Interleukin-10 administration decreases survival in murine recipients of major histocompatibility complex disparate donor bone marrow grafts.
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.
Department of Pediatrics, University of Minnesota Hospital and Clinic, Minneapolis.
B R
BR
Blazar
P A
PA
Taylor
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S
Smith
D A
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Vallera
D000818:Animals; D000911:Antibodies, Monoclonal; D016026:Bone Marrow Transplantation / Q000276:immunology*; D004906:Erythrocyte Count; D005455:Fluorescent Antibody Technique; D006085:Graft Survival / Q000187:drug effects / Q000276:immunology*; D006086:Graft vs Host Disease / Q000276:immunology*; D006183:H-2 Antigens / Q000032:analysis; D006400:Hematocrit; D006650:Histocompatibility Testing; D006801:Humans; D007165:Immunosuppression Therapy; D016753:Interleukin-10 / Q000494:pharmacology*; D008285:Major Histocompatibility Complex; D051379:Mice; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D008815:Mice, Inbred Strains; D011336:Probability; D013154:Spleen / Q000276:immunology; D013601:T-Lymphocytes / Q000276:immunology; D014184:Transplantation, Homologous; D014185:Transplantation, Isogeneic; D014916:Whole-Body Irradiation
D000911:Antibodies, Monoclonal; D006183:H-2 Antigens; D016753:Interleukin-10