564 Specific Bone Marrow Rejection

The immunological mechanisms responsible for the recognition and rejection of allogeneic bone marrow transplants have remained obscure for many years. While it was initially assumed that all transplanted allogeneic tissues are eliminated by the same cell-mediated effector mechanisms, it soon became apparent that the rejection of bone marrow allografts may involve different cellular mechanisms than those responsible for rejection of skin allografts. The key observation was that relatively small numbers of bone marrow cells transplanted into lethally irradiated T cell-deficient nude mice (1) or normal mice (2, 3) are rejected, whereas lethally irradiated beige mice, which lack natural killer (NK) 1 cell activity (4-8), fail to reject marrow grafts (6, 7). This led to the hypothesis that NK cells may be responsible for the rejection of relatively small grafts of allogeneic or semiallogeneic bone marrow by irradiated recipients (9). This hypothesis obtained strong support from our recent demonstration that injection of cloned NK cells into NK-deficient mice restores the ability of these mice to reject bone marrow allografts (7, 10). One observation presents a paradox, however: NK cells exhibit no H-2-specific target cell lysis in vitro (1 1), even though bone marrow graft rejection in vivo is exquisitely H-2 specific. The hemopoietic histocompatibility (Hh) determinants recognized during marrow graft rejection map primarily to the H-2D (12, 13) or H-2K regions (14) of the murine major histocompatibility gene complex (MHC). Therefore, if NK cells are in fact the mediators of bone marrow graft rejection in irradiated mice, the mechanisms by which they perform this specific function must be elucidated. Here we report that the apparent paradox between the finding that NK cells are not H-2 specific in vitro, but cause H-2-specific marrow graft rejection in vivo, can be explained on the basis of the ability of NK cells to lyse targets in an antibody-dependent cell-mediated (ADCC)-type reaction. We show that there is a target-specific natural antibody in responder mice, which, in conjunction with NK cells, causes specific bone marrow graft rejection. This work was supported by grants CA 15581, CA 19334, and CA 37706 from the U. S. Public Health Service and by grant IM-284 from the American Cancer Society. ~ Abbreviations used in this paper: ADCC, antibody-dependent cell-mediated cytotoxicity; Hh, hemopoietic histocompatibility; MHC, major histocompatibility complex; NK, natural killer cells; PBS, phosphate-buffered saline.