Simultaneous Transplantation of Hematopoietic Stem Cells and a Vascularized Composite Allograft Leads to Tolerance

Abstract

Background We have previously demonstrated that tolerance to a vascularized composite allograft (VCA) can be achieved after the establishment of mixed chimerism. Here, we test the hypothesis that tolerance to a VCA in our dog leukocyte antigen (DLA)-matched canine model is not dependent on the previous establishment of mixed chimerism and can be induced coincident with hematopoietic cell transplantation (HCT). Methods Eight DLA-matched, minor antigen mismatched dogs received 200 cGy of radiation and a VCA transplant. Four dogs received donor bone marrow at the time of VCA transplantation (group 1) while a second group of 4 dogs did not (group 2). All recipients received a limited course of post-grafting immunosuppression. All dogs that received HCT and VCA were given donor, third party and autologous skin grafts. Results All group 1 recipients were tolerant to their VCA (> 62 weeks). Three of the four dogs in group 2 rejected their VCA transplants after the cessation of immunosuppression. Biopsies obtained from muscle and skin of VCA from group 1 showed few infiltrating cells compared to extensive infiltrates in biopsies of VCA from group 2. Compared to autologous skin and muscle, elevated levels of CD3+ FoxP3+ T-regulatory cells were found in skin and muscle obtained from VCA of HCT recipients. All group 1 animals were tolerant to their donor skin graft and promptly rejected the third-part skin grafts. Conclusion These data demonstrated donor specific tolerance to all components of the VCA can be established through simultaneous nonmyeloablative allogeneic HCT and VCA transplant protocol.

Long-term Tolerance Toward Haploidentical Vascularized Composite Allograft Transplantation in a Canine Model Using Bone Marrow or Mobilized Stem Cells

“…28 We extended these findings into a more clinically relevant scenario by simultaneously transplanting both donor bone marrow and VCA. 29 This experiment offered proof of principle that tolerance can be established across a minor antigen mismatched DLA-identical barrier in a single-day protocol.…”

“…17,22,27 Translating these findings to VCA transplantation, we demonstrated that using marrow also allows for long-term tolerance (> 1 year) towards VCA transplants, regardless of whether HCT is administered months before or given the day of the VCA transplant. 28,29 …”

New advances in the mesenchymal stem cells therapy against skin flaps necrosis

“…And all dogs received donor bone marrow at the time of vascularized composite allograft (VCA) transplantation were tolerant to their donor skin graft and promptly rejected the third-party skin grafts. These data demonstrated that donor-specific tolerance to all components of the VCA could be established through simultaneous allogeneic hematopoietic third-party stem cells transplantation [47] . For some extreme situations, such as diabetic and radiation-induced tissue defects, stem cells therapy shows their unique advantages.…”

Dynamics of B Cell Recovery In Kidney/Bone Marrow Transplant Recipients

“…Previous studies have examined elements of immune recovery following HSCT combined with organ transplantation 17,18 . The present results depict the gradual reconstitution of B cell pools following CKBMT.…”