INTERLEUKIN-10 ADMINISTRATION DECREASES SURVIVAL IN MURINE RECIPIENTSOF MAJOR HISTOCOMPATIBILITY COMPLEX DISPARATE DONOR BONE-MARROW GRAFTS

Studies in mice and humans have indicated that the predominance of int erleukin-4 (IL-4)- and IL-10-producing T-helper type 2 (Th2) cells may serve to downregulate acute graft-versus-host disease (GVHD) reaction s, whereas IL-2-producing Th1 cells have been implicated in facilitati ng acute GVHD. We explored the possibility that the in vivo infusion o f IL-10 would inhibit acute GVHD induced by fully allogeneic donor gra fts. Unexpectedly, IL-10 infusions resulted in a dose-dependent increa se 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 withou t splenocytes, suggesting that the IL-10 effects were not due to toxic ity. Antimurine IL-10-neutralizing monoclonal antibody injections, adm inistered to diminish endogenous IL-10, reduced GVHD-associated mortal ity and improved the clinical appearance of the recipients. For BM gra ft rejection studies, IL-10 was infused into sublethally irradiated re cipients of anti-Thy 1.2 + C' T-cell-depleted, fully allogeneic BM gra fts. In a short-term (day 7) in vivo assay. IL-10 infusions significan tly inhibited allogeneic (but not syngeneic) BM proliferation in vivo, indicative of increased graft rejection. In long-term chimerism exper iments, IL-10 infusions caused a significant increase in early post-BM T mortality caused by a profound anemia typically associated with graf t rejection and aplasia. A slightly higher irradiation dose (650 cGy v 600 cGy) eliminated the anemia but did not reverse the graft rejectio n process associated with IL-10 administration. We conclude that the i n vivo infusion of exogenous IL-10 in recipients of fully allogeneic d onor grafts results in accelerated GVHD and graft rejection in the str ain combinations tested to date. (C) 1995 by The American Society of H ematology.