The Effect of MHC Antigen Matching Between Donors and Recipients on Skin Tolerance of Vascularized Composite Allografts

The emergence of skin-containing vascularized composite allografts (VCAs) has provided impetus to understand factors affecting rejection/tolerance of skin. VCA tolerance can be established in miniature swine across haploidentical MHC barriers using mixed chimerism. As the deceased donor pool for VCAs does not permit MHC antigen matching, clinical VCAs are transplanted across varying MHC disparities. Here, we investigated whether sharing of MHC class I or class II antigens between donors and recipients influences VCA skin tolerance. Miniature swine were conditioned non-myeloablatively and received hematopoietic stem cell transplants and VCAs across MHC class I (n=3) or MHC class II barriers (n=3). In vitro immune responsiveness was assessed and VCA skin-resident leukocytes were characterized by flow cytometry. Stable mixed chimerism was established in all animals. MHC class II-mismatched chimeras were tolerant of VCAs. MHC class I-mismatched animals, however, rejected VCA skin, characterized by infiltration of recipient-type CD8+ lymphocytes. Systemic donor-specific non-responsiveness was maintained, including after VCA rejection. This study shows that MHC antigen matching influences VCA skin rejection and suggests that local regulation of immune tolerance is critical in long-term acceptance of all VCA components. These results help elucidate novel mechanisms underlying skin tolerance and identify clinically relevant VCA tolerance strategies. This article is protected by copyright. All rights reserved.