USE OF ANTI-CD3-EPSILON F(AB')(2) FRAGMENTS IN-VIVO TO MODULATE GRAFT-VERSUS-HOST DISEASE WITHOUT LOSS OF GRAFT-VERSUS-LEUKEMIA REACTIVITY AFTER MHC-MATCHED BONE-MARROW TRANSPLANTATION

The use of T cell-specific mAb in vivo for prevention and treatment of graft-vs-host disease (GVHD) and its impact on graft-vs-leukemia (CVL ) reactivity was examined in a murine model of MHC-matched bone marrow transplantation (BMT). F(ab')(2) fragments of a CD3 epsilon-specific mAb were administered to irradiated AKR (H-2(k)) hosts after transplan tation of BM plus spleen cells from B10.BR donors (BMS chimeras). The effects on GVH and GVL reactivity were Ab dose- and schedule-dependent . A short course of mAb (qe2d, days 0 to 8) prevented clinical evidenc e of GVHD and mortality. Anti-CD3 F(ab')(2) mAb reversed clinical symp toms of acute GVHD when delayed up to 18 days post-transplant. Anti-ho st (Mls-1(a))-specific V beta 6(+) cells were absent from the spleens of GVH-negative control mice, but persisted in Ab-treated BMS chimeras despite the absence of GVHD. Leukemic mice given 16.7 mu g of Ab on d ays 0, 2, and 4 survived leukemia-free without developing severe GVHD. A longer course of Ab completely prevented GVHD, but led to leukemia relapse in tumor-bearing hosts, despite engraftment of donor T cells. The GVL effect was quantitatively stronger when Ab was used for GVH th erapy as compared with GVH prevention. Some Ab-treated, GVH-free chime ras relapsed with lymphomas in unusual sites, suggesting that occult t umor cells may persist in nonlymphoid tissues. These experiments demon strate that T cell-specific mAb can be used successfully in vivo to av oid severe GVHD, but that excessive or ill-timed administration of Ab may eliminate GVL reactivity.