The intragraft vascularized bone marrow component plays a critical role in tolerance induction after reconstructive transplantation

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 highor low-dose CBMT (1.5 × 10 8 or 3 × 10 7 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.

The Positive Impact of Donor Bone Marrow Cells Transplantation into Immunoprivileged Compartments on the Survival of Vascularized Skin Allografts

“…The vascularized bone marrow is the largest reservoir of these cells. Therefore, the donor B lymphocytes' level increases significantly after vascularized bone marrow transplantation promoting VSA survival (Klimczak et al 2006;Lin et al 2021). This paradox appears due to the delayed redistribution of transplanted cells from immunoprivileged regions, forming a barrier between the external environment and myeloid cells.…”

Large Animal Models of Vascularized Composite Allotransplantation: A Review of Immune Strategies to Improve Allograft Outcomes

“…The addition of VBM, however, did not induce true VCA tolerance, as grafts were promptly rejected once IS was discontinued (19). However, this study served as proof of principle that the intragraft VBM component conferred an immunological benefit on VCA survival, since confirmed in murine models (26,27).…”

“…A major contribution to CoB refractory rejection appears to be the relative resistance of memory CD8+ T cells to CoB given the lack of requirement of costimulation signaling for activation. Nevertheless, CoB based therapy blocking either the CD28-CD80/86 or CD40-CD154 pathways has shown promising results in murine VCA models ( 26 , 27 , 39 ). There have been few studies of CoB based regimen in large animals ( 40 – 42 ) ( Table 2 ).…”

The Mandible Ameliorates Facial Allograft Rejection and Is Associated with the Development of Regulatory T Cells and Mixed Chimerism

“…The induction of mixed chimerism can result in allograft tolerance without lifelong administration of immunosuppressive regimens [70,71]. Mixed chimerism, defined as a state that is composed of host and donor immune cells, and achieves a balance through both allogeneic and autologous hematopoietic differentiation systems.…”