USE OF DONOR BETA-2-MICROGLOBULIN-DEFICIENT TRANSGENIC MOUSE-LIVER CELLS FOR ISOGRAFTS, ALLOGRAFTS, AND XENOGRAFTS

Donor graft major histocompatibility complex class I antigens are targ ets for both allogeneic and xenogeneic rejection. Mice homozygous for beta2-microglobulin gene disruption express reduced amounts of surface MHC class I antigens. Liver cells from such mutant mice were transpla nted into isogeneic, allogeneic, and xenogeneic recipients to evaluate the potential of these animals as transplant donors. The survival of allografts of transgenic 129 mouse liver cells in 15 immunocompetent a nd histoincompatible mouse recipients (BALB/c, D1.C) was only slightly improved 30 days after transplantation relative to normal 129 mouse a llografts. These results could be attributable: (1) to host natural ki ller cell-mediated lysis of donor MHC class I antigen-deficient cell ; (2) to donor liver cell MHC class I determinants that are reduced but not eliminated serving as rejection targets; (3) to the plentiful hos t supply of serum beta2-microglobulin reconstituting the graft and res toring donor MHC class I. Culture studies confirmed the ability of exo genous human and bovine beta2-microglobulin to restore rapidly MHC cla ss I antigen expression on transgenic cells. Because cell surface exch ange of beta2-microglobulin is less efficient between species with div ergent beta2-microglobulin sequences, the survival of transgenic 129 m ouse liver cells in guinea pig (60% beta2-microglobulin identity) and Xenopus (34% beta2-microglobulin identity) hosts was investigated. Sig nificant prolongation of MHC class I antigen-deficient liver cell xeno grafts was apparently only in Xenopus hosts. Furthermore, transplants of transgenic 129 mouse liver cells into isogeneic normal 129 mouse re cipients showed evidence of rejection in seven of nine recipients, sug gesting that transgenic donor cells also may be susceptible to lysis b y host natural killer cells.