THE ROLE OF HOST T-CELL SUBSETS IN BONE-MARROW REJECTION DIRECTED TO ISOLATED MAJOR HISTOCOMPATIBILITY COMPLEX CLASS-I VERSUS CLASS-II DIFFERENCES OF BM1 AND BM12 MUTANT MICE

An expanded pool of unrelated donors (URD) is now being utilized for c linical allogeneic bone marrow transplantation. Because URD transplant s can involve a mismatch at least at one genotypic MHC locus, we devel oped a C57BL/6 congenic mouse model to better understand graft rejecti on based exclusively on MHC class I or class II disparities. T cell-de pleted (TCD) BM from class II-disparate mutant bm12 mice was transplan ted into irradiated C57BL/6-Ly5.2 congenic hosts. These mice express a different allelic form of the Ly5 (CD45) marker than bm12 and thus pe rmit definitive typing of reconstituted mice by flow cytometry. Periph eral blood typing indicated that host-mediated graft rejection was res tricted to class II-reactive CD4(+) cells since an anti-CD4 monoclonal antibody significantly inhibited rejection by enhancing the level of mean donor cell engraftment from 13% to 53%. The administration of ant i-CD8 had no inhibitory effect on the ability of the recipient to reje ct the donor graft. Hematologic reconstitution studies revealed that t here was a direct relationship between the level of donor cell, engraf tment and the extent of lymphoid, myeloid, and erythroid recovery. Mic e that did not engraft had sustained reductions in in hematologic reco very. In other studies, TCD BM from bm1 mice mutated only in the MHC c lass I region was rejected by C57BL/6-Ly5.2 recipients. Anti-CD8 mAb i n fusion prevented the class I response resulting in an increase in th e level of mean donor cell engraftment from 1% to 78%. Anti-CD4 alone had no effect, A CD4/CD8 T cell interaction could be important since t he combination of anti-CD4 and anti-CD8 mAb resulted in significantly better donor engraftment than with the individual antibodies. Since th e role of NK cells in these models has not been previously established and there is a reported association between NK cells and the rejectio n of BM cells that lack the expression of self-MHC antigens, we tested the role of NK cells. The elimination of NK cells using anti-NK mAb h ad no ef feet on graft rejection in either the bm1 or bm12 model. In a ddition to their value in exploring mechanisms of graft rejection, the se models may prove useful for evaluating the efficacy of anti-BM reje ction agents exclusively against class I- or class II-restricted dispa rities.