KINETICS OF TH1 AND TH2 CYTOKINE PRODUCTION DURING THE EARLY COURSE OF ACUTE AND CHRONIC MURINE GRAFT-VERSUS-HOST DISEASE - REGULATORY ROLEOF DONOR CD8(-CELLS() T)

Acute and chronic graft-versus-host disease (GVHD) in the parent-into- F-1 model are mediated by predominantly cellular or humoral immune res ponses, respectively, and are strikingly different entities by 2 wk of disease. Both forms of GVHD, however, evolve from a common starting p oint, i.e., donor CD4(+) T cell recognition of host alloantigen and IL -2 production. Our study examines the first 2 wk of GVHD to delineate the events that critically influence GVHD development. Surprisingly, b oth forms of GVHD are initially characterized by increased Th2 cytokin e (IL-4 and IL-10) production and B cell activation which persists int o wk 2. The earliest distinguishing features of acute GVHD were detect able at days 5 through 7 of disease and consisted of 1) expansion of d onor CD8(+) T cells, and 2) increased IFN-gamma production by donor CD 4(+) and CD8(+) T cells. Interestingly, IFN-gamma production by donor CD4(+) T cells was not seen if donor CD8(+) T cells were not engrafted in comparable numbers. Chronic GVHD in the DBA-into-BDF, model was fo und to be caused by a relative defect in the ability of DBA CD8(+) T c ells to induce acute GVHD and to produce IFN-gamma. These studies demo nstrate that both acute and chronic GVHD begin as a Th2 cytokine-media ted, B cell stimulatory response. The transition to acute GVHD is crit ically dependent on the engraftment of donor CD8(+) T cells, which ter minate B cell hyperactivity by 1) eliminating activated B cells and 2) promoting IFN-gamma secretion by donor CD4(+) T cells.