EFFECT OF CYCLOSPORINE ON T LYMPHOCYTE DEVELOPMENT: RELATIONSHIP TO SYNGENEIC GRAFT-VERSUS-HOST DISEASE

Abstract

This report investigates the effects of cyclosporine on the reconstitution of T lymphocytes after syngeneic bone marrow transplantation and its role in the development of a novel T cell-mediated autoimmune disease, syngeneic graft versus host disease. We analyzed the effect of CsA treatment on T lymphocyte differentiation during reconstitution after bone marrow transplantation and correlated the maturation of CD4⁺ and CDB⁺ T cell subsets with the onset of syngeneic GVHD. Administration of CsA following syngeneic bone marrow transplantation leads to a developmental arrest of mature CD4⁺ and CDB⁺ T lymphocytes in the thymus and a marked reduction in cells expressing the α,β T cell receptor. The reduction of CD4+ and CDS⁺ T cell subsets is also reflected in the peripheral lymphoid compartment with an altered CD4/CDS ratio. Functional assessment of the cells revealed that CDB⁺ cells respond normally to mitogenic signalling whereas CD4⁺ cells exhibit marginal proliferative responses. Both subsets of T lymphocytes respond to syngeneic B lymphoblasts, comparable to the response of T lymphocytes from non–CsA-treated syngeneic BMT recipients, suggesting that autoreactive cells are produced despite CsA treatment. Following discontinuation of CsA, T cell differentiation in the thymus is rapidly restored to normal. However, concurrent with the onset of syngeneic GVHD, a compensatory insurgence of CD4⁺ T helper cells is observed.