A NOVEL MODE OF IMMUNOPROTECTION OF NEURAL XENOTRANSPLANTS - MASKING OF DONOR MAJOR HISTOCOMPATIBILITY COMPLEX CLASS-I ENHANCES TRANSPLANT SURVIVAL IN THE CENTRAL-NERVOUS-SYSTEM

To determine the role of major histocompatibility complex (MHC) class I in immunological rejection of neural xenotransplants, F(ab')(2) frag ments of a monoclonal antibody to porcine MHC class I were used to mas k this complex on porcine fetal striatal cells transplanted into rat s triata previously lesioned with quinolinic acid. Presence of MHC class I on the surface of porcine striatal cells was confirmed by fluoresce nce-activated cell sorting prior to F(ab')(2) treatment. At three to f our months post-transplantation, survival of F(ab')(2)-treated xenogra fts was assessed by means of donor-specific immunostaining and compare d to that of untreated xenografts in non-immunosuppressed rats and in rats immunosuppressed with cyclosporine A. In this study, masking of d onor MHC class I by F(ab')(2) treatment resulted in enhanced xenograft s Survival compared to the non-immunosuppressed controls (graft surviv al rates, 52% and 7%, respectively; P < 0.005) at survival:times up to four months. While xenograft survival in F(ab')(2)-treated animals wa s not significantly different from that in cyclosporine-treated rats ( 74% graft survival), mean graft volume in F(ab')(2)-treated animals wa s smaller than that in cyclosporine-treated animals (1.07 +/- 0.30 mm( 3) versus 3.14 +/- 0.51 mm(3); P < 0.005). The cytoarchitectonic organ ization of the xenografts was similar in F(ab')(2)- and cyclosporine-t reated animals, and grafts in both groups exhibited long distance targ et-directed axonal outgrowth. The pattern of immunoreactivity to porci ne MHC class I in the xenografts corresponded to the regional distribu tion of donor glia. In xenografts undergoing rejection, infiltration w ith host inflammatory cells was restricted to necrotic graft remnants and spared the nearby host structures. We conclude that MHC class-I-re stricted immune mechanisms Play an important role in neural xenograft rejection and that masking of this complex on donor cells may provide a useful strategy for immunoprotection of neural xenografts.