Development of suppressor lymphocytes during acute rejection of rat cardiac allografts and preservation of suppression by anti-IL-2-receptor monoclonal antibody.

Suppressor activity was investigated in rats undergoing acute rejection of heterotopic cardiac allografts. Spleen cells were harvested at 7 days from LEW rats rejecting (LEW x BN)F1 heart grafts and fractionated into their T, T suppressor/cytotoxic, and T helper subpopulations. Transfer of alloimmune unseparated spleen cells to syngeneic recipients of (Lew x BN)F1 test grafts accelerated rejection from 8 to 6.5 days (P less than 0.01). Graft survival was prolonged to about 15 days (P less than 0.005) after transfer of the splenic T suppressor/cytotoxic fraction. Treatment of test graft recipients with ART-18, a mouse antirat monoclonal antibody directed against the rat interleukin 2 receptor on the surface of activated lymphocytes, increased graft survival to about 3 weeks (P less than 0.005), and to about 23 days (P less than 0.005) when test graft recipients were treated with ART 18 following transfer of alloimmune unseparated spleen cells. In contrast, ART-18 treatment of test graft recipients already injected with T suppressor/cytotoxic cells had no additive effect. Increased production of endogenous interleukin 2 occurred concomitantly with the onset of rejection in these animals; interleukin 2 release declined during the late stages of rejection when suppressor activity had increased. Similarly, in T-cell-depleted (B) rats, allograft rejection could be produced by immune reconstitution with sensitized lymphocytes, but could be significantly delayed by prior transfer of suppressor cells. These data document the presence of potent suppressor activity in the acutely rejecting host and suggest that the suppressor mechanisms are inhibited less than effector mechanisms by interleukin-2-receptor-targeted therapy.