Abstract
The role of the vascularized bone marrow component as a continuous source of donor-derived hematopoietic stem cells that facilitate tolerance induction of vascularized composite allografts is not completely understood. In this study, vascularized composite tissue allograft transplantation outcomes between recipients receiving either conventional bone marrow transplantation (CBMT) or vascularized bone marrow (VBM) transplantation from Balb/c (H2d) to C57BL/6 (H2b) mice were compared. Either high- or low-dose CBMT (1.5 × 108 or 3 × 107 bone marrow cells, respectively) was applied. In addition, recipients were treated with costimulation blockade (1 mg anti-CD154 and 0.5 mg CTLA4Ig on postoperative days 0 and 2, respectively) and short-term rapamycin (3 mg/kg/day for the first posttransplant week and then every other day for another 3 weeks). Similar to high-dose conventional bone marrow transplantation, 5/6 animals in the vascularized bone marrow group demonstrated long-term allograft survival (>120 days). In contrast, significantly shorter median survival was noted in the low-dose CBMT group (~64 days). Consistently high chimerism levels were observed in the VBM transplantation group. Notably, low levels of circulating CD4+ and CD8+ T cells and a higher ratio of Treg to Teff cells were maintained in VBM transplantation and high-dose CBMT recipients (>30 days) but not in low-dose VBM transplant recipients. Donor-specific hyporesponsiveness was shown in tolerant recipients in vitro. Removal of the vascularized bone marrow component after secondary donor-specific skin transplantation did not affect either primary allograft or secondary skin graft survival.
Highlights
Reconstructive transplantation, referred to as vascularized composite allotransplantation, has emerged as a viable therapeutic option for individuals suffering from devastating tissue loss that is not amenable to conventional reconstructive techniques.[1,2,3]Vascularized composite allografts (VCA) may contain any combination of tissues with unique antigenicities, such as skin, muscle, vessels, cartilage, tendon, nerve, bone, and bone marrow (BM)
Combined costimulation blockade (CoB) and short-term RPM treatment resulted in longterm allograft survival in vascularized bone marrow (VBM) and high conventional bone marrow transplantation (CBMT) but not in low CBMT recipients In this study, we compared the efficacy of CBMT and VBM transplantation in prolonging allograft survival
In this study, we directly compared the efficacy of CBMT vs VBM transplantation to establish mixed chimerism and to induce immune tolerance in a vascularized composite allotransplantation model
Summary
Vascularized composite allografts (VCA) may contain any combination of tissues with unique antigenicities, such as skin, muscle, vessels, cartilage, tendon, nerve, bone, and bone marrow (BM). The specific characteristics of the different tissue types pose a challenge for prolonged allograft survival compared to solid organ transplantation.[4] this challenge can generally be met with long-term immunosuppression using high doses of multiple drugs to prevent rejection and graft failure.[5] Such long-term administration of multiple immunosuppressants often has significant side effects and toxicities, such as infections, metabolic, and even malignant complications For this reason, the implementation of novel therapies allowing for a reduction in immunosuppressive treatment is vital to tipping the risk–benefit ratio in favor of VCA recipients and expanding the pool of eligible patients.[6] appealing for overcoming this dilemma are various cell-based approaches to induce mixed chimerism and transplant tolerance.[7,8,9,10] This is conventionally accomplished with transplantation of donor-derived BM cells to the recipient to induce chimerism.[11,12,13] Conditioning therapies with less toxicity can be used with adjunctive allogeneic BM transplantation.[14]
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