Effect of cyclosporine on immunologically mediated diabetes in nonobese diabetic mice.
Spontaneous diabetes in NOD mice has an immunologically mediated cause and is a T cell-dependent process. When diabetic NOD mice are grafted with cultured BALB/c islet tissue, the islet graft is destroyed by disease recurrence in the graft. Disease recurrence is a CD4 T cell-dependent process as determined by in vivo administration of anti-CD4 or anti-CD8 monoclonal antibody prior to the grafting of islet tissue. Cyclosporine functions in the early sequence of T cell activation by regulating the production of messenger RNA for lymphokines synthesis. Cyclosporine does not inhibit the synthesis of lymphokine once the lymphokine message is present in the cell. Thus, we might expect cyclosporine to be relatively inefficient as an agent for the regulation of disease recurrence following transplantation to actively diabetic recipients, and we would expect cyclosporine to be more effective when administered before the onset of the disease. Low-dose cyclosporine treatment can prevent development of the disease when the drug is administered before the onset of disease. Data presented here show that cyclosporine is ineffective in controlling disease recurrence in the islet graft transplanted to actively diabetic animals. Also, when we eliminate CD4 T cells from the diseased animals and graft islet tissue prior to the administration of cyclosporine, we are unable to maintain a graft with low-dose cyclosporine therapy. This result leads us to conclude that, although anti-CD4 treatment controls the expression of the disease process and allows the survival and function of the islet graft, this treatment does not return diseased animals to the prediabetic condition in which the development of diabetes can be controlled by low-dose cyclosporine therapy.
D000818:Animals; D000911:Antibodies, Monoclonal / Q000627:therapeutic use; D000945:Antigens, Differentiation, T-Lymphocyte / Q000032:analysis; D016827:CD8 Antigens; D002469:Cell Separation; D003524:Cyclosporins / Q000627:therapeutic use*; D003921:Diabetes Mellitus, Experimental / Q000276:immunology / Q000628:therapy*; D003922:Diabetes Mellitus, Type 1 / Q000628:therapy*; D007165:Immunosuppression Therapy; D016381:Islets of Langerhans Transplantation; D051379:Mice; D008817:Mice, Mutant Strains; D012008:Recurrence; D013601:T-Lymphocytes / Q000276:immunology
D000911:Antibodies, Monoclonal; D000945:Antigens, Differentiation, T-Lymphocyte; D016827:CD8 Antigens; D003524:Cyclosporins