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: 3.78). 09/2009; 88(6):773-81. DOI: 10.1097/TP.0b013e3181b47cfa
Source: PubMed

ABSTRACT 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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Available from: Yiming Huang, Aug 16, 2015
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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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    • "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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    • "T cell depletion prior to VCA transplantation followed by T-cell repopulation after allotransplantation has been associated with allograft acceptance in animal models and in humans [34] [35]. Nonspecific Tcell depletion (lymphodepletion) medications such as ATG [36] [37], Orthoclone mAb OKT3 [38], and humanized Campath-1H CD52 mAb [39] are frequently used clinically for induction therapy before transplantation for prevention and treatment of acute rejection episodes. "
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