STUDIES OF TRANSPLANTATION IMMUNOLOGY WITH MAJOR HISTOCOMPATIBILITY COMPLEX KNOCKOUT MICE

Mice deficient in the expression of either class I or class II major h istocompatibility complex (MHC) antigens have been generated by use of the technique of gene disruption by homologous recombination. These a nimals have subsequently been mated to generate mice that are deficien t in the expression of both classes of MHC antigens Class I MHC-defici ent animals have a greater than 90% reduction in cell surface expressi on 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 dete ctable expression of class II MHC molecules and a reduction in the CD4 (+) T cell population. Mice deficient in both MHC antigens share the c haracteristics of the two founder animals: low levels of class I heavy chain expression, no detectable class II expression and reduced level s of CD4(+) and CD8(+) T cells. Allotransplantation experiments with t hese animals have suggested that different mechanisms of graft rejecti on predominate depending on the target organ and have provided evidenc e for the role of the indirect pathway of antigen recognition in graft rejection. Xenotransplantation experiments involving these animals ha ve revealed that donor MHC deficiency offers no protection to the graf t, suggesting that strategies to eliminate MHC antigen expression will not be successful in generating ''universal donors.''