunotherapy of diabetes however, as in many of the prior stated examples, this attempt can only be successful in the presence of adequate biomarkers for β-cell mass and immune activity. Immunotherapy in β-cell Replacement A major obstacle preventing the recognition of islet transplantation as a chief T1D treatment is the need for a life-long immunosuppressive therapy for both cadaveric and allogeneic stem cell-derived islets. A very potent immunosuppressive regimen is needed to prevent immune-mediated rejection, because islets are targets of both alloimmune and relapsing autoimmune responses. Furthermore, many of the traditional immunotherapy regimens not only increase the risk of infection and cancer, but also have a pronounced β-cell toxicity. Overall, the major goals necessary for making islet transplantation a more viable therapy are: (i) to limit the β-cell toxicity of the initial immunosuppressive regimen and (ii) to induce long lasting graft tolerance after a short-term treatment. Classic Immunosuppressants The most potent induction therapy is the monotherapy with the calcineurin inhibitor tacrolimus, a drug with high nephrotoxicity and diabetogenicity. Currently, there is no alternative for Tacrolimus in a monotherapy setting. The combination used in the Edmonton protocol [99], with lowdose tacrolimus, high-dose sirolimus, and an anti-il-2 mab, seriously impairs initial islet engraftment. Also, sirolimus has severe side effects (mouth ulceration, proteinuria, peripheral oedema). The islet transplantation group in Edmonton currently uses a combination of tacrolimus and mycophenolate mofetil and has had good results. Trials testing different doses and application algorithms of the initial Edmonton protocol are ongoing (NCT ). T-cell Targeted Approaches Anti-CD3. The CITR registry demonstrates significantly higher 5 year insulin independence rates in studies, where thymoglobulin or a non-fc-binding humanized anti-cd3mab (teplizumab), were used as induction [100]. However, as shown in unpublished studies with a T-cell depleting anti-cd52 antibody, T-cell targeting is necessary, but probably unable to prevent initial islet rejection sufficiently on its own. Leukocyte Function Associated Antigen-1 (LFA-1). Four of the eight T1D recipients who received Efalizumab (Raptiva ), a mab that prevents the interaction between CD11a/LFA-1 and ICAM-1, in combination with thymoglobulin induction, achieved single donor insulin independence [101]. There was 588 Schneider et al. Volume 15 No. 7 July 2013

9 DIABETES, OBESITY AND METABOLISM marked expansion of peripheral T-reg (CD4+ CD25+ FoxP3+). Maintenance immunosuppression consisted of efalizumab and sirolimus with or without MMF. Unfortunately, efalizumab was withdrawn from the market in 2009 due to safety concerns and there are ongoing efforts for finding an alternative to LFA for islet transplantation. Costimulation Blockade with Belatacept (LEA29Y). A recent study has shown that a calcineurin-free immunosuppressive regimen with either belatacept, a fusion protein composed of the Fc fragment of a human IgG1 immunoglobulin linked to the extracellular domain of CTLA-4, or anti-cd11a, can have remarkable results on islet transplantation [102]. Costimulation blockade with belatacept combined with MMF monotherapy maintenance is currently the subject of a clinical islet transplant trial (NCT ) and will hopefully determine whether T-cell depletion is required for successful co-stimulation. B-cell Depletion So far, B-cells have been underestimated in islet graft destruction, thus the availability of β-cell-directed substances is low. After positive results in primates [103], a recent phase 2 clinical trial tested the combination of ATG, rituximab, and sirolimus in islet transplantation (NCT ). Results are to be published shortly. Plasmapheresis Plasmapheresis has been used for many years in solid organ transplantation and could be potentially useful to clear autoimmune antibodies in T1D recipients of islet grafts. Induction of Immune Tolerance In islet transplantation, current efforts to induce immune tolerance are mainly focusing on adoptive transfer of ex vivo autologous or allogeneic-expanded T-regs. Preclinical studies in humanized mice engrafted with skin grafts [104] have shown promising results, yet, the above named issues with the stability of the ex vivo expanded T-regs apply here too. Encapsulation in Semi-permeable Membranes The transplantation of islets or disparate β-cells in semipermeable membranes that allow for nutrients, oxygen and insulin transfer, while also blocking cellular access to the graft, has been extensively tested in animal models and has been proven effective several times [105]. Nevertheless, none of the tested encapsulation devices has reached a clinical trial thus far. Currently, the most promising results have been shown by using a more developed version of the TheraCyte device, initially developed by Baxter. In animal models, these devices preserved β-cell life and function [106] and protected islet grafts from immune mediated destruction [107]. The initial clinical trials are expected to start in review article Final Statements and Conclusions Most immunomodulatory clinical trials of the last years failed to meet their primary end-point. Reason for these failures is, in our opinion, an insufficient account for the variations among T1D patients in terms of residual β-cell mass and level of autoimmunity, caused by the lack of biomarkers to measure these aspects. In regard to the use of autoantigens or derivative peptides, the failures can be mainly attributed to insufficient knowledge about (i) the administration route, dosage and timing (ii) the use of adjuvants and (iii) site of triggering and progression of autoimmunity. With the disappointing outcomes of almost all trials based on the use of single agents, a much more effective approach for halting T1D progression would be to combine substances that address different arms of the autoimmune attack. Thus far, there have not been any clinical trials to test combinations. Overall, it seems highly unlikely that a reboot of the immune system can be achieved therapeutically, thus we will need a chronically administered therapy that has no side effects and that is limited to the diseased organ. Prior to designing successful future clinical interventions, we would suggest elucidating the following aspects: Definition of biomarkers to measure residual β-cell mass and level of immune response Definition of most efficient administration routes, timing and formulation for autoantigens Broadening of the knowledge in regard to pancreas lymphatics as primary locus for autoantigen presentation Further development of cell-based therapies and entry into phase 1 clinical trials Further development of alternative β-cell sources for the treatment of patients without residual β-cell mass Further development of encapsulation techniques that allow for minimal use of immunomodulatory drugs. Acknowledgement We thank Ghanashyam Sarikonda for helpful discussions and assistance with the figures. Conflict of Interest Matthias von Herrath and Darius Schneider designed the study and wrote the manuscript. Alexandra Kretowicz wrote the manuscript. The authors do not declare any conflict of interest relevant to this manuscript. References 1. Erlich H, Valdes AM, Noble J et al. HLA DR-DQ haplotypes and genotypes and type 1 diabetes risk: analysis of the type 1 diabetes genetics consortium families. Diabetes 2008; 57: Mueller DL. Mechanisms maintaining peripheral tolerance. Nat Immunol 2009; 11: Volume 15 No. 7 July 2013 doi: /dom

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11 DIABETES, OBESITY AND METABOLISM 42. Orban T, Bundy B, Becker DJ et al. Co-stimulation modulation with abatacept in patients with recent-onset type 1 diabetes: a randomised, double-blind, placebo-controlled trial. Lancet 2011; 378: Pescovitz MD, Greenbaum CJ, Krause-Steinrauf H et al. Rituximab, B-lymphocyte depletion, and preservation of beta-cell function. N Engl J Med 2009; 361: Nagler W, Taylor H. Diabetic coma with acute inflammation of Islets of Langerhans. JAMA 1963; 184: Sumpter KM, Adhikari S, Grishman EK, White PC. Preliminary studies related to anti-interleukin-1beta therapy in children with newly diagnosed type 1 diabetes. Pediatr Diabetes 2011; 12: Kontzias A, Efthimiou P. The use of Canakinumab, a novel IL-1beta longacting inhibitor, in refractory adult-onset Still s disease. Semin Arthritis Rheum 2012; 42: Moran A. Canakinumab, an anti-il-1 monoclonal antibody in recent-onset type 1 diabetes. Scientific Sessions of the American Diabetes Association. Philadelphia, Breit SN, Penny R. The role of alpha 1 protease inhibitor (alpha 1 antitrypsin) in the regulation of immunologic and inflammatory reactions. Aust NZ J Med 1980; 10: Koulmanda M, Bhasin M, Hoffman L et al. Curative and beta cell regenerative effects of alpha1-antitrypsin treatment in autoimmune diabetic NOD mice. Proc Natl Acad Sci USA 2008; 105: Pileggi A, Molano RD, Song S et al. Alpha-1 antitrypsin treatment of spontaneously diabetic nonobese diabetic mice receiving islet allografts. Transplant Proc 2008; 40: Strom A, Kolb H, Martin S et al. Improved preservation of residual beta cell function by atorvastatin in patients with recent onset type 1 diabetes and high CRP levels (DIATOR trial). PLoS One 2012; 7: e Ehlers M. Alpha-1 antitrypsin therapy in new-onset type 1 diabetes: interim results from Part I of the RETAIN study. 48th EASD Annual Meeting. Berlin, Gottlieb P. Metabolic and immunologic observations from a trial of alpha- 1 antitrypsin in recent onset type 1 diabetes. 48th EASD Annual Meeting. Berlin, Epstein WV. Treatment of rheumatoid arthritis with a tumor necrosis factor receptor-fc fusion protein. N Engl J Med 1997; 337: ; author reply Mastrandrea L, Yu J, Behrens T et al. Etanercept treatment in children with new-onset type 1 diabetes: pilot randomized, placebo-controlled, double-blind study. Diabetes Care 2009; 32: Fallahi-Sichani M, Flynn JL, Linderman JJ, Kirschner DE. Differential risk of tuberculosis reactivation among anti-tnf therapies is due to drug binding kinetics and permeability. J Immunol 2012; 188: Winthrop K, Baxter R, Liu L et al. Mycobacterial diseases and antitumour necrosis factor therapy in USA. Ann Rheum Dis 2013; 72: Zanin-Zhorov A, Cahalon L, Tal G, Margalit R, Lider O, Cohen IR. Heat shock protein 60 enhances CD4+ CD25+ regulatory T cell function via innate TLR2 signaling. 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12 restores normoglycemia in diabetic NOD mice. Diabetes 2008; 57: Suarez-Pinzon WL, Cembrowski GS, Rabinovitch A. Combination therapy with a dipeptidyl peptidase-4 inhibitor and a proton pump inhibitor restores normoglycaemia in non-obese diabetic mice. Diabetologia 2009; 52: Senior PA, Yau J, Dinyari P, et al. Sitagliptin plus pantoprazole enhances graft function and temporarily restores insulin independence in clinical islet transplantation. Scientific Sessions of the American Diabetes Association. Philadelphia, Marek-Trzonkowska N, Mysliwiec M, Dobyszuk A et al. Administration of CD4+ CD25highCD127- regulatory T cells preserves beta-cell function in type 1 diabetes in children. Diabetes Care 2012; 35: Clare-Salzler MJ, Brooks J, Chai A, Van Herle K, Anderson C. Prevention of diabetes in nonobese diabetic mice by dendritic cell transfer. J Clin Invest 1992; 90: Ma L, Qian S, Liang X et al. 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Transplantation of cultured islets from two-layer preserved pancreases in type 1 diabetes with anti-cd3 antibody. Am J Transplant 2004; 4: Posselt AM, Bellin MD, Tavakol M et al. Islet transplantation in type 1 diabetics using an immunosuppressive protocol based on the anti-lfa-1 antibody efalizumab. Am J Transplant 2010; 10: Posselt AM, Szot GL, Frassetto LA et al. Islet transplantation in type 1 diabetic patients using calcineurin inhibitor-free immunosuppressive protocols based on T-cell adhesion or costimulation blockade. Transplantation 2010; 90: Liu C, Noorchashm H, Sutter JA et al. B lymphocyte-directed immunotherapy promotes long-term islet allograft survival in nonhuman primates. Nat Med 2007; 13: Issa F, Hester J, Goto R, Nadig SN, Goodacre TE, Wood K. Ex vivo-expanded human regulatory T cells prevent the rejection of skin allografts in a humanized mouse model. Transplantation 2010; 90: Tarantal AF, Lee CC, Itkin-Ansari P. Real-time bioluminescence imaging of macroencapsulated fibroblasts reveals allograft protection in rhesus monkeys (Macaca mulatta). Transplantation 2009; 88: Sorenby AK, Kumagai-Braesch M, Sharma A, Hultenby KR, Wernerson AM, Tibell AB. Preimplantation of an immunoprotective device can lower the curative dose of islets to that of free islet transplantation: studies in a rodent model. Transplantation 2008; 86: Schneider DA, Boettler T, von-herrath MG. Novel approach to test for immune protecting properties of semipermeable membranes in pancreatic islet transplantation. Scientific Sessions of the American Diabetes Association. Philadelphia, Schneider et al. Volume 15 No. 7 July 2013

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