Differential effects of exogenous interleukin-10 on cardiac allograft survival - Inhibition of rejection by recipient pretreatment reflects impaired host accessory cell function

Background, There have been conflicting reports of the influence of exogeno us mammalian interleukin (IL)-10 on immune reactivity. These findings may r eflect the pleiotropic effects of IL-10 on the functions of antigen-present ing cells and immune effector cells. The purpose of this study was to exten d observations of the influence of the cytokine on organ allograft survival and to investigate its effects on the function of accessory and immune eff ector cells in a mouse cardiac transplant model. Methods. C3H (H2(k)) recipients of heterotopic vascularized B10 (H-2(b)) he art allografts were treated with recombinant (r) mouse IL-10 over a wide ra nge of doses (0.2-200 mu g/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-infilt rating cells, and circulating complement-dependent cytotoxic antibody titer s were determined by isotope release assays. Mixed leukocyte reactions were used to determine the influence of IL-10 on the function of antigen-presen ting 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-1 0 (25 mu g/ day; days -3, -2, -1) was also effective, but less. A pre-trans plant or perioperative course of IL-10, however, did not significantly affe ct the immunosuppressive action of tacrolimus given on days 0-6. If given o nly after the transplant, IL-10 either had no effect on graft survival or ( at high dosage) accelerated rejection and prevented the immunosuppressive e ffect of cyclosporine, Pretransplant treatment of graft recipients with IL- 10 reduced splenic anti-donor cytotoxic T lymphocyte activity and the incid ence of graft-infiltrating CD8(+) cells. There was no significant effect on circulating alloantibody titers, MLR assays revealed that preincubation of responder cells, but not stimulator spleen cells with IL-10, inhibited T c ell proliferation, whereas addition of IL-10 after the start of culture mod estly enhanced proliferation, Preincubation of purified T responders with I L-10 showed no inhibitory effect, Conclusion. The modest and opposing effects of exogenous IL-10 on organ all ograft survival are dependent on timing and dosage, Recipient pretreatment prolongs graft survival. This finding, together with the MLR results, sugge st 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.