Interleukin-4 bypass of the immunosuppressive effect mediated by interleukin-2 receptor antibodies.
Numerous studies have demonstrated that the generation of alloreactive effector cells depends on cytokines. Conversely, there is evidence that cytokine metabolism is altered at the clonal level in tolerant chimaeras. This has led to preclinical and clinical studies using antibodies that antagonize interleukin-2 (IL-2), with the hope of achieving immunosuppression and inducing tolerance. Monoclonal antibodies against the alpha-chain (p55) of the human IL-2 receptor are being applied to prevent transplant rejection and graft-versus-host disease in several clinical trials. The antibodies that have been applied clinically so far antagonize the binding of IL-2 to the IL-2 receptor alpha-chain which is part of the high affinity IL-2 receptor, but they do not deplete the receptor-bearing cells. Our study investigates the immunosuppressive effect of monoclonal antibodies against the alpha-chain (p55) and beta-chain (p75). In mixed lymphocyte cultures the p55 antibody causes a reduction in T-cell proliferation to about 50%. The generation of cytotoxic T cells is reduced more effectively (up to 80%). By additional blocking of the IL-2 receptor beta-chain we achieved an additional but still incomplete immunosuppressive effect. Moreover we show that IL-2 receptor-blocked alloreactive T cells escape suppression by using IL-4 as an alternative stimulating signal. To prevent T lymphocytes benefiting from this alternative and thwarting the immunosuppressive effect, cytotoxic IL-2 receptor antibodies that deplete the high affinity receptor-bearing cells are needed.
Steinmann
J
J
Institut für Immunologie, Klinikum der Universität Kiel, Germany.
Herwartz
C
C
Müller-Ruchholtz
W
W
D000906:Antibodies / Q000502:physiology; D002999:Clone Cells / Q000276:immunology; D003602:Cytotoxicity, Immunologic; D006801:Humans; D007108:Immune Tolerance / Q000187:drug effects*; D015847:Interleukin-4 / Q000502:physiology*; D008213:Lymphocyte Activation; D007959:Lymphocyte Culture Test, Mixed; D015375:Receptors, Interleukin-2 / Q000037:antagonists & inhibitors / Q000276:immunology*; D013601:T-Lymphocytes / Q000276:immunology / Q000648:ultrastructure
D000906:Antibodies; D015375:Receptors, Interleukin-2; D015847:Interleukin-4