ALPHA BETA-T CELL RECEPTOR-DIRECTED THERAPY IN RAT CARDIAC ALLOGRAFT RECIPIENTS - TREATMENT PRIOR TO ALLOANTIGEN EXPOSURE PREVENTS SENSITIZATION AND ABROGATES ACCELERATED REJECTION/

An mAb directed to the alpha/beta-heterodimer of the rat T cell recept or was used to prevent rejection of cardiac allografts in sensitized ( accelerated rejection) recipients. Over a wide dose range, alpha/beta- TCR-directed therapy abrogated accelerated rejection at 24-36 hr and e xtended cardiac allograft survival in a dose-dependent fashion, both w hen given after heart transplantation as well as during or before the sensitizing skin transplants (8.9+/-1.0 days, 12.7+/-0.6 days, or 8.7/-1.5 days, respectively). Pretreatment with R73 completely abrogated host sensitization induced by skin grafting. As a result, post-heart t ransplant cyclosporine course (15 mg/kg for 7 day) has led to long-ter m graft acceptance (> 90 days vs. 15.2+/-1.6 days with postoperative C sA therapy alone). Administration of R73 mAb produced incomplete deple tion (CD5(+) cells) and partial modulation (alpha/beta-TCR/CD5 double- positive cells) in the peripheral blood. It suppressed in situ protein expression of many cytokines to background levels, in particular that of IL-2 and IFN-gamma, both when given after as well as before cardia c transplantation. However, only pretransplant mAb application was ass ociated with augmented in situ elaboration of IL-4. alpha/beta-TCR-dir ected therapy induced strong host antiidiotypic and, to a lesser degre e, anti-isotypic antibody responses. Taken together, these results pro vide the rationale for a novel immunosuppressive strategy involving in duction of hyporesponsiveness by alpha/beta-TCR-directed therapy befor e the alloantigenic exposure.