Reversal Of New-onset Autoimmune Diabetes By A Short-time And Low-dose Treatment With Anti-CD3 Monoclonal Antibodies

Type 1 diabetes is an autoimmune disease characterized by immune disorder resulting in progressive destruction of pancreaticβcells and hyperglycemia. Many research have shown that autoreactive T cells play a critical role in the pathogenesis of diabetes. Influenced by many factors including genetics and infection, loss of tolerance to islet autoantigens leads to mass expansion of autoreactive T cells and infiltration of lymphoid mononuclear cells into islets, thereby destroying islets and the onset of type 1 diabetes. Therefore, manipulating autoreactive T cells unable to attack and destroy self islets, elucidating involving elements (cytokines, immune cells, etc) and mechanisms maybe become new regimens for treating type 1 diabetes.CD3 is a specific marker in T cell development and differentiation, whose expression is seen in all of T cell subsets including CD4~+, CD8~+, CTL, Th1, Th2, Th3, Th0, Treg and NKT cells. CD3 and T cell receptor constitute TCR/CD3 complex, and CD3 is required for transduction of Extracellular signals into T cells when TCRs interact with antigen-bearing MHC molecules. Due to intimate involvement of T lymphocytes in type 1 diabetes development, it is reasonable to apply monoclonal antibody to CD3 into the treatment of diabetes by regulating immune networks including immune cell populations, cytokines and targeted genes, retard diabetes development and acquire permanent normoglycemia, in an animal model of type 1 diabetes.In this study, we report that short-phase and low-dose administration of anti-CD3 or CD3F(ab')2 antibodies efficiently converted new-onset diabetic nonobese diabetic mice into normoglycemia and improved islet morphology, this therapeutic effect lasting over seven month. A serial in vitro and in vivo experiments revealed that the efficacy of anti-CD3 mAb was attributed not to immunosuppression following T cell depletion, but to the induction and re-establishment of tolerance to pancreaticβcells. The studies on cytokines alteration showed that anti-CD3 treatment induced Th2 deviation and the development of anti-inflammatory cytokine, marked by up-regulation of transforming growth factor (TGF)-βand heightened ratio of IL-4/IFN-γ. The further study revealed that a population of immunoregulatory lymphocytes, namely NKT cells, play an important role in the induction and maintenance of immune tolerance after anti-CD3 treatment.In summary, our data identify the efficacy of anti-CD3 mAb on the treatment of new-onset diabetes and responsible immunoregulatory pathway, which is helpful for the application of anti-CD3 mAb in the clinic in the future.