THE MECHANISM OF SPECIFIC PROLONGATION OF CLASS I-MISMATCHED SKIN-GRAFTS INDUCED BY RETROVIRAL GENE-THERAPY

In the present study, we examine the mechanism of specific hyporespons iveness to major histocompatibility complex (MHC) class I-mismatched s kin allografts induced by retrovirus-mediated gene transfer of an allo geneic class I gene into syngeneic bone marrow (BM). Using appropriate congenic recombinant mouse strains, we have mapped MHC determinants t hat are capable of restoring rapid rejection of K-b-bearing skin graft s. Our results indicate that either a single class I or a single class II alloantigen expressed on skin in association with K-b is able to r estore the rapid rejection of K-b-mismatched skin grafts. These data s uggest that third-party alloantigens expressed on skin in association with K-b abrogate hyporesponsiveness by providing T cell help. Consist ent with this interpretation, spleen cells from mice reconstituted wit h K-b-transduced BM were unable to elicit a significant anti-K-b cytot oxic T lymphocyte response in vitro unless interleukin-2 was added to the culture medium. Skin graft survival was also analyzed on B10.AKM m ice thymectomized 3-4 weeks post-reconstitution with K-b-transduced BM . Thymectomy did not result in significantly prolonged survival of B10 .MBR skin grafts compared to euthymic controls, suggesting that even e arly after reconstitution, intrathymic deletion of K-b-reactive T cell s must have been incomplete. Taken together, these data suggest that p rolongation of skin allograft survival in this model is controlled at the level of T cell help.