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Vascularized Composite Allograft Transplantation in Swine Tolerant of MHC Class I Mismatch Kidneys: Differential Survival of Vascularized Composite Allografts Transplanted During the Induction and Maintenance Phases of Tolerance.
Radbeh Torabi, MD1, Joseph R. Scalea, MD2, David Leonard, MD1, Mark Randolph, MAS3, David H. Sachs, MD2, Kazuhiko Yamada, MD PhD2, Curtis L. Cetrulo, Jr., MD1.
1Transplantation Biology Research Center/Division of Plastic and Reconstructive Surgery, Massachusetts General Hospital, Harvard Medical School, Boston, MA, USA, 2Transplantation Biology Research Center, Massachusetts General Hospital, Harvard Medical School, Boston, MA, USA, 3Division of Plastic and Reconstructive Surgery, Massachusetts General Hospital, Harvard Medical School, Boston, MA, USA.

PURPOSE:
The adverse effects of immunosuppression remain a concern in vascularized composite allotransplantation (VCA). These could be avoided by induction of donor-specific tolerance. Previous studies in large animal models have attempted to achieve VCA tolerance via a central tolerance mechanism, utilizing bone marrow transplantation to achieve mixed chimerism. In this study we have transplanted VCAs into swine already tolerant of major histocompatibility complex (MHC) class I mismatched kidneys. This model has been shown to achieve tolerance by a peripheral regulatory mechanism, and allows us to study VCA acceptance in the absence of the central effects of bone marrow transplantation.
METHODS:
MHC defined, MGH miniature swine served as donors and recipients of kidneys and VCAs. Swine leukocyte antigen (SLA) GG kidney grafts were transplanted to SLA DD animals treated with 12 days of high dose Cyclosporine A. Animals in Group 1 (n=3) animals received second, donor matched kidneys after 100 days, then >100 days later, during the maintenance phase of tolerance, a myocutaneous VCA. Animals in Group 2 (n=2) received a donor matched VCA <70 days following primary kidney grafts, during the induction phase of tolerance. In vitro cellular reactivity was measured by cell mediated lympholysis (CML) assays. Circulating T-cell subsets and anti-donor antibodies were analyzed by flow cytometry.
RESULTS:
Induction of tolerance of MHC class I mismatched kidneys was universally facilitated by a 12 day course of CyA. Donor-matched VCA transplantation did not lead to rejection of kidneys.
Group 1 (animals 18954, 18955, 18958): 18954 accepted the VCA greater than 200 days, rejecting the epidermis only when challenged with multiple split thickness skin grafts (STSG) 235 days after transplantation. 18955 and 18958 accepted their VCAs but rejected the epidermis on days 45 and 85 respectively.
Group 2 (animals 19842, 19941): 19842 rejected epidermis on day 40, and 19941 on day 28. All animals except for 19941, which underwent graftectomy due to chronic wound infection, maintained viable muscle and dermis throughout. Pathology demonstrated cellular infiltrate, localized mostly to the skin, at the time of epidermal rejection in all cases. This was more intense in animals in Group 2.
All animals remained donor specific hypo-responsive by CML, with the exception of 18955 which developed a CML response following challenge with a split-thickness skin graft 100 days following VCA. However systemic tolerance of donor MHC was maintained, as demonstrated by acceptance of a subsequent kidney retransplant. No animal developed an anti-donor antibody response.
Animal 18954 had significantly higher absolute numbers of circulating CD4/CD25/Foxp3+ regulatory T-cells at the time of VCA transplantation than any other animal. This correlates with VCA survival.
CONCLUSION:
Skin survival was prolonged in VCAs transplanted during the maintenance phase of tolerance. The animal with the longest survival had the greatest number of circulating T-regs. Skin rejection without rejection of other components of the VCA or the kidney, demonstrates split tolerance and suggests that a cellular response can be mounted toward skin specific antigens, without breaking tolerance of donor MHC.


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