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.
View: Text | PDF
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

×

Figure 8

2H7-treated hCD20 mice have increased CD4 T cells expressing regulatory markers.

Options: View larger image (or click on image) Download as PowerPoint
2H7-treated hCD20 mice have increased CD4 T cells expressing regulatory ...
(A) Splenocytes from hCD20 mice, treated at 9 weeks of age with 2H7 or IgG, were stained with anti-CD4, anti-CD25, and anti-Foxp3 antibodies. A representative flow cytometric plot is illustrated, and percentages shown in the gate represent the Foxp3+CD25+ cells as a percentage of total CD4 T cells. The graph in the middle is a summary of the values obtained from a number of mice. The graph on the right is a summary of the absolute number of CD4+CD25+FoxP3+ T cells. (B). Splenocytes from hCD20 mice, treated at 9 weeks of age with 2H7 or IgG, were stained with anti-CD4 and CTLA4. The percentages shown in the gate represent the CTLA4+ cells as a percentage of total CD4 T cells. The graph in the middle illustrates the values obtained from a number of mice. The graph on the right is a summary of the absolute number of CD4+CTLA4+ T cells.