Tolerance Induction and Endogenous Regeneration of Pancreatic β-Cells in Established Autoimmune Diabetes

Abstract

■ AbstractStudies aimed at the understanding of the multifactorial development of autoimmune diabetes have made substantial contributions toward elucidating the molecular mechanisms that open the road to an effective prevention of defective immune responses. Immunomodulatory regimens capable of inducing tolerance are shown to be effective even in the reversal of established autoimmune diabetes in animal models. Experimental trials including the reeducation of autoreactive T cells, depletion of macrophages, dendritic cells, and T cells, as well as the use of monoclonal antibodies, have yielded encouraging results, but have not yet been translated into beneficial clinical outcomes. In addition, we are now seeing an emergence of promising new directions aimed at the induction of islet regeneration by endogenous factors, suggesting that the repair of pancreatic tissue is possible without the need for an engraftment of donor tissue. These recent waves of technological progress have injected new hope for a combined therapy to offer diabetic patients longterm benefits of insulin independence. This article reviews the latest findings on diabetic pathogenesis and discusses promising avenues to tolerance induction and islet regeneration.

Remission induced by autologous hematopoietic stem cell transplantation in one newly diagnosed type 1 diabetes patient with diabetic ketoacidosis: A case report

“…Hematopoietic stem cells may preserve islet b-cell function by stimulating b-cell regeneration, enhancing neovascularization, or promoting the differentiation of progenitor cells into b-cells. [3][4][5] Indeed, increased serum C-peptide levels, accompanied by HbA1c levels below 7.0%, were found in the patient at all time points after transplantation, indicating that AHSCT enhanced endogenous insulin production and improved glycemic metabolism. Because subgroup analysis of the Diabetes Control and Complications Trial (DCCT) demonstrates that serum C-peptide levels are negatively correlated with the probability of developing chronic complications in patients with type 1 diabetes, 6,7 we believed that the patient may have been at a lower risk of developing diabetes-related complications.…”

“…Hematopoietic stem cells may preserve islet β‐cell function by stimulating β‐cell regeneration, enhancing neovascularization, or promoting the differentiation of progenitor cells into β‐cells 3–5 . Indeed, increased serum C‐peptide levels, accompanied by HbA1c levels below 7.0%, were found in the patient at all time points after transplantation, indicating that AHSCT enhanced endogenous insulin production and improved glycemic metabolism.…”

Novel therapy for type 1 diabetes: Autologous hematopoietic stem cell transplantation

“…Previous studies in animal models have proposed mechanisms by which autologous and allogenic HSCT inhibit the progression of type 1 diabetes, including the suggestions that: (i) the myeloablation associated with conditioning regimens may reduce peripheral self-reactive T cells ("immune elimination") and reverse the diabetogenic autoimmune response, thereby halting the process of islet b-cell destruction; 26 (ii) HSCT reconstitutes a new adaptive immune system with a naı¨ve T cell pool, which would not contribute to the pathogenesis of type 1 diabetes in the absence of the environmental triggers; 26 (iii) infusion of HSCs following conditioning may modulate the peripheral immunocompetent cells ("immune resetting") and, when exposed to environmental triggers, such as infections, the reconstituted immunocompetent cells present a more self-tolerant phenotype characterized by increased numbers of CD4 + CD25 + FoxP3 + T cells, 29,30 thereby shifting the balance from immune destruction to immune tolerance by altering cytokine and b-cell antigen-specific humoral responses; 28,31 and (iv) HSCs may preserve islet b-cell function by stimulating b-cell regeneration, enhancing neovascularization, promoting the differentiation of progenitor cells into b-cells, and protecting b-cells against apoptosis. [32][33][34] Notably, although allogenic HSCT is associated with an increased risk of developing GVHD, it still has some advantages over autologous HSCT. The replacement of the diabetic lymphohematopoietic system with cell populations derived from theoretically diabetesresistant donors and the introduction of donor-specific tolerance may reduce the risk of the reoccurrence of autoimmunity.…”