Transplantation of Graft Anti-Host Cytotoxic T Lymphocytes Along with Allogeneic Bone Marrow Skips Macrophage-Induced Graft-Versus-Host Disease

Graft-versus-host disease (GVHD) is a physiological response of the graft to allogeneic hosts. However, the effector cells, affected organ(s), and cytokines in the GVHD remain controversially discussed, without having determined a particular cytotoxic activity of the graft against the host. After i.v. injection of C57BL/6 (H-2(b)) spleen cells into irradiated BDF1 (H-2(b/d)) mice, the hosts developed interferon-gamma (IFN-gamma)-dependent bone marrow (BM) GVHD on days 5-17. When H-2D(d)K(d) transgenic H-2(b) lymphoma cells were i.p. inoculated into irradiated, H-2(b) splenocyte-transplanted H-2(b/d) mice, the infiltration of macrophages cytotoxic against H-2D(d)K(d) transgenic H-2(b) mouse skin epithelia (a GVHD activity) into the peritoneal cavity preceded several days the infiltration of interleukin (IL)-2-dependent cytotoxic T lymphocytes (CTLs) to achieve a graft-versus-leukemia (GVL) effect. In contrast, allogeneic BM transplanted alone into the irradiated mice did not induce GVHD for 44 days, whereas i.v. injection of graft anti-host macrophages or graft anti-host CTLs along with allogeneic BM, respectively, induced GVHD or promoted the GVL effect in the absence of GVHD. These results revealed that macrophage-induced GVHD and the CTL-mediated GVL effect were a set (Th1: IFN-gamma/IL-2) response of the graft to allogeneic hosts and leukemia cells, respectively, and that graft T cell activation rather than inhibition skipped GVHD after BM transplantation.