title: Long-term remission of diabetes in NOD mice is induced by nondepleting anti-CD4 and anti-CD8 antibodies.
abstract: Residual β-cells found at the time of clinical onset of type 1 diabetes are sufficient to control hyperglycemia if rescued from ongoing autoimmune destruction. The challenge, however, is to develop an immunotherapy that not only selectively suppresses the diabetogenic response and efficiently reverses diabetes, but also establishes long-term β-cell-specific tolerance to maintain remission. In the current study, we show that a short course of nondepleting antibodies (Abs) specific for the CD4 and CD8 coreceptors rapidly reversed clinical disease in recent-onset diabetic NOD mice. Once established, remission was maintained indefinitely and immunity to foreign antigens unimpaired. Induction of remission involved selective T-cell purging of the pancreas and draining pancreatic lymph nodes and upregulation of transforming growth factor (TGF)-β1 by pancreas-resident antigen-presenting cells. Neutralization of TGF-β blocked the induction of remission. In contrast, maintenance of remission was associated with tissue-specific immunoregulatory T cells. These findings demonstrate that the use of nondepleting Ab specific for CD4 and CD8 is a robust approach to establish long-term β-cell-specific T-cell tolerance at the onset of clinical diabetes.
authors: Department of Microbiology and Immunology, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA.
authors: Zuoan
authors: Z
authors: Yi
authors: Ramiro
authors: R
authors: Diz
authors: Aaron J
authors: AJ
authors: Martin
authors: Yves Maurice
authors: YM
authors: Morillon
authors: Douglas E
authors: DE
authors: Kline
authors: Li
authors: L
authors: Li
authors: Bo
authors: B
authors: Wang
authors: Roland
authors: R
authors: Tisch
mesh_terms: D000818:Animals; D000911:Antibodies, Monoclonal / Q000627:therapeutic use*; D015704:CD4 Antigens / Q000737:chemistry* / Q000378:metabolism; D015496:CD4-Positive T-Lymphocytes / Q000187:drug effects / Q000276:immunology / Q000378:metabolism / Q000473:pathology; D016827:CD8 Antigens / Q000737:chemistry* / Q000378:metabolism; D018414:CD8-Positive T-Lymphocytes / Q000187:drug effects / Q000276:immunology / Q000378:metabolism / Q000473:pathology; D003922:Diabetes Mellitus, Type 1 / Q000276:immunology* / Q000378:metabolism / Q000473:pathology / Q000628:therapy*; D005260:Female; D005786:Gene Expression Regulation / Q000187:drug effects; D007108:Immune Tolerance; D007166:Immunosuppressive Agents / Q000627:therapeutic use*; D007167:Immunotherapy; D051379:Mice; D016688:Mice, Inbred NOD; D018345:Mice, Knockout; D016513:Mice, SCID; D008822:Mice, Transgenic; D009928:Organ Specificity; D010179:Pancreas / Q000187:drug effects / Q000276:immunology / Q000378:metabolism / Q000473:pathology; D012333:RNA, Messenger / Q000378:metabolism; D012074:Remission Induction; D053773:Transforming Growth Factor beta1 / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism
chemical_list: D000911:Antibodies, Monoclonal; D015704:CD4 Antigens; D016827:CD8 Antigens; D007166:Immunosuppressive Agents; D012333:RNA, Messenger; C508961:Tgfb1 protein, mouse; D053773:Transforming Growth Factor beta1