Sensitization, a state of the presence of donor-specific antibody (DSA) in recipient, has usually been considered an absolute contraindication to solid organ transplantation. Currently, the donor-recipient matching process for vascularized composite tissue allotransplantation (VCA) closely follows the standard practices for renal transplantation. However, the role of sensitization in VCA rejection is largely unstudied. We recently reported that rejection of VCA was accelerated but not hyperacutely in the presence of allosensitization. In striking contrast, renal transplants were hyperacutely rejected. The rejection of VCA in sensitized recipients is mainly cellular-mediated evidenced by dense lymphocytic infiltrates and no antibody deposition in biopsies. To define the cell populations in VCA rejection of sensitized recipients and further overcome the rejection, major histocompatibility-mismatched ACI (RT1^a) donors and WF (RT1^u) recipients were used. WF rats were presensitized to ACI antigens by skin transplantation and high levels of DSA were detected post skin rejection. Sensitized WF rats rejected VCA grafts from ACI rats between day 3 and 5, which was significantly more rapid (P < 0.05) compared with unsensitized controls. The accelerated rejection in sensitized recipients could not be prevented with cyclosporine A (CyA) as it did in unsensitized rats. The accelerated rejection in sensitized rats was occurred between day 3 and 5. When anti-ΑΒTCR and/or anti-CD8 were injected in sensitized recipients with circulating DSA, VCA survived long-term (> 100 days) with both antibodies used in combination and the maintenance treatment of CyA but not either of them alone (survival time: 4 to 5 days). Anti-ΑΒTCR treatment did not deplete a population with a phenotype of CD8⁺ΑΒTCR^–. In these CD8⁺ΑΒTCR^– cells, about 47.6 ± 20.3% were NKR-P1A⁺ NK cells. When both anti-ΑΒTCR and anti-CD8 were used, all CD8⁺ cells including CD8⁺ΑΒTCR⁺ T cells and CD8⁺/ΑΒTCR^–/NKR-P1A⁺ NK cells were depleted. Moreover, when purified CD8⁺ or ΑΒTCR⁺ cells from sensitized recipients were adoptively transferred to naÏve recipients, the VCA rejected promptly with rejection prevention treatment of CyA. These data suggest that the CD8⁺ and ΑΒTCR⁺ cells are the effectors mediating rejection and the depletion of CD8⁺ plus ΑΒTCR⁺ cells overcomes the rejection of VCA in sensitized recipients.

Ildstad, S.: Other, Regenerex, LLC, CEO.

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