Major Histocompatibility Complex Class I Matching is Necessary but not Sufficient for Tolerance Induction to Vascularized Composite Allografts After Donor Hematopoietic Cell Transplantation

Background: We previously reported a porcine model of vascularized composite allograft (VCA) transplantation with concurrent hematopoietic cell transplantation (HCT). Tolerance developed when major histocompatibility complex (MHC) class I was matched in the absence of class II matching but not when class II was matched without class I matching. We investigated whether rejection resulted from a mismatch between class I and class II. Methods: Recipient pigs were either mismatched from donors by a single class I haplotype or matched by a single class II haplotype. They received CD3 immunotoxin and total-body irradiation followed by HCT and VCA transplantation from the same donor. Cyclosporine immunosuppression was discontinued after 45 d. Results: Pigs mismatched for only 1 MHC class I haplotype maintained peripheral chimerism and accepted the VCA graft, except for 1 animal that rejected the epidermis. Pigs matched for only 1 MHC class II haplotype lost bone marrow engraftment and rejected the VCA graft. Conclusions: When combined with our prior experiments, our results suggest that some degree of MHC class I matching is necessary for tolerance induction to HCT/VCA, but this is dependent on the degree of class II matching. Full class I matching reliably generates VCA tolerance, regardless of the degree of class II matching. VCA tolerance fails to develop reliably when MHC class I is fully mismatched, regardless of the degree of class II matching. When a single class I haplotype is matched, VCA tolerance depends on the degree of class II matching.