Toward more selective therapies to block undesired immune responses

Our results provide important evidence that IL-2 receptor bearing cells are required for undesired immune reactions involved in autoimmunity, allograft rejection and nephritogenic processes. Administration of anti-IL-2 receptor monoclonal antibodies prolonged vascularized heart allograft survival across major histocompatibility barrier in mice and rats and renal monkey grafts. Indeed, several grafts survived indefinitely, although the antibody was administered only for the first 10 days post-transplantation. Rejection of the remaining grafts may well reflect inadequate dosage of antibody; dose-response studies have not been performed to date. In addition to preventing rejection, delayed treatment with anti-IL-2R monoclonal antibody was shown to reverse ongoing rejection in other recipients of heart allografts. Such long-term engraftment following cessation of therapy makes it unlikely that anti-IL-2R treatment prolongs graft survival by pharmacologic blockade of the IL-2R. Furthermore, exogenous IL-2 does not diminish the beneficial effects of anti-IL-2R antibody therapy in rodents. Whether or not such prolonged graft survival represents deletion of the responding T cell clones is a subject of current investigation. Results in a delayed-type hypersensitivity model indicate that complement fixation, is required to achieve optimal immunosuppression. Moreover, only anti-receptor antibodies that block IL-2 binding mediate optimal immunosuppression. Passive transfer experiments clearly prove that immediate post-transplant courses of anti-IL-2R monoclonal antibody spares suppressor T cells. In rodent models, delayed type hypersensitivity and lupus and diabetic autoimmunity are prevented by anti-IL-2R treatment. Finally, the availability of monoclonal antibodies directed against the human IL-2R provides an opportunity to extend this principle to clinical transplantation.(ABSTRACT TRUNCATED AT 250 WORDS)