Interleukin-10 administration decreases survival in murine recipients of major histocompatibility complex disparate donor bone marrow grafts

Abstract

Studies in mice and humans have indicated that the predominance of interleukin-4 (IL-4)- and IL-10-producing T-helper type 2 (Th2) cells may serve to downregulate acute graft-versus-host disease (GVHD) reactions, whereas IL-2-producing Th1 cells have been implicated in facilitating acute GVHD. We explored the possibility that the in vivo infusion of IL-10 would inhibit acute GVHD induced by fully allogeneic donor grafts. Unexpectedly, IL-10 infusions resulted in a dose- dependent increase in GVHD-induced mortality. The acceleration of lethal GVHD by IL-10 occurred in irradiated recipients of T-cell- depleted bone marrow (BM) plus 5, 15, or 25 x 10(6) splenocytes but did not influence the post-BM transplantation (post-BMT) survival rate of recipients of BM without splenocytes, suggesting that the IL-10 effects were not due to toxicity. Antimurine IL-10-neutralizing monoclonal antibody injections, administered to diminish endogenous IL-10, reduced GVHD-associated mortality and improved the clinical appearance of the recipients. For BM graft rejection studies, IL-10 was infused into sublethally irradiated recipients of anti-Thy 1.2 + C′ T-cell-depleted, fully allogeneic BM grafts. In a short-term (day 7) in vivo assay, IL- 10 infusions significantly inhibited allogeneic (but not syngeneic) BM proliferation in vivo, indicative of increased graft rejection. In long- term chimerism experiments, IL-10 infusions caused a significant increase in early post-BMT mortality caused by a profound anemia typically associated with graft rejection and aplasia. A slightly higher irradiation dose (650 cGy v 600 cGy) eliminated the anemia but did not reverse the graft rejection process associated with IL-10 administration. We conclude that the in vivo infusion of exogenous IL- 10 in recipients of fully allogeneic donor grafts results in accelerated GVHD and graft rejection in the strain combinations tested to date.