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The Effect of MHC Antigen Matching Between Donors and Recipients on Skin Tolerance of Vascularized Composite Allografts
Author(s) -
Shanmugarajah K.,
Powell H.,
Leonard D. A.,
Mallard C.,
Albritton A.,
Harrington E.,
Randolph M. A.,
Farkash E.,
Sachs D. H.,
Kurtz J. M.,
Cetrulo C. L.
Publication year - 2017
Publication title -
american journal of transplantation
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 2.89
H-Index - 188
eISSN - 1600-6143
pISSN - 1600-6135
DOI - 10.1111/ajt.14189
Subject(s) - immunology , major histocompatibility complex , cd8 , immune tolerance , antigen , mhc class i , immune system , medicine , histocompatibility , human leukocyte antigen
The emergence of skin‐containing vascularized composite allografts ( VCA s) has provided impetus to understand factors affecting rejection and tolerance of skin. VCA tolerance can be established in miniature swine across haploidentical MHC barriers using mixed chimerism. Because the deceased donor pool for VCA s does not permit MHC antigen matching, clinical VCA s are transplanted across varying MHC disparities. We investigated whether sharing of MHC class I or II antigens between donors and recipients influences VCA skin tolerance. Miniature swine were conditioned nonmyeloablatively and received hematopoietic stem cell transplants and VCA s across MHC class I (n = 3) or class II (n = 3) barriers. 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 VCA s. MHC class I–mismatched animals, however, rejected VCA skin, characterized by infiltration of recipient‐type CD 8 + lymphocytes. Systemic donor‐specific nonresponsiveness 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.