Cyclosporin A blocks receptors for HLA-DR antigens on T cells

Abstract

Recent studies have shown that cyclosporin A, an undecapeptide extracted from two species of fungi (Cylindrocarpon lucidum and Tricoderma polysporum), has potent immunosuppressive effects with low myelocytotoxicity¹. In different experimental systems in both animals and humans, cyclosporin A administration decreased antibody production to T cell-dependent antigens, prolonged survival of skin, kidney and heart allografts^1–3, inhibited cytotoxic activity generated in the allogeneic mixed lymphocyte reaction⁴ and abrogated suppressor T-cell activity induced by concanavalin A (ref. 5). However, the mode of action of cyclosporin A and its role in establishing tolerance remains unclear. Continuous proliferation of T cells after stimulation with antigens or mitogens is maintained by growth factors, released by lectin- or antigen-activated T cells^5,6. One of these factors, interleukin 2 (IL-2), supports growth of activated but not of resting T cells^5–6, so that, to achieve a proliferative response a cell population must be ‘activated’ both to produce IL-2 and to become responsive to it. In the autologous mixed lymphocyte reaction (AMLR), purified human T lymphocytes proliferate when co-cultured with autologous B cells and/or macrophages^7,8. Recently, we found that antibodies against either the heavy non-polymorphic chain or the light polymorphic chain of HLA-DR antigens of the stimulator cells, prevented T cells from acquiring responsiveness to IL-2, inhibited the production of the growth factor and abrogated the T-cell proliferative response in AMLR and hapten-labelled autologous cell systems^9,10. These results suggested that the HLA-DR antigens rendered resting T cells sensitive to IL-2 and participated actively in the production of the growth factor. We have now studied the effect of cyclosporin A on the AMLR response, and found that the drug inhibited the proliferative response by blocking the receptors for HLA-DR antigens on T cells.