Treatment with CD20-specific antibody prevents and reverses autoimmune diabetes in mice.
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.
Section of Endocrinology, Department of Internal Medicine, Yale School of Medicine, New Haven, Connecticut 06520, USA.
Chang-yun
CY
Hu
Daniel
D
Rodriguez-Pinto
Wei
W
Du
Anupama
A
Ahuja
Octavian
O
Henegariu
F Susan
FS
Wong
Mark J
MJ
Shlomchik
Li
L
Wen
D000818:Animals; D000911:Antibodies, Monoclonal / Q000494:pharmacology* / Q000627:therapeutic use; D017951:Antigen Presentation / Q000187:drug effects; D018951:Antigens, CD20 / Q000235:genetics / Q000276:immunology*; D001323:Autoantibodies / Q000276:immunology; D001402:B-Lymphocytes / Q000276:immunology / Q000473:pathology; D016207:Cytokines / Q000276:immunology; D003922:Diabetes Mellitus, Type 1 / Q000188:drug therapy* / Q000235:genetics / Q000276:immunology / Q000473:pathology; D006801:Humans; D006943:Hyperglycemia / Q000188:drug therapy* / Q000235:genetics / Q000276:immunology; D008212:Lymphocyte Depletion; D051379:Mice; D016688:Mice, Inbred NOD; D016513:Mice, SCID; D008822:Mice, Transgenic; D050378:T-Lymphocytes, Regulatory / Q000276:immunology / Q000473:pathology
D000911:Antibodies, Monoclonal; D018951:Antigens, CD20; D001323:Autoantibodies; D016207:Cytokines