ALLOSPECIFIC CD8(-VERSUS-LEUKEMIA EFFECT AND GRAFT-VERSUS-HOST DISEASE() TC1 AND TC2 POPULATIONS IN GRAFT)

Allogeneic CD8(+) T cells mediate both a graft-vs-leukemic (GVL) effec t and graft-vs-host disease (GVHD). To evaluate whether CD8 cells of d efined cytokine phenotype differentially mediate these processes, allo reactive donor CD8(+) T cells preferentially secreting type I or type II cytokines were generated by alloantigenic priming in vitro in the p resence of IL-12 or IL-4, respectively. Both cytokine-secreting subset s lysed allogeneic tumor targets in vitro (''Tc1'' and ''Tc2'' subsets ). A transplantation model was established (B6 into B6C3F(nu) 1050 cGy host irradiation) using the 32Dp210 myeloid line (bcr/abl transfected , H-2(k); 1 x 10(4) tumor cells/recipient). Compared with leukemia con trols (death at 12.9 days post-bone marrow transplantation), both Tc1 and Tc2 recipients were conferred a survival advantage. At cell doses of 2 to 2.5 x 10(7), the Tc1-mediated GVL effect (mean survival of 34. 2 days) was more potent than the Tc2-mediated GVL effect (mean surviva l of 20.5 days; Tc1 > Tc2, p = 0.009). On day 15, histologic examinati on showed that Tc1 recipients had undetectable tumor burdens, whereas Tc2 recipients had extensive leukemic infiltrates. However, Tc2 recipi ents had essentially no histologic evidence of GVHD, whereas Tc1 recip ients had mild to moderate GVHD (average GVHD scores of 1/40 and 9.3/4 0, respectively). In contrast, recipients of uncultured CD8(+) donor T cells developed severe GVHD (average GVHD score of 26.7/40). Because in vitro-generated, alloreactive Tc1 and Tc2 populations mediated GVL with reduced GVHD, we conclude that both subsets may improve the thera peutic outcome of allogeneic T cell transfers in patients with leukemi a.