Reversal Of Type 1 Diabetes Research Articles

B lymphocytes protect islet β cells in diabetes prone NOD mice treated with imatinib.

Imatinib (Gleevec) reverses type 1 diabetes (T1D) in NOD mice and is currently in clinical trials in individuals with recent-onset disease. While research has demonstrated that imatinib protects islet β cells from the harmful effects of ER stress, the role the immune system plays in its reversal of T1D has been less well understood, and specific cellular immune targets have not been identified. In this study, we demonstrate that B lymphocytes, an immune subset that normally drives diabetes pathology, are unexpectedly required for reversal of hyperglycemia in NOD mice treated with imatinib. In the presence of B lymphocytes, reversal was linked to an increase in serum insulin concentration, but not an increase in islet β cell mass or proliferation. However, improved β cell function was reflected by a partial recovery of MafA transcription factor expression, a sensitive marker of islet β cell stress that is important to adult β cell function. Imatinib treatment was found to increase the antioxidant capacity of B lymphocytes, improving reactive oxygen species (ROS) handling in NOD islets. This study reveals a novel mechanism through which imatinib enables B lymphocytes to orchestrate functional recovery of T1D β cells.

“Alarming" T-Regulatory Cells (Tregs) to Protect from Type 1 Diabetes (T1D)

Defects in IL-2 signaling and Tregs correlate with susceptibility to T1D. Helminth burden also negatively correlates with the incidence of T1D. The alarmin IL-33 and its receptor ST2 are elicited in anti-helminth immunity, which also increase Tregs, M2 macrophages and Th2 response. We hypothesized that IL-33 may cooperate with IL-2 in promoting Tregs to protect from T1D. Indeed, a major subset of Tregs express ST2, thus enabling a role for IL-33 in Treg biology. Non-obese diabetic (NOD) mice, which have less Tregs than the nondiabetic NOD.Idd3 congenic mice, also exhibit less ST2+ Tregs (13±3%) than NOD.Idd3 (38±11%). For better cooperativity and preferential targeting of Tregs, we generated a hybrid cytokine (IL233) bearing IL-2 and IL-33 activities in a single molecule. Recent-hyperglycemia onset NOD mice (n≥6/group) were treated with daily injections (3.3pmol/g) of IL-2 and/or IL-33 or IL233 for 5 days. IL-33 alone offered a similar, if not better reversal of T1D with a 70% cumulative incidence (CI) compared to IL-2 alone (80% CI), whereas IL233 offered the best protection with 50% of mice remaining in remission 10-weeks post-treatment. There was a robust increase in the proportion of Tregs in pancreatic lymph node in IL233 group (25±3.7%) compared to 10±3.9%, 16±4.1%, 14±4.3% and 19±4.3% in Saline, IL-2 only, IL-33 only and IL-2 and IL-33 groups respectively. IL233 treatment also increased the levels of Tregs and group-2 innate lymphoid cells in an alternate species (rats) and blocked high-dose streptozotocin (STZ)-induced beta-cell death. Interestingly, the average islet size was bigger in the rats treated with IL233 in the STZ model, indicating a role of IL233 in islet growth and repair. Thus, IL233 utilizes the synergy of IL-2 and IL-33 to promote Tregs and bears strong therapeutic potential for T1D. Disclosure R. Sharma: None. V. Sabapathy: None.

It’s Time to Bring Dendritic Cell Therapy to Type 1 Diabetes

Type 1 diabetes (T1D) is an autoimmune disease that results from a deficient induction or maintenance of tolerance to islet β-cell antigens, allowing the eventual T-cell–mediated destruction of insulin-producing β-cells within the pancreatic islets (1). Under homeostatic conditions, immune tolerance is established by various subsets of antigen-presenting cells (APCs) with tolerance-inducing/maintaining (tolerogenic) functions and reinforced by other cells with suppressor and immunomodulatory properties. T-cell tolerance manifests itself through elimination (deletion), inactivation (anergy), or suppression of self-reactive T cells (Fig. 1 A ). These functions may be performed by a variety of tolerogenic APCs (Table 1), some of which have the ability to induce/boost regulatory T cells (Tregs) and/or B cells (Bregs). Genetic and environmental factors that vary among different individuals contribute to the development of T1D, in part by impacting mechanisms of tolerance (Fig. 1 B ). Therefore, a major goal for the prevention and/or reversal of T1D is to restore effective and durable tolerance to either prevent further destruction of remaining islet β-cells, help islet β-cell regeneration, or protect islet transplants and obviate the use of nonspecific immunosuppressive drugs. The approach reviewed here consists of developing a personalized therapy using the patient’s own cells manipulated to perform as tolerogenic APCs (Fig. 1 C ). In this review, we will explain why dendritic cells (DCs) are the tolerogenic cells of choice to fulfill the goal of restoring immune tolerance in T1D as part of a potentially powerful and safe cellular immunotherapy, the next generation of therapies (2). We will present the clinical considerations and challenges ahead and the plans to address them, taking into account lessons learned from animal models such as the NOD mouse. Figure 1 Tolerance to β-cell antigens: induction, loss, and restoration. A : Tolerance to β-cell antigens is induced and maintained by tolerogenic cells comprised of migratory DCs transporting antigens from peripheral to lymphoid …

Combination Treatment With Anti-CD20 and Oral Anti-CD3 Prevents and Reverses Autoimmune Diabetes

Type 1 diabetes (T1D) is a T cell–mediated autoimmune disease, although B cells also play an important role in T1D development. Both T cell– and B cell–directed immunotherapies have shown efficacy in the prevention and reversal of T1D. However, whether the combined strategy of targeting both T and B cells could further improve therapeutic efficacy remains to be explored. We show that combined treatment with intravenous antihuman CD20 (hCD20) and oral anti-CD3 significantly delays diabetes development in prediabetic hCD20 transgenic NOD mice. More importantly, the combined treatment reverses diabetes in >60% of mice newly diagnosed with diabetes. Further mechanistic studies demonstrated that the addition of oral anti-CD3 to the B-cell depletion therapy synergistically enhances the suppressive function of regulatory T cells. Of note, the oral anti-CD3 treatment induced a fraction of interleukin (IL)-10–producing CD4 T cells in the small intestine through IL-10– and IL-27–producing dendritic cells. Thus, the findings demonstrate that combining anti-CD20 and oral anti-CD3 is superior to anti-CD20 monotherapy for restoring normoglycemia in diabetic NOD mice, providing important preclinical evidence for the optimization of B cell–directed therapy for T1D.

Combined antibody therapy for type 1 diabetes (107.2)

Abstract Studies have shown that oral tolerance is effective in treating different models of autoimmune diseases including type 1 diabetes (T1D). Both T and B cells play important roles in the development of T1D. Antibodies targeting either T or B cells have shown to be effective in treating T1D in both patients and NOD mice. However, individual antibodies are only effective in a proportion of those treated. Furthermore, the beneficial effects have not been long lasting. To test whether the combination of anti-CD20 and oral anti-CD3 treatment can improve the efficacy in prevention and reversal of T1D and prolong the beneficial effects, we treated a group of human CD20 transgenic NOD mice with anti-hCD20 monoclonal antibody and oral anti-CD3. The results suggested that anti-CD20 and anti-CD3 have synergistic effects in the diabetes prevention and reversal. Mechanistic studies have demonstrated that the combination treatment induced FoxP3+ Tregs and enhanced the regulatory function of Treg. A subset of IL-10+ CD4 T cells was also induced in peyer’s patches of the mice treated with combined therapy. Our preliminary study may provide a novel therapeutic approach to treating T1D.

P039 Cooperativity between bone marrow cells and culture-expanded mesenchymal stem cells during reversal of type-1 diabetes

P039 Cooperativity between bone marrow cells and culture-expanded mesenchymal stem cells during reversal of type-1 diabetes

Limitations in Immunotherapy with CD3 Antibodies: Comment on the Article by Drs. Chatenoud and Bach

Limitations in Immunotherapy with CD3 Antibodies: Comment on the Article by Drs. Chatenoud and Bach