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 hyporesponsiveness to major histocompatibility complex (MHC) class I-mismatched skin allografts induced by retrovirus-mediated gene transfer of an allogeneic class I gene into syngeneic bone marrow (BM). Using appropriate congenic recombinant mouse strains, we have mapped MHC determinants that are capable of restoring rapid rejection of K-b-bearing skin grafts. 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 restore the rapid rejection of K-b-mismatched skin grafts. These data suggest that third-party alloantigens expressed on skin in association with K-b abrogate hyporesponsiveness by providing T cell help. Consistent with this interpretation, spleen cells from mice reconstituted with K-b-transduced BM were unable to elicit a significant anti-K-b cytotoxic T lymphocyte response in vitro unless interleukin-2 was added to the culture medium. Skin graft survival was also analyzed on B10.AKM mice 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 early after reconstitution, intrathymic deletion of K-b-reactive T cells must have been incomplete. Taken together, these data suggest that prolongation of skin allograft survival in this model is controlled at the level of T cell help.