Autoimmune Diabetes and the Circle of Tolerance

Abstract

The concept of immunological tolerance is central to our understanding of type 1 diabetes and the development of strategies for its prediction, prevention, and cure. Tolerance simply refers to the absence of an immune response. Most of us are born with an immune system that develops tolerance to all the other systems of our bodies as well as to the things that we eat. It is the loss of immunological tolerance that leads to autoimmunity. And when that autoimmune response directly or indirectly targets the ␤-cell, type 1 diabetes is the result. In the U.S., 1 in 600 of us loses tolerance to pancreatic ␤-cells. Interference with T-cell function after the loss of tolerance, as can be achieved with immunosuppressive drugs like cyclosporin, arrests the disease, but the cost in side effects is high. Clearly, stopping the loss of tolerance would be preferable. If we can stop the loss of tolerance, we can prevent the disease. We and many others have investigated both approaches. But what of the people who already have diabetes? For them a separate but related strategy, tolerance induction, is required. Specifically, islet transplantation tolerance induction holds out the promise of being able to cure the disease. This has been the ultimate goal of our laboratory's work for the past two decades. Diabetes 53: [267][268][269][270][271][272][273][274][275] 2004

MHC-Mismatched Mixed Chimerism Mediates Thymic Deletion of Cross-Reactive Autoreactive T Cells and Prevents Insulitis in Nonobese Diabetic Mice

“…n autoimmune type 1 diabetes (T1D), improper thymic selection leads to the presence of autoreactive T cells in the periphery that destroy the insulin producing b cells of the pancreas (1)(2)(3). Years of work in the NOD mouse model of T1D has indicated that appearance of the autoreactive clones in the periphery is due to the failure of negative selection in the thymus (4)(5)(6)(7).…”

Autologous Nonmyeloablative Hematopoietic Stem Cell Transplantation in New-Onset Type 1 Diabetes: A Multicenter Analysis

“…T1D is characterized by a selective and aggressive destruction of insulin-producing b-cells orchestrated by autoreactive T cells (2,3). Unfortunately, exogenous insulin therapy does not always achieve the necessary metabolic control (4), nor does it prevent the occurrence of disease-associated degenerative macrovascular and microvascular complications (5) or halt b-cell decline (6).…”

“…Several clinical trials-designed based on the preclinical successful targeting of components of innate and adaptive immune responses-performed thus far have failed to cure T1D (3,8); only in the anti-CD3 monoclonal antibody (mAb) trial (using teplizumab in the Protégé Study) did 5% of individuals become insulin independent (9). In this daunting scenario, a trial conducted by Voltarelli et al (10) succeeded in exploiting hematopoietic stem cells (HSCs) to treat new-onset T1D and achieved encouraging results, paving the way for another three trials, which were initiated worldwide (11,12).…”

Elimination of insulitis and augmentation of islet β cell regeneration via induction of chimerism in overtly diabetic NOD mice

“…hematopoietic cell transplantation ͉ type 1 diabetes ͉ anti-CD3-conditioning ͉ reversal of diabetes ͉ reversal of autoimmunity T ype 1 diabetes is an autoimmune disease resulting from destruction of insulin-secreting ␤ cells by pathogenic T cells (1,2). The nonobese diabetic (NOD) mouse is currently the most widely used animal model of human type 1 diabetes (3).…”