Plastic Surgery Research Council
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PSRC 60th Annual Meeting
Program and Abstracts

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The Impact and Mechanisms of Antibody-Mediated Rejection in Vascularized Composite Allotransplantation
Devin T. Miller, BS1, Denver Lough, MD, PhD1, Barbara Kern, MD2, Georg J. Furtmüller, MD1, Giorgio Raimondi, PhD1, W.P. Andrew Lee, MD1, Zhaoli Sun, MD, PhD1, Gerald Brandacher, MD1.
1The Johns Hopkins School of Medicine, Baltimore, MD, USA, 2Medical University Vienna, Vienna, Austria.

PURPOSE:
The immediate clinical management of devastating tissue injuries often requires multiple blood transfusions and/or skin allografts as life-saving interventions for patients suffering from severe trauma. However, the consequent formation of alloantibodies (anti-HLA IgG Abs) after these procedures is a great barrier facing patients who wish to receive definitive treatment in the form of reconstructive transplantation as sensitization currently stands as a major contraindication for vascularized composite allotransplantation (VCA). The role of donor-specific antibodies (DSA) and mechanisms of antibody-mediated rejection (AMR) in VCA are still largely unknown. These phenomena must be understood in an effort to provide reconstructive transplantation options to the large population of sensitized patients in need of VCA.
METHODS:
Major histocompatibility-mismatched Dark Agouti (RT1Aa) donors and Lewis (RT11) recipients were utilized to examine the effect that sensitization to donor antigens has on the rejection scheme of VCA. Lewis rats were sensitized with 1.5 x 1.5 cm full-thickness skin grafts from Dark Agouti donors and after 30 days received orthotopic hind-limb transplantation. Serum antibody titers, tissue biopsies, and clinical observations were obtained and analyzed with regards to rejection kinetics and processes.
RESULTS:
Serum antibody titers after skin graft sensitization peaked in Lewis recipients at post-operative days 10 and 14 for IgM and IgG respectively. All sensitized rats (n=6) in the control group receiving no immunosuppression rejected their hind limb grafts within 4-5 days after transplantation, while non-sensitized control rats rejected their grafts within 9-10 days (p<0.05). Treatment of non-sensitized recipients with tacrolimus (0.5 mg/kg) resulted in rejection-free long-term graft survival (>30 days), whereas the same treatment regimen given to sensitized recipients resulted in accelerated allograft rejection around POD 10 (Figure). Immunofluorescence and immunohistochemical staining showed that IgG and C4d were present in the epidermis, dermis, and capillaries in hind limb allografts recovered from sensitized control rats 3 days after transplantation. In contrast, non-sensitized rats showed only very isolated IgG or C4d dermal staining at 3 days postoperatively.
CONCLUSIONS:
Sensitized recipients reject VCA in an accelerated manner as compared to non-sensitized recipients. Additionally, antibody-specific markers of rejection such as IgG and C4d deposition appear at earlier time points in sensitized recipients as compared with non-sensitized controls. Treatment with standard immunosuppressive agents proves to be insufficient in stifling the rejection processes caused by DSA.


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