Background
Sensitization, a state of the presence of donor-specific antibody (DSA) in recipient, has usually been considered an absolute contraindication to solid organ transplantation including vascularized composite tissue allotransplantation (VCA), due to the antibody-mediated rejection (AMR). However, the role of sensitization in VCA rejection is largely unstudied. We recently reported in a rat model that rejection of VCA was accelerated but not hyperacutely in the presence of allosensitization. The rejection of VCA in sensitized recipients is mainly cellular-mediated as evidenced by dense lymphocytic infiltrates and no antibody deposition in biopsies.
Methods
To define the cell populations in VCA rejection of sensitized recipients, major histocompatibility-mismatched ACI (RT1a) donors and WF (RT1u) recipients were used. WF rats were presensitized to ACI antigens by skin transplantation and high levels of DSA were detected post skin rejection.
Results
Sensitized WF rats rejected VCA 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 was in unsensitized rats. 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. 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.
Conclusions
Our study suggests the specificity of VCA rejection in sensitized recipients is cellular-mediated, not AMR, and more readily treated. The management of sensitized VCA recipients should be different from other organ recipients in the clinic and sensitization possibly should not be considered as an absolute contraindication to VCA.