Dissociation Between Peripheral Blood Chimerism and Tolerance to Hindlimb Composite Tissue Transplants: Preferential Localization of Chimerism in Donor Bone

Institute for Cellular Therapeutics, University of Louisville, Louisville, KY 40202-1760, USA.
Transplantation (Impact Factor: 3.83). 09/2009; 88(6):773-81. DOI: 10.1097/TP.0b013e3181b47cfa
Source: PubMed


Mixed chimerism induces donor-specific tolerance to composite tissue allotransplants (CTAs). In the present studies, we used a nonmyeloablative conditioning approach to establish chimerism and promote CTA acceptance.
Wistar Furth (RT1A(u)) rats were conditioned with 600 to 300 cGy total body irradiation (TBI, day-1), and 100 x 10(6) T-cell-depleted ACI (RT1A(abl)) bone marrow cells were transplanted on day 0, followed by a 11-day course of tacrolimus and one dose of antilymphocyte serum (day 10). Heterotopic osteomyocutaneous flap transplantation was performed 4 to 6 weeks after bone marrow transplantation.
Mixed chimerism was initially achieved in almost all recipients, but long-term acceptance of CTA was only achieved in rats treated with 600 cGy TBI. When anti-alphabeta-T-cell receptor (TCR) monoclonal antibody (mAb) (day-3) was added into the regimens, donor chimerism was similar to recipients preconditioned without anti-alphabeta-TCR mAb. However, the long-term CTA survival was significantly improved in chimeras receiving more than or equal to 300 cGy TBI plus anti-alphabeta-TCR mAb. Higher levels of donor chimerism were associated with CTA acceptance. The majority of flap acceptors lost peripheral blood chimerism within 6 months. However, donor chimerism persisted in the transplanted bone at significantly higher levels compared with other hematopoietic compartments. The compartment donor chimerism may be responsible for the maintenance of tolerance to CTA. Long-term acceptors were tolerant to a donor skin graft challenge even in the absence of peripheral blood chimerism.
Mixed chimerism established by nonmyeloablative conditioning induces long-term acceptance of CTA, which is associated with persistent chimerism preferentially in the transplanted donor bone.

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    • "Recently, the role of donor bone marrow cells for chimerism induction was reported in a rat heterotopic osteomyocutaneous flap model transplanted to a mixed allogeneic chimera [56]. Mixed allogeneic chimeras were created 4 to 6 weeks before osteomyocutaneous flap transplantation. "
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    ABSTRACT: The preclinical experimental models of vascularized composite allografts (VCAs) have been rapidly developed for the assessment of immunomodulatory protocols for clinical application. Recently, researchers have focused on immunomodulatory protocols which overcome the immunologic barrier between the allogeneic donor and recipient and may lead to tolerance induction. In order to test the feasibility of chimerism induction, experimental VCAs have been performed in different models including rodents, large animals, and nonhuman primates. These models differ in the complexity of transplanted tissue and in their responses to immunomodulatory protocols. In most applications, VCA contains multiple-tissue components; however, each individual component of CTA possesses unique immunologic characteristics that ultimately contribute to the chimerism induction and successful outcome of the VCA. Heterogenic character and complexity of tissue components in different VCA models determine the quality and robustness of donor-specific chimerism. As introduced in experimental studies, variable immunomodulatory options have been studied to achieve tolerance to VCA in rodents and large animal models allowing for widespread application in clinic. In this paper, based on our own experience, we have analyzed the current knowledge of tolerance-inducing strategies via chimerism induction in VCA experimental models in the context of immunomodulatory protocols and VCA complexity and their relevance and applicability to clinical practice.
    Full-text · Article · Mar 2013 · Clinical and Developmental Immunology
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    • "At the present, transplant tolerance of certain organs or tissues has been induced successfully by the induction of hematopoietic chimerism with different recipient conditionings (myeloablation or cytoreduction) or a " megadose " bone marrow transplantation in animals or humans [6] [7] [8] [9]. However, although full chimerism in which donor-derived hematopoietic cells completely replace the counterpart of the host [10] always leads to transplant tolerance [11], dissociation between transplant tolerance and mixed hematopoietic chimerism has been reported [12] [13]. Additionally, " split "
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    ABSTRACT: Organ/tissue transplantation has become an effective therapy for end-stage diseases. However, immunosuppression after transplantation may cause severe side effects. Donor-specific transplant tolerance was proposed to solve this problem. In this study, we report a novel method for inducing and maintaining heart allograft tolerance rats. First, we induced indefinite vascularized hind-limb allograft survival with a short-term antilymphocyte serum + Cyclosporine A treatment. Peripheral blood chimerism disappeared 6-7 weeks after immunosuppression was withdrawn. Then the recipients accepted secondary donor-strain skin and heart transplantation 200 days following vascularized hind-limb transplantation without any immunosuppression, but rejected third party skin allografts, a status of donor-specific tolerance. The ELISPOT results suggested a mechanism of clone deletion. These findings open new perspectives for the role of vascularized hind-limb transplant in the induction and maintenance of organ transplantation tolerance.
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    • "However, a safe and reliable method to facilitate the induction of mixed hematopoietic chimerism for VCA tolerance is needed. Rahhal et al. [51] had recently reported that the long-term acceptance of VCA could be induced by mixed chimerism established by nonmyeloablative conditioning with TBI as low as 300 cGy combined with a short course of immunosuppressive therapy (anti-αβ- TCR mAb, FK-506, and antilymphocyte serum). The BMT conditioning strategies based on costimulatory blockade of CD28 or CD40 ligand in combination T-cell depletion and low doses of irradiation have also reported to induce longterm acceptance of VCA in rat [64] and to prolong VCA survival in mouse [67]. "
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    ABSTRACT: Successful hand and face transplantation in the last decade has firmly established the field of vascularized composite allotransplantation (VCA). The experience in VCA has thus far been very similar to solid organ transplantation in terms of the morbidity associated with long-term immunosuppression. The unique immunological features of VCA such as split tolerance and resistance to chronic rejection are being investigated. Simultaneously there has been laboratory work studying tolerogenic protocols in animal VCA models. In order to optimize VCA outcomes, translational studies are needed to develop less toxic immunosuppression and possibly achieve donor-specific tolerance. This article reviews the immunology, animal models, mixed chimerism & tolerance induction in VCA and the direction of future research to enable better understanding and wider application of VCA.
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