DIFFERENTIAL EFFECTS OF EXOGENOUS INTERLEUKIN-10 ON CARDIAC ALLOGRAFT SURVIVAL1,2

Abstract

Background. There have been conflicting reports of the influence of exogenous mammalian interleukin (IL)-10 on immune reactivity. These findings may reflect the pleiotropic effects of IL-10 on the functions of antigen-presenting cells and immune effector cells. The purpose of this study was to extend observations of the influence of the cytokine on organ allograft survival and to investigate its effects on the function of accessory and immune effector cells in a mouse cardiac transplant model. Methods. C3H (H2^k) recipients of heterotopic vascularized B10 (H-2^b) heart allografts were treated with recombinant (r) mouse IL-10 over a wide range of doses (0.2-200 μg/day), either before the transplant (days −3, −2, −1), peri-operatively (days −1, 0, 1), or after the transplant (days 0-6). Anti-donor cytotoxic T lymphocyte activity of host spleen and graft-infiltrating cells, and circulating complement-dependent cytotoxic antibody titers were determined by isotope release assays. Mixed leukocyte reactions were used to determine the influence of IL-10 on the function of antigen-presenting cells and allogeneic responder T cells. Results. Recipient pre-transplant administration of IL-10 (days −3, −2, −1) prolonged graft survival at all doses tested. Donor pretreatment with IL-10 (25 μg/day; days −3, −2, −1) was also effective, but less. A pre-transplant or perioperative course of IL-10, however, did not significantly affect the immunosuppressive action of tacrolimus given on days 0-6. If given only after the transplant, IL-10 either had no effect on graft survival or (at high dosage) accelerated rejection and prevented the immunosuppressive effect of cyclosporine. Pretransplant treatment of graft recipients with IL-10 reduced splenic anti-donor cytotoxic T lymphocyte activity and the incidence of graft-infiltrating CD8⁺ cells. There was no significant effect on circulating alloantibody titers. MLR assays revealed that pre-incubation of responder cells, but not stimulator spleen cells with IL-10, inhibited T cell proliferation, whereas addition of IL-10 after the start of culture modestly enhanced proliferation. Preincubation of purified T responders with IL-10 showed no inhibitory effect. Conclusion. The modest and opposing effects of exogenous IL-10 on organ allograft survival are dependent on timing and dosage. Recipient pretreatment prolongs graft survival. This finding, together with the MLR results, suggest that IL-10 inhibits the function of host immune accessory cells and that the direct pathway of alloantigen presentation may be less susceptible to inhibition by IL-10.