![[ Visit Client Website ]](images/banner.gif)
The incidence of acute rejection (AR) of the skin within the first year after hand or face transplantation is approximately 85%, with up to 56% of patients experiencing multiple episodes [1]. Significant immunosuppresive treatment is required to prevent allograft loss, and recent murine studies have shown that repeated AR episodes can lead to eventual VCA dysfunction and loss[2]. However, the mechanisms underlying variability in AR presentation remain poorly defined.
METHODS
7 cynomolgus monkeys received either an orthotopic hand (n=2) or heterotopic face VCA from MHC-mismatched donors. The induction and maintenance regimen included anti-thymocyte globulin with post-operative triple immunosuppression – tacrolimus, mycophenolate mofetil, methylprednisolone – for up to 120 days. Protocol biopsies of VCA and host skin were performed at 30-day intervals for flow cytometric analysis of resident skin leukocyte populations based on CD3, CD4, CD8, and CD207 staining; VCA-resident cells were differentiated by H38 status (mouse antihuman HLA class I monoclonal antibody that cross reacts with cynomolgus monkeys) for donor or recipient derivation. Clinical AR was treated by steroids with further biopsies taken for histopathology; corresponding anti-donor responses were evaluated by mixed lymphocyte reaction (MLR) and the presence of allo-antibodies.
RESULTS
By day 14 post-VCA, more than 80% of skin-resident T lymphocytes (CD4+, CD8+) within VCA dermis were of recipient origin, demonstrating rapid immigration of various lineages into the VCA. In the epidermis, Langerhans cells were approximately 75% donor-origin during AR, and decreased to 17% after treatment. Of note, these observations coincided with the first episode of AR in full MHC-mismatched recipients. However, no AR developed in haplomatched animals despite the same immunosuppressive regimen and comparable leukocyte numbers in VCA dermis and epidermis by flow cytometry. All but one episode of AR were successfully treated. No allo-antibodies were detected and anti-donor responses by MLR were comparable to that against third-party. Histological grading of AR was Banff 0 to II with corresponding higher ratios of CD8:CD4 T cells.
CONCLUSION
Here we show a clinically-appropriate model for studying AR in VCA. Our results suggest that further understanding of the relative importance of MHC differences in transplant pairs may lead to differences in outcomes for VCA recipients maintained under standard immunosuppressive regimens. In turn, the potential to avoid or negate AR may have implications on both long-term management and the likelihood of success in future tolerance induction strategies.