The effect of the immunosuppressive drug 15-deoxyspergualin (DSG) on xenogeneic human anti-porcine cellular reactivity in vitro, including MLR induced proliferation, interleukin-2 (Il-2) production, generation of cytotoxic cells, and the effect on antibody-dependent cellular cytotoxicity (ADCC), were compared with the effects of cyclosporin A (CsA) and/or FK506. The cytotoxic response was evaluated for both direct and indirect pathways for antigen presentation. In addition, the effects of DSG and CsA on antibody production to pig peripheral blood lymphocytes (PBL) in mice was studied. The degree of immunosuppression of xenogeneic and allogeneic cellular responses was compared. CsA and FK506 effectively inhibited proliferation and Il-2 production induced by allogeneic human PBL or xenogeneic porcine PBL, whereas DSG did not have any effect on these responses. However, DSG suppressed both the allogeneic and xenogeneic in vitro induced cytotoxic responses, to the same level whether induced via the direct or indirect pathways of immune activation. In contrast, CsA inhibited cytotoxicity induced by xenogeneic cells via the direct but not via the indirect pathway. No effect of FK506 and DSG on ADCC was demonstrated. A 5-day treatment with DSG or CsA of mice immunized with pig PBL partly suppressed antibody production. In DSG treated mice anti-pig PBL antibodies were produced, but titers were lower than in nontreated or CsA treated mice. The results indicate that DSG may be more effective than CsA/FK506 in inhibiting cytotoxic responses and antibody production induced by xenogeneic pig cells. A possible explanation could be that cytotoxicity induced via the indirect activation pathway of xenoreactivity is mediated to a high degree by CD3(-)CD16(+) (natural killer) NK-like cells, and that stimulation of these cells may be more sensitive to DSG than to CsA/FK506.
