INTERLEUKIN-10 DOSE-DEPENDENT REGULATION OF CD4(-CELL-MEDIATED GRAFT-VERSUS-HOST DISEASE() AND CD8(+) T)

Background. Endogenous interleukin (IL)-10 production has been associa ted with the lack of graft-versus-host disease (GVHD) in human recipie nts of MHC-disparate donor grafts. Paradoxically, we have shown that t he exogenous administration of high doses (80 mu g/dose) of IL-10 to m urine recipients of MHC-disparate grafts accelerates GVHD lethality. M ethods. The effects of IL-10 on GVHD mediated by either CD4(+) or CD8( +) T cells was examined in studies involving exogenous IL-IO administr ation or the infusion of T cells from IL-10-deficient (-/-) donor mice . The role of interferon (IFN)-gamma on IL-10-induced GVHD acceleratio n was studied using IFN-gamma-deficient (-/-) donor mice or neutralizi ng monoclonal antibody. Results. IL-10 was found to have a dose-depend ent effect on the GVHD lethality mediated by either CD4(+) or CD8(+) T cells. High doses of exogenous IL-10 accelerated GVHD lethality. IFN- gamma release was not responsible for the IL-10 facilitation of GVHD l ethality, Paradoxically, low doses of IL-10 protected mice against GVH D lethality. The GVHD protective effect of the bioavailability of smal l amounts of IL-10 was confirmed by demonstrating that the infusion of T cells from IL-10 -/- donors accelerated GVHD lethality. Conclusions . The results suggest that IL-10 has a dose-dependent effect on the GV HD lethality mediated by CD4(+) or CD8(+) T cells, such that high dose s accelerate lethality, while low amounts of bioavailable IL-10 are pr otective.