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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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 5

Diabetes reversal following 2H7 treatment.

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Diabetes reversal following 2H7 treatment. Diabetic hCD20 mice were trea...
Diabetic hCD20 mice were treated within 6 days of diagnosis with (A) 2H7 or (B) IgG as described in the legend for Figure 3, and their blood glucose was monitored daily. A subtherapeutic dose of insulin was administered, and this was discontinued when the blood glucose level was reduced to less than 250 mg/dl. Seven of the 14 mice treated with 2H7 are represented in A. Five of these mice recovered (3 of which remained euglycemic for more than 120 days and 1 of which was euglycemic for more than 150 days), and 2 mice remained diabetic. Five of the 10 mice treated with IgG are represented in B, none of which recovered from diabetes. The transient reduction in blood glucose seen in some mice was likely to be related to exogenous insulin treatment. The difference between 2H7- and IgG-treated mice was statistically significant (P = 0.03). (C) Three long-term anti-hCD20–treated euglycemic mice in A were challenged with glucose (1.5 mg/g body weight) i.p. Five newly NOD mice used as controls for dysfunctional islet β cells also had an ipGTT performed, and their blood glucose levels before fasting were all above 300 mg/dl. Five young NOD mice were used as controls for normal functional β cells, and their blood glucose levels before fasting were between 93 and 121 mg/dl.