Anti-interleukin 2 receptor monoclonal antibodies spare phenotypically distinct T suppressor cells in vivo and exert synergistic biological effects.

The therapeutic efficacies of ART-18, ART-65, and OX-39, mouse antibodies of IgG1 isotype recognizing distinct epitopes of the p55 beta chain of the rat IL-2-R molecule, were probed in LEW rat recipients of (LEW X BN)F1 heterotopic cardiac allografts (acute rejection in untreated hosts occurs within 8 d). A 10-d course with ART-18 prolongs graft survival to approximately 21 d (p less than 0.001). Therapy with ART-65, but not with OX-39, was effective (graft survival approximately 16 and 8 d, respectively). Anti-IL-2-R mAb treatment selectively spared T cells with donor-specific suppressor functions; the CD8+ (OX8+ W3/25-) fraction from ART-18-modified recipients, and primarily the CD4+ (W3/25+ OX8-) subset from ART-65-treated hosts conferred unresponsiveness to naive syngeneic rats after adoptive transfer, increasing test graft survival to approximately 16 and 45 d, respectively. Concomitant administration of ART-18 and ART-65 to recipient animals in relatively low doses exerted a strikingly synergistic effect, with 30% of the transplants surviving indefinitely and 50% undergoing late rejection over 50 d. These studies provide evidence that anti-IL-2-R mAbs selectively spare phenotypically distinct T cells with suppressor functions. The data also suggest that in vivo targeting of functionally different IL-2-R epitopes may produce synergistic biological effects

Therapy with monoclonal antibody to interleukin 2 receptor spares suppressor T cells and prevents or reverses acute allograft rejection in rats.

The mouse hybridoma ART 18 monoclonal antibody (mAb), which binds to the rat interleukin 2 (IL-2) receptor, was studied for its effect on heterotopic cardiac allograft survival in two histoincompatible inbred rat strain combinations. Treatment with ART 18 mAb for 10 days after transplantation prolonged allograft survival in a dose-dependent fashion up to about 3 weeks (acute rejection normally occurs within 8 days). ART 18 mAb therapy started at 5 days after transplantation the time of major rejection activity) abrogated acute rejection and extended the survival to about 18 days. The dense cellular infiltrate noted histologically in acute rejection had virtually disappeared after ART 18 mAb treatment. Thus, IL-2 receptor-targeted therapy can be successfully used to prevent and/or treat acute rejection. When spleen cells from antibody-treated recipients bearing well-functioning allografts were adoptively transferred to normal untreated rats that received cardiac allografts 24 hr later, the survival of donor-specific, but not third-party, test cardiac allografts was prolonged significantly; this supports the idea that ART 18 mAb induced "sparing" of suppressor T lymphocytes. Combining infusion of ART 18 mAb with exogenous IL-2-rich conditioned medium produced the same effect as if the mAb alone had been administered, suggesting that an excess of IL-2 does not prevent binding of ART 18 mAb to IL-2 receptor-bearing cells in vivo. These results support the important role of the IL-2 receptor-bearing cells in the mechanism of allograft rejection; they may represent an important target for immunosuppression in clinical organ transplantation