Studies of transplantation immunology with major histocompatibility complex knockout mice

Mice deficient in the expression of either class I or class II major histocompatibility complex (MHC) antigens have been generated by use of the technique of gene disruption by homologous recombination. These animals have subsequently been mated to generate mice that are deficient in the expression of both classes of MHC antigens. Class I MHC-deficient animals have a greater than 90% reduction in cell surface expression of MHC I molecules; however, they do express low levels of class I heavy chains on their cells. Furthermore, class I-deficient mice have very few CD8S+R T cells. Class II MHC-deficient animals have no detectable expression of class II MHC molecules and a reduction in the CD4+ T cell population. Mice deficient in both MHC antigens share the characteristics of the two founder animals: low levels of class I heavy chain expression, no detectable class II expression and reduced levels of CD4+ and CD8+ T cells. Allotransplantation experiments with these animals have suggested that different mechanisms of graft rejection predominate depending on the target organ and have provided evidence for the role of the indirect pathway of antigen recognition in graft rejection. Xenotransplantation experiments involving these animals have revealed that donor MHC deficiency offers no protection to the graft, suggesting that strategies to eliminate MHC antigen expression will not be successful in generating "universal donors."