CRITICAL ROLE OF INTERLEUKIN-2 IN THE DEVELOPMENT OF ACUTE GRAFT-VERSUS-HOST DISEASE

Prior work using the parent-into-F1 model of graft-versus-host disease (GVHD) has shown that production of IL-2 by donor CD4+T cells is an early, initiating event in either acute or stimulatory forms of GVHD. The alm of the present study was to determine whether acute GVHD could be prevented by blocking the effects of IL-2 in vivo during the first 2 weeks of disease. Acute GVHD was induced in B6D2F1 mice by the injection of C57BL/6 spleen cells i.v. Mice were untreated or received either anti-IL-2 mAb (S4B6) or control mAb at the time of GVHD induction and 1 week later. At 2 weeks, untreated or control mAb treated GVHD mice exhibited findings typical of acute GVHD, i.e. (i) in vitro donor anti-host cytotoxic T lymphocyte (CTL) activity, (ii) significant reductions in both numbers and function of splenic lymphocytes, and (iii) in vitro suppressor cell activity which profoundly blocked IL-2 production by normal syngeneic spleen cells. All of these findings were reversed or significantly inhibited in acute GVHD mice receiving anti-IL-2 treatment. Additionally, anti-IL-2 treated GVHD mice exhibited features previously observed in stimulatory GVHD such as: (i) B cell hyperactivity, (ii) a mild defect in CD4+ T cell production of IL-2 in vitro, and (iii) the ability to induce in co-culture a similar CD4+ cell defect in normal, syngeneic F1 spleen cells. B cell hyperactivity, observed in the form of increased B cell expression of MHC class II, increased serum anti-DNA antibody, and increased serum IgG1 and IgE levels, is consistent with the presence of B cell stimulatory cytokines (possibly IL14 and/or IL-10) in vivo. Thus, it appears that IL-2 production plays a critical role in the early development of acute GVHD, most likely by facilitating the development of donor - anti-host CTL. In contrast, production of B cell stimulatory cytokines in this model in much less dependent (if at all) on the presence of IL-2.