Treatment with CD20-specific antibody prevents and reverses autoimmune diabetes in mice
Chang-yun Hu, … , Mark J. Shlomchik, Li Wen
Chang-yun Hu, … , Mark J. Shlomchik, Li Wen
Published December 3, 2007
Citation Information: J Clin Invest. 2007;117(12):3857-3867. https://doi.org/10.1172/JCI32405.
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Treatment with CD20-specific antibody prevents and reverses autoimmune diabetes in mice

Abstract

The precise roles of B cells in promoting the pathogenesis of type 1 diabetes remain undefined. Here, we demonstrate that B cell depletion in mice can prevent or delay diabetes, reverse diabetes after frank hyperglycemia, and lead to the development of cells that suppress disease. To determine the efficacy and potential mechanism of therapeutic B cell depletion, we generated a transgenic NOD mouse expressing human CD20 (hCD20) on B cells. A single cycle of treatment with an antibody specific for hCD20 temporarily depleted B cells and significantly delayed and/or reduced the onset of diabetes. Furthermore, disease established to the point of clinical hyperglycemia could be reversed in over one-third of diabetic mice. Why B cell depletion is therapeutic for a variety of autoimmune diseases is unclear, although effects on antibodies, cytokines, and antigen presentation to T cells are thought to be important. In B cell–depleted NOD mice, we identified what we believe is a novel mechanism by which B cell depletion may lead to long-term remission through expansion of Tregs and regulatory B cells. Our results demonstrate clinical efficacy even in established disease and identify mechanisms for therapeutic action that will guide design and evaluation of parallel studies in patients.

Authors

Chang-yun Hu, Daniel Rodriguez-Pinto, Wei Du, Anupama Ahuja, Octavian Henegariu, F. Susan Wong, Mark J. Shlomchik, Li Wen

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Figure 7

Adoptive transfer of diabetes.

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Adoptive transfer of diabetes. (A) NOD/SCID mice were injected intraveno...
(A) NOD/SCID mice were injected intravenously with (a) 107 spleen cells from diabetic mice alone (closed circles); (b) 107 spleen cells from diabetic mice cotransferred with spleen cells (107) from nondiabetic IgG-treated mice (open circles); (c) 107 spleen cells from diabetic mice cotransferred with spleen cells (107) from nondiabetic 2H7-treated mice (closed triangles); or (d) spleen cells (107) from nondiabetic 2H7-treated mice alone (open squares). There was a significant delay in the onset of diabetes in the group cotransferred with cells from 2H7-treated mice (P = 0.007). The experiments were performed twice with similar results. Figure 7A shows results of 1 of the 2 experiments. (B). NOD/SCID mice were injected intravenously with (a) 107 spleen cells from diabetic mice alone (filled circles); (b) 107 spleen cells from diabetic mice cotransferred with purified CD4 T cells (3 × 106) from nondiabetic 2H7-treated mice (open triangles); (c) 107 spleen cells from diabetic mice cotransferred with purified splenic B cells (3 × 106) from nondiabetic 2H7-treated mice (open circles); (d) purified CD4 T cells (3 × 106) alone from nondiabetic 2H7-treated mice (closed squares); and (e) purified splenic B cells alone (3 × 106) from nondiabetic 2H7-treated mice (closed triangles). There was a significant delay in the onset of diabetes in the group cotransferred with CD4+ T cells from 2H7-treated mice compared with spleen cells from diabetic mice alone (P = 0.029) and in the group cotransferred with purified splenic B cells compared with spleen cells from diabetic mice alone (P = 0.029). There was no statistical significance between the groups cotransferred with CD4+ T cells or B cells (P = 0.28). The results shown in Figure 7B were from 1 of the 2 sets of experiments.