Treatment with CD20-specific antibody prevents and reverses autoimmune diabetes in mice
Chang-yun Hu, Daniel Rodriguez-Pinto, Wei Du, Anupama Ahuja, Octavian Henegariu, F. Susan Wong, Mark J. Shlomchik, Li Wen
Chang-yun Hu, Daniel Rodriguez-Pinto, Wei Du, Anupama Ahuja, Octavian Henegariu, F. Susan Wong, Mark J. Shlomchik, Li Wen
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Research Article

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 9

Antigen presentation of antigenic peptides to islet autoantigen-specific T cells.

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Antigen presentation of antigenic peptides to islet autoantigen-specific...
(A) Peritoneal macrophages were harvested from hCD20/NOD mice 1 month after 2H7 or IgG treatment and used as APCs after irradiation in a proliferation assay with BDC2.5 CD4 cells responding to BDC2.5 mimotope or 6426 cloned CD8 T cells responding to 9-mer insulin B chain peptide of amino acid position 15–23 (B15–B23). 3H-thymidine incorporation is presented as Δ cpm (cpm in the presence of antigenic peptide minus cpm in the absence of antigenic peptide). Macrophages from 2H7-treated mice presented peptides poorly to both CD4 and CD8 T cells compared with macrophages from IgG-treated mice (P < 0.005). (B) One month after 2H7 or IgG treatment, splenic CD11c+ DCs of hCD20/NOD mice were used as APCs after irradiation. 6426 CD8 cloned T cells were cultured with irradiated DCs in the presence or absence of 9-mer insulin B chain peptide of amino acid position 15–23 (B15–B23) (at 3 μg/ml) in a 3H-thymidine incorporation proliferation assay. (C) Splenic CD11c+ DCs were purified from hCD20/NOD mice 1 month after 2H7 or IgG treatment and used as APCs after irradiation. Purified splenic BDC2.5 CD4 T cells were cultured with irradiated DCs in the presence or absence of BDC2.5 mimotope. IL-2 production was measured by cytotoxic T lymphocyte line (CTLL) assay in culture supernatants after a 48-hour incubation.