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Reversal of established autoimmune diabetes by restoration of endogenous β cell function
Shinichiro Ryu, … , David A. Schoenfeld, Denise L. Faustman
Shinichiro Ryu, … , David A. Schoenfeld, Denise L. Faustman
Published July 1, 2001
Citation Information: J Clin Invest. 2001;108(1):63-72. https://doi.org/10.1172/JCI12335.
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Article

Reversal of established autoimmune diabetes by restoration of endogenous β cell function

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Abstract

In NOD (nonobese diabetic) mice, a model of autoimmune diabetes, various immunomodulatory interventions prevent progression to diabetes. However, after hyperglycemia is established, such interventions rarely alter the course of disease or allow sustained engraftment of islet transplants. A proteasome defect in lymphoid cells of NOD mice impairs the presentation of self antigens and increases the susceptibility of these cells to TNF-α–induced apoptosis. Here, we examine the hypothesis that induction of TNF-α expression combined with reeducation of newly emerging T cells with self antigens can interrupt autoimmunity. Hyperglycemic NOD mice were treated with CFA to induce TNF-α expression and were exposed to functional complexes of MHC class I molecules and antigenic peptides either by repeated injection of MHC class I matched splenocytes or by transplantation of islets from nonautoimmune donors. Hyperglycemia was controlled in animals injected with splenocytes by administration of insulin or, more effectively, by implantation of encapsulated islets. These interventions reversed the established β cell–directed autoimmunity and restored endogenous pancreatic islet function to such an extent that normoglycemia was maintained in up to 75% of animals after discontinuation of treatment and removal of islet transplants. A therapy aimed at the selective elimination of autoreactive cells and the reeducation of T cells, when combined with control of glycemia, is thus able to effect an apparent cure of established type 1 diabetes in the NOD mouse.J. Clin. Invest.108:63–72 (2001). DOI:10.1172/JCI200112335.

Authors

Shinichiro Ryu, Shohta Kodama, Kazuko Ryu, David A. Schoenfeld, Denise L. Faustman

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Figure 1

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Kaplan-Meier cumulative survival curves (a) as well as blood glucose con...
Kaplan-Meier cumulative survival curves (a) as well as blood glucose concentrations and histology of the pancreata and graft site (b) for diabetic NOD female mice subjected to transplantation of islets from various donor types in the absence or presence of CFA treatment. Treatment groups A–G correspond to those described in Table 1. Blood glucose concentrations were measured at the indicated times after transplantation. The histology of the pancreas and of the islet graft site under the kidney capsule was examined by staining of paraffin-embedded sections with hematoxylin and eosin. Intense lymphocyte invasion of the pancreatic islets is apparent in groups D and E but not in group F. ×400.

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