Therapeutic Role Of ICOS Pathway Blockade By MICOSIg Adenovirus In MLD-STZ Induced Type 1 Diabetic Mice

Type 1 diabetes(T1D) is an autoimmune disease resulting from specificdestruction of the insulin-producing βcells of the pancreas which characterized by two stages. In its initial stage, inflammatory cytokines are secreted unpon various stimuli, which induce local lymphocyte infiltration and pancreatitis.Then after breakdown or loss of immunologic self-tolerance, activated CD4~+ and CD8~+ T lymphocytes attack and destroy most pancreatic β cells, eventually leading to insulin secretion defects, hyperglycaemia and diabetes.Studies on T cell activation reveal that optimal activation of T lymphocytes requires costimulatory signal. Immunologic tolerance will be induced when stimulated with antigen in the absence of the costimulatory signal. Without costimulatory molecules, such as CD28,CD40L and CTLA-4, or upon blockage of costimutory signal, T cells can not be effectively activated or proliferate properly. Monoclonal antibody (mAb) against CD40L, which blocks costimulatory signal pathway, has been approved to be used in a clinical trail to prevent graft rejection. These discoveries provide a new way to maintain tolerance induced by self antigen via blocking costimulatory signal and CTL activation. Several independent groups have investigated the effects of CD28 and CD40 pathway on the T1D development. Arreaza, etal. and Balasa, et al. found that insulities and T1D could beprevented by administration of mAbs against CD28 or CD40L on neonatal NOD mice starting at age of 2wk, but not at age of 5-6wk. These results suggest that costimulatory signal through CD28 or CD40L may not be important when the disease becomes clinically overt, there may be other costimulatory signal pathway to maintain T cells cytotoxicity.In recent years, great progresses have been made on costimulatory signal for T cell activation studies. B7-1/B7-2, CD28/CTLA-4 and CD40L/CD40 costimulatory signal pathways have been identified to play a critical role in priming of naive T cell, but are not involved in the CD4~+ and CD8~+ effector T cells function and second response mediated by memory T cells. So at the second stage of T1D, blockage of these signal pathways could not...