Immunomodulation of experimental allergic encephalomyelitis by antibodies to the antigen–Ia complex

Abstract

AUTOIMMUNE diseases occur when T lymphocytes become activated on recognizing self antigen linked to the autologous class II molecule of the major histocompatibility complex (MHC)^1,2. The resulting complex of antigen MHC T-cell receptor could be a target for treatment of autoimmune diseases. Studies in which each component is blocked separately^3–10 might be limited by interference in non-relevant immune responses that either use the same set of T-cell-receptor V gene segments or are linked to the same MHC. We report here an attack by a specific antibody on the unique antigenic site formed by the binding of two components of the trimolecular complex, the autoantigen bound to the self MHC^11–14. We tested its effect in experimental allergic encephalomyelitis, an acute neurological autoimmune disease which is widely regarded as a model for autoimmune disorders^15–17 and which is mediated by CD4⁺ T cells recognizing myelin basic protein (BP), or its peptides, in association with self Ia^18,19. We made monoclonal antibodies which bound only the complex of BP and I–A^s. These antibodies blocked the proliferative response in vitro to the encephalitogenic determinant of BP and reduced the response to intact BP, without affecting the response to a nonrelevant antigen–purified protein derivative of tuberculin presented on syngeneic macrophages. They also inhibited experimental allergic encephalomyelitis in H–2^s mice. Hence, antibodies directed specifically to the autoantigen–Ia complex, may offer a highly selective and effective treatment in autoimmune diseases.