W209 - Matching of Major Histocompatibility Complex Class I Is Neccessary but to Sufficient for Tolerance Induction to Vascularized Composite Allografts Following Donor Hematopoietic Stem Cell Transplantation

Abstract Text: Hematopoietic stem cell transplantation (HSCT) can facilitate tolerance of concomitantly transplanted tissue. Previous research in a preclinical porcine model has evaluated tolerance development after combined HSCT/vascularized composite allografts (VCA) across various major histocompatibility complex (MHC) class I and class II barriers. In the present study, we used the same preclinical model to further investigate the relative importance of class I versus class II matching for induction of tolerance to tissue-specific skin antigens in a situation where the recipients are made tolerant to donor MHC through HSCT. Recipient pigs received CD3 immunotoxin and total body irradiation followed by HSCT and VCA transplantation from the same donor. Cyclosporine immunosuppression was discontinued after 45 days. Our results indicate that combined HSCT/VCA transplantation between fully MHC class I matched pairs generates durable multi-lineage mixed chimerism in peripheral blood and tolerance of both donor MHC and tissue-specific antigens, regardless of degree of class II matching. When MHC class I is fully mismatched, however, the degree of durable mixed chimerism in peripheral blood, bone marrow engraftment, and rejection correlates with the number of mismatched class II alleles. When a single class I allele is matched, combined HSCT/VCA generates durable multilineage mixed chimerism, but consistent tolerance of both donor MHC and tissue-specific antigens occurs only when just a single class II allele is also matched. Our results suggest that, in the absence of full class I matching, the development of tolerance is influenced by the degree of class II matching in a manner consistent with linked suppression.