Introduction

Type 1 diabetes mellitus (T1D) results from autoimmune destruction of pancreatic β-cells. Autoimmunity is thought to occur in genetically predisposed individuals after exposure to one or more environmental triggers such as dietary factors, viral infections, etc. Infiltrating T cells, B cells, and NK cells in pancreatic islets initiate the autoimmune response and progressively destroy the insulin-producing β-cells. The entire process of β-cell destruction can take anywhere from a few months to a few years, finally resulting in hyperglycemia. HLA-DQ8 and HLA-DQ2 have been associated with high risk to T1D, and 89 % of newly diagnosed children from Sweden are positive for these HLA alleles (Sanjeevi et al. 1994, 1995a, b, 1996). Association of these HLA alleles with T1D has been shown to be inversely proportional to age (Graham et al. 1999).

Latent autoimmune diabetes in adults (LADA) is a slowly progressive form of autoimmune diabetes. Patients initially diagnosed as classical type 2 diabetics are identified as LADA according to the following criteria of the Immunology of Diabetes Society: (i) adult age (>30 years) at onset of diabetes, (ii) the presence of circulating islet autoantibodies, and (iii) lack of a requirement for insulin for at least 6 months after diagnosis.

Considering this sequence of events, preventing β-cell destruction is vital to preserving the residual β-cells in individuals with progressive β-cell loss and those at risk of developing T1D and LADA (referred to as autoimmune diabetes in adults). Antigen-specific and antigen-nonspecific immune therapies that aim to reduce islet cell autoimmunity are in different stages of clinical development. Recent insights into the autoimmune process are elucidating the etiology of autoimmune diabetes, conceivably identifying therapeutic targets. Stand-alone and/or combinational therapies that reduce autoimmunity in islets, regenerate β-cells, and restore insulin secretion are ongoing and appear to be the future of autoimmune diabetes intervention. Aggressive autoimmunity appears significantly earlier than overt disease, and therefore, pursuing therapeutic strategies before disease presentation should be beneficial for susceptible patients. Early intervention before the autoimmunity is initiated is the best. Second best is intervention after autoimmunity is initiated but before the disease becomes insulin dependent. The detailed discussion of immunological β-cell destruction can be found here as follows: “Immunology of β-cell Destruction” and “Inflammatory Pathways Linked to β Cell Demise in Diabetes” .

Preservation of β-cells is advantageous in autoimmune diabetes as it may significantly reduce both short- and long-term complications (hypoglycemia, retinopathies, etc.) while at the same time stabilize blood glucose levels and improve quality of life. To this end, pharmaceuticals are being developed using the available knowledge to generate target antigen-specific immune response. Ideally, tolerance induction would be a short time course, leading to a long-lasting tolerant stage, without debilitating the capability of the immune system to mount effective immune response against invading pathogens. In the following sections, the authors have discussed recent strategies employed to prevent β-cell destruction and preserve residual β-cells in autoimmune diabetic patients in the following categories: (i) antigen-based therapy, (ii) antibody-based therapy, (iii) other forms of therapy, and (iv) failed therapies in the past (summarized in Table 1).

Table 1 List of therapeutics used in prevention of β-cell death in autoimmune diabetes
Full size table

Antigen-Based Therapy

Insulin

Autoimmunity against insulin in T1D has long been observed since the 1980s that T1D patient had circulation insulin autoantibodies (IAA) before the insulin treatment (Palmer et al. 1983). As one of the major autoantigens in T1D, insulin is also among the earliest used antigens to induce immune tolerance in T1D patients (to preserve β-cells) as well as T1D relatives (to prevent the disease). The diabetes prevention trial 1 (DPT-1) was performed to access the capability of insulin administered as injections to prevent T1D among T1D relatives. The study, however, failed to demonstrate any beneficial preventive outcome (2002). The insignificant outcome led to subsequent change in insulin administration in similar trials.

Oral tolerance is a term used to describe the immune tolerance, which can be induced by the exogenous administration of antigen to the peripheral immune system via the gut. The active suppression of low doses of administered antigen appears to be mediated by the oral antigen-generating regulatory T cells that migrate to lymphoid organs and to organs expressing the antigen, thus conferring suppression via the secretion of downregulatory cytokines including IL-4, IL-10, and TGF-β. Since Oral administration is one of the easiest ways to induce immune tolerance. Another prevention approach in the DPT-1 was to administer insulin orally in first-degree relatives of T1D patients; however, the treatment failed to delay or prevent T1D (Skyler et al. 2005). At the same time, it was also found that in DPT-1 trial, oral administration did not alter IAA levels over time in those already positive for IAA at the start of treatment (Barker et al. 2007).

Similar to oral tolerance, immune tolerance could also be induced by administration of antigen to the respiratory tract (mucosal tolerance). At first, insulin administration through the respiratory tract was developed as an alternative to subcutaneous insulin injection. However, the inhaled insulin is associated with increased risk of lung cancer (Gatto et al. 2012). The use of inhaled insulin to prevent β-cell destruction requires further safety studies. While at the same time, the safety of nasal insulin administration is well documented. However, nasal insulin administration in children carrying high-risk HLA (for T1D) soon after detection of autoantibodies failed to prevent or delay the disease (Nanto-Salonen et al. 2008).

Exposure of the nasal mucous membranes to insulin may also cause act like a vaccine effect whereby protective immune cells are stimulated and then counteract the autoreactive immune cells which damage the β cells. There is an ongoing trial that aims to determine if intranasal insulin can protect β cells and stop progression to diabetes in individuals who are at risk (NCT00336674). The Pre-POINT (Primary Oral/intranasal Insulin Trial) is a dose-finding safety and immune efficacy pilot study aiming primary prevention in children genetically at risk to T1D, using oral or intranasal insulin (Achenbach et al. 2008). The results from Pre-POINT, in the future can give us more information on the effectiveness of insulin tolerance induction in T1D.

While most of the above trials end with insignificant outcomes, trials using insulin with modifications was then carried out to treat or prevent T1D. A recent published phase I trial used intramuscular human insulin B chain in incomplete Freund’s adjuvant for T1D treatment (Orban et al. 2010). After 2-year follow-up, although there was no statistical difference in stimulated C-peptide responses between treated and untreated patients, a robust insulin-specific humoral and regulatory T-cell (Treg) response was developed in treated patients (Orban et al. 2010). Results from long-term follow-up or trials using upgraded insulin modification can probably give us more data on the treatment.

Insulin and Cholera Toxin

A mechanism of tolerance induction that is currently showing promise is oral insulin conjugated to β-subunit of the cholera toxin (CTB) (Bergerot et al. 1997). It has been shown recently that oral administration of microgram amounts of antigen coupled to the CTB subunit can effectively suppress systemic T-cell reactivity in animal models. Bergerot et al. report that feeding small amounts (2–20 μg) of human insulin conjugated to CTB can effectively suppress β-cell destruction and clinical diabetes in adult nonobese diabetic (NOD) mice (Bergerot et al. 1997). The protective effect could be transferred by T cells from CTB-insulin-treated animals and was associated with reduced lesions of insulitis. Furthermore, adoptive cotransfer experiments show concomitant reduction in islet cell infiltration. These results suggest that protection against autoimmune diabetes can be achieved by feeding minute amounts of a pancreas islet cell autoantigen linked to CTB and appears to involve the selective migration and retention of protective T cells into lymphoid tissues draining the site of organ injury.

CTB subunit carries the insulin to the intestine and helps in the transfer of the insulin molecule across the intestinal barrier. The CTB conjugation also helps in the reduction of the dosage of insulin that can be administered orally without causing hypoglycemia. Further, this approach has also been tried successfully by intranasal administration. Both approaches have prevented the development of diabetes in the NOD mouse model of the autoimmune disease. CTB-insulin β-chain fusion protein produced in silk worms has been shown to suppress insulitis in NOD mice (Gong et al. 2007).

GAD65

Glutamic acid decarboxylase isoform 65 (GAD65) is a major autoantigen in T1D. Studies in NOD mouse have shown that destruction of islet β-cells was associated with T cells recognizing GAD65. Kaufman et al. showed that in NOD mice, intravenously injection of GAD65 before diabetes onset effectively prevents autoimmune β-cell destruction and reduce the development of spontaneous diabetes (Kaufman et al. 1993).

Diamyd AB evaluated this by using alum-formulated human recombinant GAD65 in LADA patients. They selected diabetic patients of both sexes aged 30–70 years, diagnosed with type 2 diabetes (T2D) and positive for GAD65 antibodies in their phase I/II trial. These patients were treated with either diet or oral tablets. A total of 34 patients and 13 controls were tested with 4, 20, 100, and 500 μg dose. This was injected subcutaneously twice but 4 weeks apart. No serious adverse effects were reported. In the follow-up, the C-peptide level (both fasting and stimulated) was significantly elevated in the group receiving 20 μg dose compared to placebo. Likewise, the HbA1c and mean glucose levels were significantly lowered in the 20 μg dose compared to placebo. The CD4+CD25+ T cells which reflect the increase in regulatory T cells associated with nondestructive response to β-cell were elevated in the 20 μg dose but not in other doses. All these findings were relevant even after a follow-up period of 24 months and 5 years (www.diamyd.com; Agardh et al. 2005). It is thought that the prevention of β-cell destruction and β-cell recovery is due to shifting of immune response from destructive to nondestructive which is mediated by the Diamyd GAD65 vaccine.

Subsequent phase IIb trials in Swedish T1D patients with alum-formulated GAD65 showed significant preservation of β-cell function 30 months after the first 20 μg dose administrations. It also induced antigen-specific T-cell population, cytokines involved in regulation of the immune system, and a long-lasting B cell memory, suggesting that modulation of general immune responses to GAD65 can be helpful in preserving residual β-cells (Ludvigsson et al. 2008). In the extended evaluation of the Swedish phase IIb trials, it showed that the alum-formulated GAD65 was able to delay the progressive β-cell destruction (Ludvigsson et al. 2011). However, the phase IIb trial in Canada did not significantly differ C-peptide levels between alum-formulated GAD65 treated and control groups at 1 year (Wherrett et al. 2011). Whether it is due to the shorter follow-up duration or the immunological difference between populations is not clear. A phase III trial recently concluded to verify the previous observed effect of alum-formulated GAD65 did not meet the end point when the results were analyzed from the European sites. If Sweden and Finland were excluded in the analysis, the results in the rest of the European sites showed significant end point. The reason why Sweden and Finland sites showed nonsignificant end point was because all the children in the trial had taken state-recommended H1N1 vaccine, which were not a part of the inclusion criteria. Even in Sweden, if the results were analyzed in those children who completed the study before the H1N1 vaccine was recommended by the state, significant result was obtained. It is not clear what H1N1 does to the protective effect of the alum-formulated GAD65 vaccine. Meanwhile, few studies are in progress like the phase II trial which is ongoing in Norway to see whether the difference in the effect of alum-formulated GAD65 is in association with enterovirus infections (NCT01129232). In supplementation with other anti-inflammatory drugs, another phase II trial is ongoing in Sweden to see the effect of using alum-formulated GAD65, vitamin D, and ibuprofen (NCT01785108).

Alum-formulated GAD65 is the only antigen-based vaccine candidate which has been shown to be effective in LADA. LADA is often misdiagnosed as type 2 diabetes and treated accordingly. This may lead to additional stress on an already declining β-cell mass (due to autoimmune destruction). Hence, diagnosis and treatment of LADA are vital.

DiaPeP277

Heat shock protein 60 (hsp60) is a 60 kDa protein which is one of the self-antigens in T1D. DiaPeP277 is a 24-amino-acid peptide which comprises 24 residues (437–460) analog to hsp60 (www.develogen.com). Administration of DiaPep277 in NOD mice arrested diabetes (Elias et al. 1990). A randomized double-blind phase II trial using DiaPeP277 in human subjects with newly onset disease (<6 months) resulted in preservation of the endogenous insulin production compared to the placebo group (Raz et al. 2001). In a follow-up study (Elias et al. 2006), the findings were reiterated. In both studies, immunomodulation was observed and associated with downregulation of Th1 cells and upregulation of IL-10 producing T cells. The immune responses were antigen specific as T-cell responses to bacterial antigens remained unaffected. However, studies performed in children did not show any improvement in the preservation of β-cell function or metabolic control (Lazar et al. 2007).

The preliminary results from phase III trials of DiaPep277 showed that T1D patients treated with DiaPep277 maintained C-peptide level better than in placebo group. Meanwhile, patients in the treated group had lower HbA1c level (Ziegler et al. 2010). Subsequent analysis found that T1D adults with low- and moderate-risk HLA genotypes would benefit the most from the intervention with DiaPep277 (Buzzetti et al. 2011). Additional phase III trial is ongoing for further evaluation on the efficacy/safety (NCT01103284, NCT01898086) and treatment effect (NCT01460251) of DiaPep277.

Monoclonal Antibody-Based Therapy

Anti-CD3 Antibodies

Experiments in the early 1990s in NOD mice demonstrated that hamster-derived anti-CD3 monoclonal antibodies reversed diabetes in hyperglycemic mice (Chatenoud et al. 1994, 1997). In order to increase safety in future clinical application, Fc-mutated (Fc-nonbinding) monoclonal anti-CD3 antibodies were engineered and were found to be less mitogenic, but were equally tolerogenic compared to functional Fc anti-CD3 antibodies (Chatenoud et al. 1994, 1997). These series of experiments demonstrated several unique features of the antibody therapy. First, continuous immunosuppression was not required, and second, the ability of the antibody to reverse disease after hyperglycemia has occurred was demonstrated. Treated NOD mice were resistant to transfer of diabetes by diabetogenic spleen cells, implying the involvement of active immune regulation preventing diabetes (Chatenoud et al. 1997).

Two of the earliest monoclonal antibody specific for the CD3 T-cell epitope that were tested in clinical trials are the ChAglyCD3 antibody (known after as otelixizumab), having a single mutation (Asn→Ala) at residue 297 in the Fc region that prevents glycosylation, derived from rat YTH 12.5 antibody (Routledge et al. 1995), and the hOKT3Ala-Ala antibody (known after as teplizumab), having two mutations at residues 234 (Lue→Ala) and 235 (Lue→Ala) in the Fc region. This antibody is derived from OKT3 (Bolt et al. 1993). A 6-day otelixizumab treatment in newly diagnosed T1D patients was found to be associated with lower requirement of insulin, however, susceptibility to infection at 1-year follow-up time (Keymeulen et al. 2005). When these T1D patients were followed longer (4 years), the treatment with otelixizumab after their T1D diagnosis was still able to suppress the rise in insulin requirements (Keymeulen et al. 2010). At the same time, teplizumab was also showed to change the ratio of CD4+ T cells to CD8+ T cells within 3 months and subsequently preserved insulin production up to 5 years (Herold et al. 2002, 2009) with better clinical parameters found in teplizumab-treated T1D patients (Herold et al. 2005). A current ongoing trial is undergoing to evaluate the effect of teplizumab to prevent or delay the onset of T1D in relatives determined to be at very high risk for developing T1D (NCT01030816).

The FcR-nonbinding anti-CD3 antibody (anti-CD3 antibody with a mutated Fc portion) therapy was effective only if the immune response was primed and ongoing. Locally, they target autoreactive T cells, and the strength of the T-cell receptor (TCR)/CD3 is important in determining the efficacy. Thus, it can be hypothesized that though CD3 is expressed on all T cells, anti-CD3 antibodies mediate signaling depending on the functional stage of the target T cell whether it is naive or effector or memory. Administration of anti-CD3 antibodies induces depletion of effector T cells in the target tissue and lymphoid organs. In the pancreas-draining lymph nodes, apoptosis is induced in effector T cells compared to regulatory T cells and resting T cells (Hirsch et al. 1988; Wong and Colvin 1991; Carpenter et al. 2000). Apoptotic effector T cells are engulfed and digested by phagocytes (macrophages and immature dendritic cells [DC]). These phagocytes secrete large amounts of transforming growth factor (TGF-β) which creates a noninflammatory environment and also plays a major role in the maturation of DCs. TGF-β production has been suggested and experimental data demonstrate that TGF-β is central to the tolerance induced by FcR-nonbinding anti-CD3 antibodies. TGF-β-neutralizing antibodies are shown to completely neutralize the tolerogenicity induced by anti-CD3 therapy (Belghith et al. 2003). Local production of TGF-β has been shown to have the capability to convert a proinflammatory environment to a noninflammatory and tolerogenic environment (Li et al. 2006). A high concentration of TGF-β also promotes upregulation of inhibitory receptor ligands (programmed cell death ligand 1, ICOS ligand) and downregulation of MHC and costimulatory molecules on antigen-presenting cells (Li et al. 2006; Rutella et al. 2006). This in turn induces the induction or expansion of CD4+CD25+FOXP3+ T-regulatory cells (Treg) (Rutella et al. 2006). From the available experimental data, it has been proposed that the FcR-nonbinding anti-CD3 antibody treatment triggers a massive local production of TGF-β, by phagocytes engulfing activated effector T cells (You et al. 2008).

Improving the Existing anti-CD3 Antibody Therapy

Administration of drugs which promote β-cell survival and growth (such as exendin-4) may increase the β-cell growth and replication in the “tolerant” environment. In NOD mice, combination of exendin-4 and anti-CD3 monoclonal antibodies led to effective reversal or the disease with increased insulin content of the β-cell as compared with individual exendin-4 or anti-CD3 monoclonal antibody treatment (Sherry et al. 2007). Frequent side effects because of interferences with the T-cell population in proximity with treatment periods and recurrent autoimmunity might be a problem in anti-CD3 antibody-treated individuals. Repetitive treatment can be a possible way out in such a situation but formation of anti-idiotypic antibodies should be taken into consideration.

Anti-CD20 Antibodies

B cells constitute about 60–70 % of the immune cells infiltrating the pancreatic islets (Green and Flavell 1999). Until recently B cells were thought to play an important role in priming T cells (Wong and Wen 2005). However, a recent study showed for the first time that B cells promote the survival of CD8+ T cells in the islets and thereby promote the disease (Brodie et al. 2008). CD20 is a cell surface marker expressed on all mature B cells. Rituximab (Roche/Genentech), a humanized anti-CD20 monoclonal antibody (CD20 mAb), has been shown to successfully deplete human B cells from peripheral circulation via mechanisms involving Fc- and complement-mediated cytotoxicity and probably via proapoptotic signals (Rastetter et al. 2004; Martin and Chan 2006). Given the important role of B cells in the pathogenesis of T1D, depleting B cells is a very interesting therapeutic option. Transgenic NOD mice engineered to express human CD20 on B cells, when treated with a single dose of CD20 mAb, gave interesting results (Hu et al. 2007; Xiu et al. 2008). First, treatment of mice in the early stage of the disease (insulitis) prevented or delayed the progression to disease; second, clinical hyperglycemia could be reversed in over one-third of the experimental animals; third, B cell levels were restored to pre-depletion levels within 3 months of treatment, but the progression to T1D was delayed almost indefinitely. Recent published data from TrailNet anti-CD20 study group showed that four infusions of rituximab in the first month after diagnosis of T1D can preserve β-cell function at 1-year follow-up (Pescovitz et al. 2009). A recent clinical trial (NCT01280682) is ongoing to investigate further the immunomodulating role of rituximab in the treatment of T1D.

CTLA4 Immunoglobulin (CTLA4 Ig)

Cytotoxic T-lymphocyte antigen 4 (CTLA4) is expressed on the surface of T-helper (Th) cells. CTLA4 binds CD80 and CD86 on the antigen-presenting cells and blockades the most important second signal (costimulation signal) for full activation of T cells transduced by the binding between CD80/CD86 and CD28 on the T cells. Thus, CTLA4 functions as a negative regulator of T-cell activation, and the costimulation blockade has been proposed as a therapeutic modality for autoimmunity and transplantation (Bluestone et al. 2006; Teft et al. 2006). The CTLA4 Ig (or lately named abatacept) is a fusion protein of human CTLA4 and the Ig–Fc region designed to bind CD80/CD86 and block the T-cell costimulatory signal (Lenschow et al. 1992). A study in NOD mice showed that costimulatory blockade with CTLA4 Ig fusion protein prevented diabetes when administered before overt diabetes (Lenschow et al. 1995). A recent phase II trial showed that abatacept infusion regularly after T1D diagnosis can preserve β-cell function throughout the 2 years during the investigation (Orban et al. 2011). Further trial is ongoing (NCT01773707) to determine whether the infusion of abatacept can delay or prevent the development of T1D among T1D relatives at risk.

IL-1 antagonist and anti-IL-1β Antibody

Interleukin-1β (IL-1β) is a proinflammatory factor secreted by several cell types in response to tissue insult. It has been shown that IL-1β bound to pancreatic β-cell interleukin-1 (IL-1) type 1 receptors (IL-1R), IL-1 induces β-cell dysfunction and apoptosis through mitogen-activated protein kinase pathways (Mandrup-Poulsen et al. 2010). In addition, IL-1β enhances expansion and survival of T cells, promotes differentiation of T cells toward pathological phenotypes, and enables effector T cells to proliferate despite the presence of Tregs (Dinarello et al. 2012). These evidence makes blockade of IL-1β is an attractive therapeutic target. A recent report combined results from two independent studies blocking IL-1 (anakinra, IL-1 receptor antagonist, and canakinumab, anti-IL-1β mAb) showed that both treatment did not preserve C-peptide level at 9-month or 12-month time (Moran et al. 2013). Although future results of long follow-up duration might give us more information, the investigator questioned that the IL-1 blockade treatment should be given as prevention for T1D before T1D onset. However, up to date, there is no registered trial investigating the preventive effect of IL-1 blockade treatment in T1D. There are currently trials investigating the use of other IL-1 blockade in the treatment of T1D (rilonacept, IL-1 Trap, NCT00962026, and gevokizumab, anti-IL-1β antibody, NCT01788033 and NCT00998699).

Anti-TNF-α Antibody

It was found in NOD mouse that TNF-α mRNA is produced by CD4+ T cells within inflamed islets during the development of diabetes (Held et al. 1990). In vitro models show that TNF-α potentiates the destruction of β-cells by other cytokines (Mandrup-Poulsen et al. 1987). Transgenic mice with increased β-cell expression of TNF-α have significant lymphocytic insulitis, which is abrogated in TNF receptor knockout mice (Herrera et al. 2000). It was also indicated clinically that anti-TNF therapy may induce IL-10-secreting regulatory cells with a consequent resolution of the inflammation in the pancreatic islets (Arif et al. 2010). Etanercept is a recombinant fusion protein of TNF receptor to the constant end of the IgG1 antibody that binds to TNF-α, thereby clearing the TNF-α from circulation. The usage of etanercept twice a week subcutaneously resulted in lower A1C and increased endogenous insulin production at 6-month follow-up (Mastrandrea et al. 2009). However, long-term effect of etanercept in T1D is currently unknown and awaiting future investigations.

Others (Anti-CD52 Antibody and Anti-CD2 Antibody)

Mycophenolate mofetil (MMF) is rapidly absorbed after oral administration and hydrolyzed to MPA, an inhibitor of inosine monophosphate dehydrogenase that inhibits guanosine nucleotide synthesis and thus inhibits T and B cell proliferation with no obvious effect on other cell types. It was found that MMF was effective in diabetic animal models (Hao et al. 1992, 1993). Recent study in DRBB rat model demonstrated a synergistic effect of MMF with daclizumab in the treatment of diabetes (Ugrasbul et al. 2008). Daclizumab is a humanized monoclonal antibody that binds to CD25, the α subunit of the interleukin-2 (IL-2) receptor on the surface of activated lymphocytes, functioning to arrest the proliferation of activated lymphocytes. However, clinical trial in human using MMF and daclizumab or alone did not have an effect on the loss of C-peptide in subjects with new-onset T1D (Gottlieb et al. 2010). In addition, the increased risk of virus infection after coadministration of MMF and daclizumab might impede further investigations (Loechelt et al. 2013). An ongoing trial using daclizumab alone (NCT00198146) is under investigation.

Alefacept is a soluble LFA3/IgG1 fusion protein that binds CD2 on T cells. Alefacept was found recently to be efficacious in treatment of chronic psoriasis (Ellis and Krueger 2001). Alefacept was found to downregulate circulating memory (CD45RO+) T cells (da Silva et al. 2002). The trial using alefacept in the treatment of T1D (NCT00965458) is ongoing.

Immunomodulating Therapy

Autologous Hematopoietic Stem Cell Transplantation

It was shown as early as in the late 1980s that diabetes in NOD mice may be prevented by allogeneic transplantation of hematopoietic stem cells (HSC) from a non-disease-prone strain (LaFace and Peck 1989). In the 1990s, it was demonstrated that environmentally induced animal autoimmune diseases such as experimental autoimmune encephalomyelitis and adjuvant arthritis could be cured by syngeneic, autologous, or pseudo-autologous (using syngeneic animals in the same stage of disease as the recipient) HSC transplants (Burt et al. 1995; Kroger et al. 1998; Karussis et al. 1999). These studies in animal models indicated that HSC transplantation can probably reintroduce tolerance to autoantigens. Indeed, in a recent published uncontrolled clinical trial, HSC transplantation procedure in human showed that it is associated with more insulin independence and lower insulin usage and increased C-peptide level (Couri et al. 2009). Aside from classic HSC transplantation, autologous non-myeloablative hematopoietic stem cell transplantation also showed effectiveness in slowing C-peptide decrease, decreasing GAD65 antibody, and better diabetic metabolism measurements (Voltarelli et al. 2007). However, since earlier trials had shown that low-dose immunosuppression can induce a slow decline or even improvement in C-peptide level (see below in section “Immunosuppression Drugs”), it was argued whether the effect is due to repopulation of the immune cells or the high-dose immunosuppression itself before the transplantation. There are two ongoing trials in China (NCT01341899 and NCT00807651) that might provide more knowledge on the HSC transplantation in T1D.

While the transplantation of HSC was showed to halt the autoimmune destruction of β-cells, research and trials on the transplantation of islets heightened further the importance of transplantation in the treatment of T1D (discussed elsewhere: “Human Islet Autotransplantation ,” “Islet Encapsulation ,” “Islet Xenotransplantation: Recent Advances and Future Prospect ,” and “Successes and Disappointments with Clinical Islet Transplantation” ).

Stem Cell Therapies

Mesenchymal stem cells (MSCs) were found to be able to protect NOD mice from diabetes by induction of Tregs (Fiorina et al. 2009; Madec et al. 2009). On one side, it was shown that MSC and PBMC mixture is capable of switching T-cell response from Th1 to Th2 when it encounters autoantigen GAD65 (Zanone et al. 2010), and on the other hand, MSCs were found to be able to home to injured tissue and stimulate endogenous islet regeneration (Yagi et al. 2010; Bell et al. 2012). Being capable of shooting two birds with one stone, MSC attracts researchers’ interest and there are several ongoing trials investigating different types of MSCs (NCT00690066, NCT01322789, NCT01374854, NCT01068951, NCT01219465, NCT01496339).

In addition to MSC, immature unprimed functional regulatory T cells (Tregs) were found abundant in the umbilical cord blood (Godfrey et al. 2005). These highly functional Tregs might limit inflammatory cytokine responses and anergize effector T cells in autoimmune processes (Fruchtman 2003). Thus, the umbilical cord blood has become a focus of researchers to design cell-based therapies for T1D patients. However, umbilical cord blood transfusion did not demonstrate efficacy in preserving C-peptide in the newly diagnosed after 1 year of transfusion (Haller et al. 2009). Larger randomized studies as well as 2-year post-infusion follow-up of this cohort are needed to determine whether autologous cord blood-based approaches can be used to slow the decline of endogenous insulin production in children with T1D is an idea source to be transplanted to patients with T1D. An ongoing trial is investigating the effectiveness of autologous cord blood transfusion in the treatment of T1D (NCT00989547). At the same time, the combination of MSC transplantation and umbilical cord blood transfusion is also under investigation (NCT01143168).

It has been reported in NOD mouse model that the autologous CD4+CD62L+ Tregs co-cultured with the human cord blood stem cells (CB-SC) can eliminate hyperglycemia and promote β-cell regeneration (Zhao et al. 2009). Although the underlying mechanism is not clear, it was proposed that CB-SC could suppress the proliferation of β-cell-specific autoreactive T cells (Zhao et al. 2007). The phase I trial was published recently using CB-SC-treated peripheral lymphocytes (stem cell educator) reinfusion to patients with existing T1D (Zhao et al. 2012). The stem cell educator showed its safety and capability of persistently improving metabolic control after a single treatment (Zhao et al. 2012). A phase II trial (NCT01350219) is currently ongoing to investigate the effectiveness of this method in the treatment of T1D.

The other usage of stem cell therapies prospered in the production of islets in vitro as well as in vivo. The in vitro islets generated from human embryonic stem cells and its potential clinical implementation is further discussed in “Making Islets From Human Embryonic Stem Cells” . Potential usage of in vivo stem cells is discussed in “Stem Cells in Pancreatic Islets” .

Other Cell Therapies

Dendritic cell (DC) is one of the most important antigen-presenting cells that also showed immunoregulatory characteristics (Hackstein et al. 2001). Studies in mouse models showed that treating NOD mice dendritic cells ex vivo with antisense oligonucleotides targeting the primary transcripts of CD40, CD80, and CD86 (costimulatory molecules) can downregulate those cell surface molecules, thus increasing CD4+CD25+ T cells (Tregs) in NOD recipients (Machen et al. 2004). This regulation effect in mice was then found to be mediated by IL-7 produced by the treated DCs (Harnaha et al. 2006). The trial using this method (NCT00445913) is ongoing and awaiting results.

Tregs (T-regulatory cells) can act through DC to prevent autoreactive T-cell differentiation, thus preventing or slowing down the progression of autoimmune diseases (Tang and Bluestone 2006). The shortage of Tregs can lead to the development and accumulation of Treg-resistant pathogenic T cells in patients with autoimmune diseases (Tang and Bluestone 2006). Thus, restoration of self-tolerance using Tregs in these patients will likely be able to control ongoing tissue injury. A recent report showed the feasibility of expanding Tregs isolated from patient with recent-onset T1D (Putnam et al. 2009). The ongoing trial using autologous expanded Tregs transfusion in T1D patients (NCT01210664) will investigate the effectiveness of this hypothesis.

IFN-α and IL-2

Early trial showed that parenteral IFN-α (interferon-α) provided no benefits in patients with newly diagnosed T1D patients (Koivisto et al. 1984). However, it was found later that ingested IFN-α has immunomodulatory effect in experimental autoimmune animal model and in multiple sclerosis in humans (Brod and Burns 1994; Brod et al. 1997). In a recent phase I trial using ingested human recombinant IFN-α in T1D, it was found that 5,000 units of IFN-α administered once daily in newly diagnosed T1D patients for 1 year could maintain more β-cell function (Rother et al. 2009). Future study is required to verify the results and pave the way for clinical use of IFN-α.

Interleukin 2 (IL-2) is a dependant cytokine for Tregs to maintain viability and function. IL-2 down signaling events activate Akt/Erk pathway and targets CTLA4 gene. At the same time, IL-2 also signals through STAT5 pathway and activates FOXP3 and CD25 genes (Hulme et al. 2012). Reduction in IL-2 in T1D may contribute to Treg decline. Aldesleukin (Proleukin) is a commercialized IL-2 and currently under the investigation of several trials (NCT01353833, NCT01827735, NCT01862120).

Anti-T-Cell Globulin

Early clinical experience on immunomodulating therapy using anti-T-cell globulin (ATG) in T1D showed effectiveness in delaying and lowering insulin requirement (Eisenbarth et al. 1985) A recent clinical trial using polyclonal ATG confirmed that short-term ATG therapy in newly diagnosed T1D contributes to the preservation of residual C-peptide production and to lower insulin requirements at 1 year after diagnosis (Saudek et al. 2004). A current ongoing trial (NCT00515099) is further investigating the therapeutic effect of ATG in T1D.

Other Forms of Therapy

DNA Vaccination

DNA vaccination involves administration of a gene that encodes the target antigen, instead of the antigen as in classical vaccination. Variety of vectors can be used to transfer the target gene as DNA or RNA, along with genes encoding immunomodulatory molecules. Several studies have been performed using administration of plasmids encoding antigens such as insulin B chain, GAD65, and immunoglobulin G–Fc fusion constructs in animal models. However, plasmids carry unmethylated CpG motifs (ISS, immunostimulatory sequences) which activate the innate immune system. Therefore, DNA vaccination against T1D should block or overcome the effect of such stimulatory elements. DNA vaccine hold good promise in treatment of autoimmune diseases as they have been used, in experimental models, to direct the immune response toward a Th1 or a Th2 response (Prud’homme 2003).

DNA Vaccination with GAD65

Intramuscular injections of plasmid containing GAD65 fused with IgG–Fc and IL-4 were reported to generate a GAD65-specific Th2 response, protecting NOD mice from developing T1D (Tisch et al. 2001). A study performed to evaluate two different modes of delivery of a plasmid coding for GAD65 reported the elicitation of IL-4 secreting T-cell response. Two methods of plasmid delivery, intramuscular and a novel gene gun method, were tested in this study. Intramuscular injections fail to stop the ongoing β-cell autoimmunity, whereas the gene gun method was successful in eliciting immunomodulation, significantly delaying the disease onset in NOD mice (Goudy et al. 2008).

Microsphere-Based Vaccine

Microparticulate carriers have the capability to shape the functional phenotype of dendritic cells (DC) (Waeckerle-Men et al. 2006; Yoshida and Babensee 2006). A nucleic acid-based vaccine using antisense oligonucleotides coated on microspheres, directed against CD40, CD80, and CD86 (costimulatory molecules important in DC maturation), has been shown to prevent T1D in NOD mice as well as reverse new-onset disease (Phillips et al. 2008). Microspheres administered are taken up by DCs by phagocytosis. Inflammation in the pancreatic islets associated with β-cell apoptosis is suggested to drive the antisense oligonucleotide-loaded DCs to acquire the β-cell antigen(s). This is followed by the accumulation of these DCs in the pancreatic lymph nodes, where they are hypothesized to interact with regulatory T cells inducing a β-cell-specific immune hyporesponsiveness or functional tolerance to β-cell antigens (Tarbell et al. 2006). The detailed mode of action of the microsphere-based vaccine is yet to be established and clinical trials in human subjects will decide the efficacy of this approach in the prevention of T1D.

Anti-Inflammatory Agents

Use of anti-inflammatory drugs such as aspirin (Hundal et al. 2002), statins (Tan et al. 2002), and glitazone (van de Ree et al. 2003) has been shown to be beneficial in type 2 diabetes. These drugs have been shown to have anti-inflammatory effect by affecting either the signaling pathways (such as NFkB signaling) or cytokines involved in inflammation. Such drugs can be vital in bringing down the overall islet inflammation and thereby creating a better islet environment which can respond to other forms of treatment.

Newly developed anti-inflammatory drugs have joined the tide against T1D recently. α-1 antitrypsin or α1-antitrypsin (AAT) is a naturally occurring anti-inflammatory glycoprotein; AAT is a protease inhibitor belonging to the serpin superfamily. AAT has been shown to facilitate Treg expansion in the NOD mice mode, protecting the mice from diabetes (Koulmanda et al. 2008). AAT alters CCR7 expression on DC surface; thus, promoting semimature DC migration to the lymph nodes subsequently activates Tregs (Ozeri et al. 2012). There are two trials now investigating AAT in the treatment of T1D (NCT01319331, NCT01661192).

Vitamin D

Vitamin D has been shown to suppress proinflammatory responses by suppressing enhanced activity of immune cells taking part in autoimmune processes. In NOD mice, vitamin D has been shown to prevent autoimmune diabetes (Mathieu et al. 1994). Supplementation of vitamin D has been shown to be protective in children against T1D. High dosage and the timing of the dose have also been shown to play a role. A randomized open-label, pilot trial is currently under way (NCT00141986), where increased dose of vitamin D (2,000 IU/day instead of the current practice of 400 IU/day) is administered to children genetically at risk of developing T1D. However, trials with vitamin D in new-onset T1D have shown mixed results, with one showing benefit (Gabbay et al. 2012) while the other two did not (Bizzarri et al. 2010; Walter et al. 2010). The dosing and timing of the treatment using vitamin D require future studies.

N-3 Polyunsaturated Fatty Acids and Other Dietary Supplements

It has been shown early that synthesis of IL-1β, IL-1α, and tumor necrosis factor can be suppressed by dietary supplementation with long-chain n-3 fatty acids (Endres et al. 1989). An ongoing trial (NCT00333554) investigating the effect of long-chain n-3 fatty acids in the prevention of T1D might provide us more useful information.

In addition, study using streptozotocin-treated diabetic rats showed that chromium supplementation lowered blood levels of proinflammatory cytokines. Although there is no benefit in plasma glucose level from chromium supplement found in the animal study (Vinson 2007), the investigators believed T1D patients could benefit from chromium supplement. The effect of chromium supplement human T1D is currently under investigation (NCT01709123).

Other Drugs

Lansoprazole and other proton-pump inhibitors consistently elevated serum gastrin levels (Ligumsky et al. 2001). It has already been found as early as the mid-1950s that gastrin has the potential to increase new β-cell formation (Zollinger and Ellison 1955). Thus, it was hypothesized that lansoprazole could probably induce β-cell regeneration by increasing serum gastrin level. There are two current trials investigating the safety of coadministration of cyclosporin and lansoprazole among patients with existing T1D (NCT01762657) and newly diagnosed T1D (NCT01762644).

The lipid-lowering drug atorvastatin was also found to have immunomodulating effect in rheumatoid arthritis intervention trials (McCarey et al. 2004). Atorvastatin treatment was found to be able to preserve β-cell function in T1D patients with median inflammation mediator levels (Strom et al. 2012). There is an ongoing trial (NCT00529191) which might give further information on the effect of atorvastatin treatment in T1D. Similarly, another lipid-lowering drug simvastatin is also under investigation in a current trial (NCT 00441844).

Imatinib is originally designed as a specific inhibitor of Abl protein tyrosine kinases and used in the treatment of chronic myeloid leukemia (Druker et al. 1996). Recent studies showed that imatinib had a strong anti-inflammatory effect by inhibiting TNF-α production in macrophages (Wolf et al. 2005). A recent study showed that both imatinib and sunitinib treatments led to durable remission in NOD mice (Louvet et al. 2008). The underlying mechanism is probably due to the multikinase inhibiting characteristics of imatinib and sunitinib which inhibited platelet-derived growth factor receptor (PDGFR) (Louvet et al. 2008). The phase I trial using imatinib for the treatment of T1D (NCT01781975) is planned and awaiting participant recruitment.

Diazoxide is a potassium channel activator that is frequently used in the treatment for hypertension. It was found that diazoxide can provide β-cell rest by reversibly suppressing glucose-induced insulin secretion through opening ATP-sensitive K+ channels in the β-cell (Trube et al. 1986). Early trial using diazoxide in T1D showed that those treated T1D displayed higher residual insulin secretion than the placebo group (Bjork et al. 1996; Ortqvist et al. 2004). However, a recent trial did not observe the preservation effect from diazoxide, although better metabolic control was found among diazoxide-treated T1D patients (Radtke et al. 2010). More studies in the future with regard to diazoxide function may unveil more on the effect of diazoxide as well as T1D pathogenesis. Ongoing clinical trials for new therapy in managing type 1 diabetes is listed in Table 2.

Table 2 Ongoing trials
Full size table

Past Trials

Immunosuppression Drugs

Cyclosporin was one of the first immunosuppressive drugs used in treatment of T1D, which could delay the onset of the disease (Bougneres et al. 1988). However, cyclosporin achieved immunosuppression by targeting intracellular processes, which is nonspecific and unrelated to autoantigens involved in the disease. Withdrawal of the treatment resulted in invariable recurrence of the pathogenic immune response. Considering the nephrotoxic potential of the drug, it was not a choice of long-term treatment, and therefore, it was not considered for therapy (Behme et al. 1988).

Other early used drugs are prednisone (Elliott et al. 1981), azathioprine (Harrison et al. 1985; Cook et al. 1989), and coadministration of prednisone plus azathioprine (Silverstein et al. 1988). Although these drugs showed slow decline or even improvement in C-peptide level, they were not used in clinic afterward due to considerable side effects.

Nicotinamide

The European Nicotinamide Diabetes Intervention Trial (ENDIT) tested the efficacy of nicotinamide in preventing diabetes in human subjects. Previous studies in animal models demonstrated that the administration of nicotinamide can prevent T1D (Yamada et al. 1982). Nicotinamide is speculated to confer protection by inhibiting DNA repair enzyme poly-ADP-ribose polymerase and prevent the depletion of β-cell NAD. However, in the ENDIT, nicotinamide treatment did not result in successful prevention of T1D (Gale et al. 2004).

BCG

Bacille Calmette–Guerin (BCG) vaccination has been proposed as an adjuvant therapy to prevent T1D. A study reported that administration of BCG vaccination soon after T1D onset preserves β-cell function (Allen et al. 1999). However, this was not the case in the trials that followed. BCG vaccination could not prevent the development of T1D in children genetically at risk (Huppmann et al. 2005).

Ongoing Prediction Studies

Several international collaborative efforts are under way. These studies will identify potential population/risk groups who would benefit from various therapies for prevention of β-cell death.

Potential therapies aiming at prevention of β-cell death would directly benefit patients suffering from autoimmune diabetes (T1D/LADA). Successful therapies can also benefit prediabetics, first-degree relatives of T1D patients, and individuals at risk of developing autoimmune diabetes.

TEDDY: The Environmental Determinants of Diabetes in the Young (TEDDY) study are an effort to screen more than 360,000 children around the world to the environmental factors that might play a role in T1D pathogenesis (2008). Several genome-wide association scans have been completed and are under way, with an aim to identify the T1D risk loci across the human genome. Identification of environmental and genetic factors involved in the etiology of T1D can broaden the scope of therapeutic interventions.

TrailNet: It is an international consortium of clinical research centers working toward achieving prevention of T1D (Skyler et al. 2008).

TRIGR: Trial to reduce T1M in the genetically at-risk (TRIGR) study is another collaborative effort, which aims at testing the hypothesis that weaning to an extensively hydrolyzed infant formula will decrease the incidence of T1D in children who carry high-risk HLA and in those who have a first-degree relative with T1D (2007). Initial findings from TRIGR suggest that introduction of cow’s milk at an early age in children with dysfunctional gut immune system might result in aberrant immune response, leading to T1D (Luopajarvi et al. 2008).

DAISY: The DAISY study (the Diabetes Autoimmunity Study in the Young) aims at elucidating the interaction between genes and the environment that can trigger T1D. Children who are genetically at risk or those who have a first-degree T1D relative are being studied and followed up.

BABY-DIAB: BABY-DIAB is (Roll et al. 1996) a prospective study conducted from birth among children of mothers with T1D or gestational diabetes or fathers with T1D to investigate the temporal sequence of antibody responses to islet cells (ICA), insulin (IAA), GAD65 (GADA), and the protein tyrosine phosphatase IA-2/ICA512 (IA-2A). A total of 78.6 % of children (17,055 out of 21,700) born in the southeast of Sweden were entered in the ABIS (All Babies in Southeast Sweden) study with an aim to study environmental factors affecting the development of immune-mediated diseases in children, with special focus on T1D (Ludvigsson et al. 2002).

DIPP: The DIabetes Prediction and Prevention Project was launched in 1994 in Finland. In the study, general population newborns are screened for increased genetic risk for T1D in the University Hospitals of Turku, Tampere, and Oulu.

BABYDIET: BABYDIET study (Schmid et al. 2004) is a primary prevention trial in Germany initiated to investigate whether delay of the introduction of dietary gluten can prevent the development of islet autoimmunity in newborns with a first-degree relative with T1D, who are at genetically high risk of T1D. However, the result showed that delaying gluten exposure until the age of 12 months is safe but does not substantially reduce the risk for islet autoimmunity in genetically at-risk children (Hummel et al. 2011).

TIRGR: The Trial to Reduce IDDM in the Genetically at Risk (TRIGR) study is an international randomized double-blind controlled intervention trial that was designed to establish whether weaning to a highly hydrolyzed formula in infancy reduces the risk of T1D later in childhood (Group 2007). A recent report from the study showed that dietary intervention using casein hydrolysate formula had a long-lasting effect on markers of β-cell autoimmunity (Knip et al. 2010). And the difference in fecal microbiota composition between children with β-cell autoimmunity and those without has been found (de Goffau et al. 2013). Further trial (NCT01735123) is ongoing to investigate whether extensively hydrolyzed casein formula is able to protect children at risk for type 1 diabetes.

Future Directions

Intervention/prevention of β-cell destruction in T1D is the final goal resulting in good metabolic control of blood glucose. Balancing the risks and benefits in intervention/prevention of T1D is very complicated. Individual response to a particular therapy might differ. Biomarkers which can identify individuals who would or would not respond to a particular therapy are the need of the hour. T1D is associated with end-organ complications. The number of adverse events in an individual undergoing a particular therapy might differ from another, depending upon the time and intensity of progress to end-organ complications. Therefore, identification of those at risk becomes important while considering therapy.

Disease diagnosis is another important factor. T1D is usually diagnosed when the existing β-cells fail to meet the insulin needs of the body and thereby insufficient metabolic control. Earlier identification of existing autoimmunity is very crucial.

Research in the past few decades has highlighted many ways in which this can be achieved. Several promising candidates (such as alum-formulated GAD65 and anti-CD3 antibodies) have also reached different stages of clinical trials. Alum-formulated GAD65 was tested in several phase III clinical trials, including a trial in nine countries in Europe apart from Norway and a 4-year follow-up in Sweden (www.diamyd.com). It is interesting to note that although alum-formulated GAD65 and anti-CD3 seem to show similar efficacy the alum-formulated GAD65 product has not been associated with any relevant side effects and moreover it is easy to administer. Considering the complex etiology of the disease, involving several susceptibility factors and immune cells, it is possible that multi-therapy, involving more than one therapeutic agent, may be of advantage. With the increasing insights into the etiology of the disease, more and more targets are being identified for prevention/intervention.

Strategies on Islet Expansion

Nutrient ingestion stimulates the gastrointestinal tract to secrete incretin hormones to enhance glucose-dependent insulin secretion, thereby maintaining glucose homeostasis. The success of several therapies in reversing islet cell autoimmunity has led to the search of agents that enhance β-cell preservation or restoration. The safety of the combined usage of the above strategies was under investigation (NCT00873925, NCT00064714) which might give exciting results in the near future.

Glucagon-like peptide-1 (GLP-1) is a gut hormone secreted from the intestinal L cells. GLP-1 has a very short circulating half-life due to rapid inactivation by the enzyme dipeptidyl peptidase IV (DPP-4). Since GLP-1 has been well identified as an insulin stimulator and glucagon inhibitor, both GLP-1 and DPP-4 inhibitor were widely tested in the treatment for T2D (Mari et al. 2005; Mu et al. 2006; Duttaroy et al. 2011). It was recently found that GLP-1 peptide could not only induce β-cell proliferation and neogenesis but also suppress β-cell apoptosis and delay the onset of T1D in mouse model (Hadjiyanni and Drucker 2007; Zhang et al. 2007; Hadjiyanni et al. 2008; Xue et al. 2010). Meanwhile, clinical trials showed that GLP-1 improve glucose control in T1D patients (Behme et al. 2003). Sitagliptin (a DPP-4 inhibitor) improved glucose control in T1D patients (Ellis et al. 2011). There are several ongoing trials investigating GLP-1 agonist (NCT01722227, NCT01722240 and NCT01879917), DPP-4 inhibitor (NCT00813228, NCT01159847, NCT01099618 and NCT01559025), and the co-application of both GLP-1 agonist and DPP-4 inhibitor (NCT01782261). The effect of GLP-1 in T1D might soon be revealed in the near future.

Islet Regeneration

When the treatment aimed to suppress autoimmunity is developing rapidly, treatment aimed to induce islet/β-cell regeneration is also under way. Currently, there are several stem cell therapies under different stages of investigation. An ongoing trial (NCT00465478) is using autologous bone marrow stem cell transplantation to stimulate islet stem cell regeneration. Similarly, another trial (NCT00703599) using autologous adipose-derived stem cells to stimulate islet stem cell regeneration is also under investigation. The combination of stem cell therapies is also interesting, a current trial (NCT01143168) combining bone marrow mononuclear cells and umbilical cord MSC for treating T1D patients is also ongoing.

Probiotic Approach

Identification of the role of environmental agents (viruses and more recently bacteria) and their potential use as therapeutics throws open a vast range of possibilities. Use of food supplements or even a probiotic yoghurt containing “friendly bacteria” in prevention of autoimmune diabetes has been suggested. The idea seems farfetched but considering the influx of information on the disease etiology, it is not completely impractical; however, such concepts should be approached with extreme caution. In conclusion, therapies aiming at preserving/preventing β-cell function should aim at providing safe, long-term, and clinically relevant improvements over standard insulin therapy.

Promising Therapies

  • Alum-formulated GAD65: Specific modulation of long-lasting immune response to β-cells GAD65

  • Anti-CD3 antibodies: Prevention of β-cell destruction by depletion of T cells

  • Anti-CD20 antibodies: Prevention of β-cell destruction by depletion of B cells

  • DiaPep277: Immunomodulation and shift from Th1 response to a Th2 response

  • Cell/stem cell therapies: Reintroduce immune tolerance and induce islet regeneration

Key Points

  • Therapeutic interventions can be beneficial to individuals identified at risk and to individuals with existing autoimmunity to prevent the damage to residual β-cells.

  • Modern therapies aimed at reducing β-cell autoimmunity should ideally be short-term treatment which can induce long-lasting “tolerance,” but does not debilitate the capacity of the immune system to fight pathogens.

  • Successful intervention using autoantigen-specific therapies like alum-formulated GAD65 is the need of the hour.

  • Combinatorial therapies can be very helpful in β-cell regeneration and arresting aggressive β-cell autoimmunity.

  • The correct timing of immunomodulating therapies could be very important.

  • New approaches such as DNA vaccines can be beneficial, but should be approached with caution.

Cross-References

Generating Pancreatic Endocrine Cells from Pluripotent Stem Cells

Human Islet Autotransplantation

Immunology of β-Cell Destruction

Inflammatory Pathways Linked to β Cell Demise in Diabetes

Islet Encapsulation

Islet Xenotransplantation: Recent Advances and Future Prospects

Stem Cells in Pancreatic Islets

Successes and Disappointments with Clinical Islet Transplantation