Sensitized Recipients Exhibit Accelerated but not Hyperacute Rejection of Vascularized Composite Tissue Allografts
ABSTRACT Currently, the donor-recipient matching process for vascularized composite tissue allotransplantation (VCTA) closely follows the standard practices for solid organ transplantation. Sensitization is considered a contraindication to VCTA. However, the role of sensitization in VCTA rejection is largely unstudied.
Major histocompatibility-mismatched ACI (RT1) donors and Wistar Furth (WF) (RT1) recipients were used to determine whether sensitization would lead to hyperacute rejection in VCTA as in other organs, such as kidneys. WF rats were presensitized to ACI antigens by skin transplantation and received heterotopic osteomyocutaneous VCTA flaps. Kidney transplants served as controls.
Production of anti-donor antibody was detected in WF recipients after rejection of the ACI skin grafts. Sensitized WF rats rejected VCTA grafts from ACI rats significantly faster (P<0.05) than unsensitized recipients, but not hyperacutely. Rejection in the sensitized recipients was not prevented by immunosuppression with FK506 and mycophenolate mofetil. In contrast, kidney allografts from ACI rats were hyperacutely rejected within 30 min by sensitized recipients. To confirm the role of antibody-mediated rejection in the sensitized recipients, serum from presensitized rats was adoptively transferred into naïve WF rats. Hyperacute rejection occurred only in transplanted kidneys but not VCTA. Histologic examination of tissues from acceleratedly rejected VCTA showed dense lymphocytic infiltrates, and no antibody deposition.
VCTA are rejected in an accelerated fashion but not hyperacutely in the presence of allosensitization and preformed anti-donor antibody. The rejection of VCTA in sensitized recipients is mainly cell mediated and differs mechanistically from that for renal transplants.
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- "Recently, a study using a rat heterotopic hindlimb transplant model showed that rejection is accelerated but does not occur hyperacutely in the presence of allosensitization and preformed DSA. This type of rejection was mainly cell mediated, and differed mechanistically from that observed in solid organ transplants (52). Although AMR has been identified as a major cause for allograft failure in renal transplantation (53), the long-term effects of these antibodies in VCA remain to be elucidated. "
ABSTRACT: Advances in microsurgical techniques and immunomodulatory protocols have contributed to the expansion of vascularized composite allotransplantation (VCA) with very encouraging immunological, functional, and cosmetic results. Rejection remains however a major hurdle that portends serious threats to recipients. Rejection features in VCA have been described in a number of studies, and an international consensus on the classification of rejection was established. Unfortunately, current available diagnostic methods carry many shortcomings that, in certain cases, pose a great diagnostic challenge to physicians especially in borderline rejection cases. In this review, we revisit the features of acute skin rejection in hand and face transplantation at the clinical, cellular, and molecular levels. The multiple challenges in diagnosing rejection and in defining chronic and antibody-mediated rejection in VCA are then presented, and we finish by analyzing current research directions and novel concepts aiming at improving available diagnostic measures.Frontiers in Immunology 11/2013; 4:406. DOI:10.3389/fimmu.2013.00406
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ABSTRACT: Mixed chimerism induces donor-specific tolerance to kidney and vascularized composite allotransplants (VCA). However, simultaneous kidney or VCA and bone marrow transplantation (BMT) is problematic because of the combined risk and time required for conditioning. Here, we developed a delayed tolerance induction strategy with mixed chimerism through BMT in prior kidney or VCA recipients. Wistar Furth rats that received kidney transplantation (KTx) or VCA from allogeneic August-Copenhagen Irish donors were maintained on immunosuppression (IS) for 8 weeks. These recipients were then conditioned with anti-αβ-T-cell receptor and anti-CD8 monoclonal antibodies, total body irradiation, cyclosporine A and mycophenolate mofetil (12 doses), and antilymphocyte serum (one dose); and transplanted with T-cell-depleted donor marrow. All IS was discontinued on day 11 after BMT. Cyclosporine A monotherapy prevented acute rejection of KTx or VCA. However, all allografts were rejected after IS withdrawal in KTx or VCA recipients who were conditioned but did not receive BMT. After delayed BMT, mixed chimerism was initially achieved in all KTx or VCA recipients with 200-, 300-, and 400-cGy total body irradiation. Long-term tolerance to KTx or VCA was achieved in most of these recipients with total IS withdrawal. The tolerance achieved with delayed BMT was donor specific as confirmed by acceptance of donor skin and rejection of third-party skin graft. IS-free donor-specific tolerance can be successfully induced with delayed BMT to previous recipients of kidney transplantation or VCA. These findings have significant clinical implications for transplant recipients who receive an organ from either a living donor or a deceased donor with frozen bone marrow cells available.Transplantation 08/2012; 94(7):671-8. DOI:10.1097/TP.0b013e318264fbc1 · 3.83 Impact Factor
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ABSTRACT: Hand transplantation, despite all initial skepticism, has developed from myth to reality over the past decade and has shown highly encouraging immunological and functional outcomes. However, the requirement of life-long, multidrug immunosuppression bearing the risk of serious side effects still remains the limiting factor for widespread clinical application of this novel reconstructive modality. Recent advances in immunosuppressive drug development and the design of novel cell-based therapeutic strategies that take into consideration the unique immunological and biological aspects of vascularized composite allografts have shown favorable results with regard to minimization of immunosuppressive medication and tolerance induction in both translational animal studies and first clinical trials in reconstructive transplantation. This review provides an overview of the current available conventional treatment protocols and novel immunosuppression minimization concepts for hand transplantation, which ultimately could significantly favor the risk-benefit ratio for this life-changing type of transplant.Expert Review of Clinical Immunology 09/2012; 8(7):673-84. DOI:10.1586/eci.12.54 · 2.48 Impact Factor