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 transplantation may provide a means of attenuating the potent immune response 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 complex (MHC). In the current study we examined whether skin, heart, or pancreatic islet xenografts harvested from lines of transgenic mice rendered deficient in MHC antigen expression by gene disruption would exhibit 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 pancreatic islet grafts were harvested from control C57Bl/6 and each of three lines of mice deficient in MHC antigen expression. MHC-deficient lines included (1) mice selectively lacking MHC class I antigens, (CID), produced by disruption of the β-2 microglobulin gene; (2) mice lacking MHC class II expression (CIID), produced by targeting the I-A β-chain-genes; and (3) mice devoid of both class I and class II molecules (CI,IID). Results. In contrast to the prolonged survival that has been observed for certain allografts deficient in MHC antigen expression, 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 sensitization of T-cells specific for graft antigens presented by rat antigen-presenting cells. Conclusions. The strategies of gene targeting of donor species to produce less immunogenic xenografts may be hampered by the presence of a strong response through the indirect pathway of immunity. Immune intervention directed at the indirect antigen presentation pathway may be of benefit in xenotransplantation.