Background
Following face or hand transplantation, maintenance immunosuppression is required to prevent VCA loss However, despite such immunosuppression, up to 85% of patients develop at least an episode of acute skin rejection (AR) within the first year post-transplantation with 56% experiencing multiple episodes The mechanisms underlying AR in VCA remain poorly defined and are explored both before and after tolerance induction in this study.
Methods
Eight cynomolgus monkeys received either an orthotopic hand (n=2) or heterotopic face VCA from MHC-mismatched donors Recipients underwent induction therapy with ATGAM followed by standard post-operative maintenance (FK506, MMF, steroids) before tolerance induction with bone marrow transplantation (BMT) at a later date Protocol biopsies of VCA and host skin were performed and immune cells were isolated for flow cytometric analysis of skin resident leukocyte populations Clinically diagnosed AR was treated with steroid bolus and additional biopsies were taken for histologic correlation Corresponding in vitro immunologic assessment was performed with mixed lymphocyte reaction (MLR) and serum allo-antibody assays.
Results
By POD 14, more than 80% of skin-resident T lymphocytes (CD4+, CD8+) within VCA dermis were recipient-derived, demonstrating rapid immigration of various lineages into the allograft Of note, this observation coincided with the first episode of clinical AR in full MHC-mismatched recipients; in haplomatched recipients however, no AR developed while on the same immunosuppressive regimen Diagnosis and treatment of AR at this time point mitigates recurrence up to POD 60 without alloantibody formation or increased anti-donor responses (comparable to anti-third party) on MLR Following BMT, VCAs remained free of AR for up to 64 d (36 d off of all immunosuppression) Subsequent development of clinical AR could be treated with steroid and FK506 to achieve both clinical and histological resolution.
Conclusions
Here we show a clinically-appropriate model to study AR in VCA Our results suggest that further understanding of the role of MHC sharing may lead to predictable outcomes on AR while on standard immunosuppression The early and rapid infiltration of recipient-derived lymphocytes into the VCA may have implications on both the long-term management of patients and the likelihood of success of tolerance induction.