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STUDIES OF ALLOGRAFT TOLERANCE IN CLASS I AND CLASS II MHC DEFICIENT TRANSGENIC MICE WITHOUT IMMUNOSUPPRESSION

Mayor histocompatibility complex class I deficient (C1D) and class II deficient (C2D) transgenic animals afford an excellent opportunity to study allograft tolerance mechanisms without immunosuppression A variety of combinations of C1D and C2D animals were used as donors and recipients of heterotopic cardiac allografts. In 10 normal recipients, C1D donor cardiac allografts were strikingly prolonged to 65 +/-16 days without immunosuppression. Similarly, C2D donor hearts were prolonged to 34+/-4.8 days (p<0.05, control 5 +/- 2 days). Donor hearts will both C1D and C2D transplanted to normal recipients had a mean survival of 66 +/-14 days. Thus, the absence of donor class I or class II produced a robust tolerance of cardiac allografts surviving without immunosuppression. The cardiac allograft results indicate that natural killer cells (NK) are probably not critical to rejection since the NK cell is known to respond to an absence of class I antigens on the donor cell surface. Ten C1D recipients had only a mild increase in allograft survival of 10.6 +/-3 days. In contrast, 10 C2D recipients tolerated normal incompatible donor hearts for 92+/-26 days. C2D donor animal tolerance could be related to a defect in the donor antigen presenting cell (APC) function. Similarly, the prolonged survival of allografts in the C2D recipients could be related to an indirect recipient APC defect producing defective indirect allosensitization. Studies suggest that this long tolerance (mean 90 days) is not due to CD4 deficiency (intrinsic to the C2D recipient) since reconstitution of CD4 cells to normal levels using 1x10⁸ purified syngenic CD4 cells did not change the tolerogenicity in the recipients. The absence of class I and/or class II MHC antigens on the graft would seem to result in a robust tolerogenic state. Since NK cells have been implicated in graft rejection, the superior prolongation when class I MHC antigens are absent, provides confidence that class I deficiency does not activate NK cells. The best results were seen with C1D donors and addition of C2D to the C1D donor state did not improve results. Finally, C2D defiant recipients (even when CD4 cells were replaced) had the best survival of all groups and the CD1 recipients had little, if any, prolongation of normal donor hearts. These results suggest that the indirect pathway of allosensitization is critcal in allograft rejection.

F Thomas,*K Pittman, J Contreras, J Thomas. Transplant Center, The University of Alabama at Birmingham, Birmingham, Alabama, *Department of Surgery, East Carolina University, Greenville, North Carolina, U S A.