Toward more selective therapies to block undesired immune responses

Abstract

Although vigorous immune responses are required to preserve a healthy state, a plethora of undesired immune reactions can also occur, such as systemic autoimmunity, allograft rejection and nephritogenic processes. T cells are the dominant cell type present in many of these unwanted reactions and are responsible for tissue damage. For example, in insulin dependent diabetes mellitus (IDDM) both CD4+ and CD8+ lymphocytes infiltrate the islets and trigger immunologically-mediated beta cell destruction. Studies in animal models and human disease indicate that insulitis requires intact T cell dependent immune function. Splenic T cells obtained from diabetic NOD mice can transfer diabetes to younger non-diabetic NOD mice. Both CD4+ T cells are required to transfer the diabetic state from diabetic hosts to young syngeneic animals. Treatment of experimental animals with anti-T cell antibodies, anti-CD4 monoclonal antibodies, anti-IL2 receptor monoclonal antibodies, neonatal thymectomy, total lymphoid irradiation or cyclosporine can all prevent progressive beta cell loss. Many of the undesirable immune reactions characteristic of IDDM can also be identified in the tissues and inflammatory sites of other autoimmune diseases during allograft rejection and in nephritogenic states. Thus, it is not surprising that therapeutic strategies directed toward eliminating or blocking T cell functions in experimental diabetes also abort many undesired immune reactions in a variety of nephritogenic processes.