LYMPHOCYTE FUNCTION IN PATIENTS TREATED WITH MONOCLONAL ANTI-T3 ANTIBODY FOR ACUTE CADAVERIC RENAL-ALLOGRAFT REJECTION

A multicenter trial was conducted testing the efficacy of a murine monoclonal antihuman peripheral T lymphocyte antibody (OKT3; PAN) as immunosuppressive therapy for the treatment of acute cadaveric renal allograft rejection. Although clinical data indicate that administration of this antibody clears the circulating lymphocyte pool of T3-positive cells, some in vitro studies have called into question whether the antibody is indeed lymphocytotoxic. Other in vitro data suggest that the antibody is a potent mitogen. To address these problems and investigate the effect of the antibody on T cell function, spontaneous blastogenesis, response to the lectins phytohemagglutinin (PHA) and concanavalin A (Con A) and response to donor-specific and non-donor-specific alloantigen were assessed in a 1-way MLC [mixed lymphocyte culture] in 9 patients treated with anti-T3 for acute rejection and 9 steroid-treated controls. Patient cells were harvested with standard techniques and studied after transplantation, but prior to acute rejection, on days 3 and 12 of therapy and 1 wk after cessation of therapy. All patients received baseline immunosuppression with azathioprine and steroids. Acute rejection was reversed with .alpha.T3 antibody (5 mg i.v./day-1 .times. 14 days) in 8 of 9 patients and in 6 of 9 steroid-treated controls. Spontaneous blastogenesis was not enhanced by anti-T3 nor did it rise during therapy. PHA and Con A responsiveness were dramatically and significantly depressed by therapy with anti-T3 or steroids on days 3 and 12. Although PHA responsiveness rebounded past baseline 1 wk after monoclonal therapy, it was depressed compared with the steroid-treated patients. Con A responsiveness was still significantly depressed 1 wk after monoclonal therapy compared with preejection values or with controls. Response to donor-specific and to non-donor-specific alloantigen was significantly depressed with anti-T3 therapy compared with steroid controls, and it did not rise during therapy. Donor-specific response tended to be slower in returning to pretreatment values in the OKT3 patients compared with steroid controls. Anti-T3 antibody did not enhance spontaneous blastogenesis in patients treated for acute rejection. Con A and PHA responses were dramatically depressed by anti-T3 therapy and returned to baseline following different time courses. Non-donor-specific alloresponse and, more important, donor-specific alloresponse, was more depressed, and for longer periods, by anti-T3 than by conventional steroid anti-rejection therapy. The clinical efficacy of anti-T3 antibody therapy in acute rejection may be mediated by depletion from the circulation of lymphocyte subsets responsive to PHA and Con A and to donor-specific and non-donor-specific alloantigen.