Paradoxical effects of interleukin-18 on the severity of acute graft-versus-host disease mediated by CD4+ and CD8+ T-cell subsets after experimental allogeneic bone marrow transplantation

Administration of exogenous interleukin-18 (IL-18) regulates experimental acute graft-versus-host disease (GVHD) in a Fas-dependent manner when donor CD4+ T cells are required for mortality after experimental allogeneic bone marrow transplantation (BMT). However, CD4+ and CD8+ T cells can induce acute GVHD after clinical allogeneic BMT, and the role of IL-18 in CD8+-mediated acute GVHD is unknown. We, therefore, determined the role of IL-18 in GVHD mediated by CD4+ or CD8+ T cells across major histocompatibility complex (MHC) class II- and class I-disparate allogeneic BMT, respectively. Administering IL-18 significantly increased survival in CD4+-mediated GVHD but reduced survival in CD8+-mediated GVHD. This increase in deaths was associated with significantly greater clinical, biochemical, and histopathologic parameters of GVHD damage and was independent of Fas expression on donor T cells. Administering IL-18 significantly enhanced allospecific cytotoxic function and expansion of CD8+ cells. Endogenous IL-18 was critical to GVHD mediated by CD8+ donor T cells because IL-18 receptor-deficient donors caused significantly less GVHD but exacerbated CD4+-mediated, GVHD-related death. Furthermore, administering anti-IL-18 monoclonal antibody significantly reduced CD8+-mediated, GVHD-related death. Together these findings demonstrate that IL-18 has paradoxical effects on CD4+ and CD8+ cell-mediated GVHD. (Blood. 2004;104:3393-3399)