Tolerance to Vascularized Composite Allografts in Canine Mixed Hematopoietic Chimeras

Abstract

Background Mixed donor-host chimerism, established through hematopoietic cell transplantation (HCT), is a highly reproducible strategy for the induction of tolerance towards solid organs. Here, we ask whether a nonmyeloablative conditioning regimen establishing mixed donor-host chimerism leads to tolerance of highly antigenic vascularized composite allografts. Methods Stable mixed chimerism was established in dogs given a sublethal dose (1–2 Gy) total body irradiation before and a short course of immunosuppression after dog leukocyte antigen-identical marrow transplantation. Vascularized composite allografts from marrow donors were performed after a median of 36 (range 4-54) months after HCT. Results All marrow recipients maintained mixed donor-host hematopoietic chimerism and accepted composite tissue grafts for periods ranging between 52 and 90 weeks; in turn, marrow donors rejected vascularized composite allografts from their respective marrow recipients within 18–29 days. Biopsies of muscle and skin of vascularized composite allografts from mixed chimeras showed few infiltrating cells compared to extensive infiltrates in biopsies of vascularized composite allografts from marrow donors. Elevated levels of CD3+ FoxP3+ T-regulatory cells were found in skin and muscle of vascularized composite allografts of mixed chimeras compared to normal tissues. In mixed chimeras, increased numbers of T-regulatory cells were found in draining compared to non-draining lymph nodes of vascularized composite allografts. Conclusion These data suggest that nonmyeloablative HCT may form the basis for future clinical applications of solid organ transplantation and that T-regulatory cells may function towards maintenance of the vascularized composite allograft.

Stem Cell-based Tolerance Induction in Transplantation

“…Subsequently, a myocutaneous VCA transplant was performed in an MHC-matched canine model using nonmyeloablative conditioning and HSCT to achieve persistent mixed chimerism and tolerance induction [96]. In this study, all five recipients successfully accepted their allograft for over one year, with evidence of increased levels of Tregs in skin, muscle, and graft-draining lymph node.…”

Skin Allograft and Vascularized Composite Allograft

“…[65][66][67] Experiments using animal models have demonstrated indefinite graft survival without the need for long term systemic immunotherapy. 68 In addition, this novel concept is currently being translated into the clinical setting with preliminary findings suggesting prolonged upper extremity survival with low dose tacrolimus therapy. 69 Similarily, induction of mixed chimerism by donor bone marrow transplant was found to be a promising method for skin allograft acceptance.…”

Minimization of Immunosuppression and Tolerance Induction in Reconstructive Transplantation

“…A translational, clinically relevant protocol was recently developed by Mathes et al [40] in a MHC-matched canine model that has led to tolerance to all components of the VCA, including skin using a hematopoietic mixed chimerism protocol with non-myeloablative induction. Furthermore, indefinite graft survival without long-term immunosuppression could also be achieved with the use of an immunomodulatory protocol employing donor BM cells in the more stringent setting of a complete MHC-mismatched swine heterotopic hindlimb transplant model [41,42].…”