DIFFERENTIAL-EFFECTS OF THE ABSENCE OF INTERFERON-GAMMA AND IL-4 IN ACUTE GRAFT-VERSUS-HOST DISEASE AFTER ALLOGENEIC BONE-MARROW TRANSPLANTATION IN MICE

Graft-versus-host disease (GVHD), in which immunocompetent donor cells attack the host, remains a major cause of morbidity after allogeneic bone marrow transplantation (BMT), To understand the role of cytokines in the pathobiology of GVHD, we used cytokine knockout (KO) mice as a source of donor T cells. Two different MHC-disparate strain combinati ons were examined: BALB/c (H2(d)) donors into lethally irradiated CS7B L/6 (H2(b)) recipients or C57BL/6 (H2(b)) donors into B10.BR (H2(k)) r ecipients. Donor cells were hom mice in which either the interferon-ga mma (IFN-gamma) or the IL-4 gene was selectively disrupted to understa nd the role of these cytokines in acute GVHD. In both strain combinati ons the same pattern was noted with regard to GVHD onset and morbidity . All mice exhibited the classic signs of acute GVHD: weight loss with skin, gut, and liver pathology resulting in morbidity and mortality. Surprisingly, donor cells obtained from mice lacking IFN-gamma gave ri se to accelerated morbidity from GVHD when compared with cells from wi ld-type control donors. Similar results were obtained using normal don ors when neutralizing antibodies to TFN-gamma were administered immedi ately after the BMT. These results suggest that IFN-gamma plays a role in protection from acute GVHD, In marked contrast, cells obtained fro m IL-4 KO mice resulted in protection from GVHD compared with control donors. Splenocytes from IFN KO mice stimulated with a mitogen prolife rated to a significantly greater extent and produced more IL-2 compare d with splenocytes obtained from IL-4 KO or control mice. Additionally , there was increased IL-2 production in the spleens of mice undergoin g GVHD using IFN-gamma KO donors.