GENETICALLY-ENGINEERED GRAFTS TO STUDY XENOIMMUNITY - A ROLE FOR INDIRECT ANTIGEN PRESENTATION IN THE DESTRUCTION OF MAJOR HISTOCOMPATIBILITY COMPLEX ANTIGEN DEFICIENT XENOGRAFTS

Background. The genetic engineering of xenogeneic donor species for tr ansplantation may provide a means of attenuating the potent immune res ponse elicited by tissues from foreign species. Because of their well- established role in allograft rejection, a logical target for genetic manipulation is the genes encoded by the major histocompatibility comp lex (MHC), In the current study we examined whether skin, heart, or pa ncreatic islet xenografts harvested from lines of transgenic mice rend ered deficient in MHC antigen expression by gene disruption would exhi bit a survival benefit when transplanted to xenogeneic rat recipients. In addition, we characterized the in vitro response of rat T cells to normal and MHC-deficient mouse cells. Methods. Skin, heart, and pancr eatic islet grafts were harvested from control C57Bl/6 and each of thr ee lines of mice deficient in MHC antigen expression. MHC-deficient li nes included (7) mice selectively Inciting MHC class I antigens (CID), produced by disruption of the beta-2 microglobulin gene; (2) mice lac king MHC class II expression (CIID), produced by targeting the I-A bet a-chain gene; and (3) mice devoid of both class I and class II molecul es (CI,IID). Results. In contrast to the prolonged survival that has b een observed for certain allografts deficient in MHC antigen expressio n, we did not detect significant extension of survival in the case of xenografts. Using in vitro assays of T-cell function, we demonstrated that rats that rejected grafts lacking MHC expression evidenced sensit ization of T cells specific for graft antigens presented by rat antige n-presenting cells. Conclusions. The strategies of gene gene targeting of donor species to produce less immunogenic xenografts may be hamper ed by the presence of a strong response through the indirect pathway o f immunity. Immune intervention directed at the indirect antigen prese ntation pathway may be of benefit in xenotransplantation.