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

Abstract

Background The development of safe and reliable protocols for the transplantation of the face and hands may be accomplished with animal modeling of transplantation of vascularized composite allografts (VCA). Previously, we demonstrated that tolerance to a VCA could be achieved after canine recipients were simultaneously given marrow from a dog leukocyte antigen (DLA) identical donor. In the present study, we extend those findings across a DLA mismatched barrier. Methods Eight Recipient dogs received total body irradiation (4.5 cGy), hematopoietic cell transplantation (HCT), either marrow (n=4) or granulocyte-colony stimulating factor (G-CSF) mobilized peripheral blood stem cells (n=4), and a VCA transplant from the HCT donor. Post grafting immunosuppression consisted of mycophenolate mofetil (28 days) and cyclosporine (35 days). Results In 4 dogs receiving bone marrow, 1 accepted both its marrow transplant and demonstrated long-term tolerance to the donor VCA (>52 weeks). Three dogs rejected both their marrow transplants and VCA at 5–7 weeks posttransplant. Dogs receiving mobilized stem cells all accepted their stem cell transplant and became tolerant to the VCA. However, 3 dogs developed graft-versus-host disease (GVHD) while 1 dog rejected its stem cell graft by week 15 but exhibited long-term tolerance towards its VCA (>90 weeks). Conclusion The data suggest that simultaneous transplantation of mobilized stem cells and a VCA is feasible and leads to tolerance towards the VCA in a haploidentical setting. However, there is a higher rate of donor stem cell engraftment compared to marrow HCT and an increase in the incidence of GVHD.

A phase I study of CAR‑T bridging HSCT in patients with acute CD19⁺ relapse/refractory B‑cell leukemia

“…However, it is difficult to achieve remission via traditional treatment methods in patients with relapsed/refractory (R/R) B-ALL due to a high tumor burden and poor patient physical condition, and these patients lose the best chance of receiving transplantation. Previously, only 5% of patients with R/R B-ALL who underwent conventional chemotherapy were able to undergo allo-HSCT (5,6). Minimal residual disease (MRD) status has been demonstrated to be a strong prognostic factor for adult patients with ALL (7).…”

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

“…Unlike NHP, swine and canine models are generally conducive to the induction of stable mixed chimerism and therefore long-term tolerance to VCA grafts (22)(23)(24)35). Based on these consistently achievable results, swine and canine VCA models allow for mechanistic insights into VCA tolerance including the effect of MHC antigen matching on skin tolerance, the temporal relationship between BMT and VCA necessary for tolerance induction, and the effectiveness of BM versus cytokine mobilized HSC in VCA tolerance induction.…”

Induction of Tolerance towards Solid Organ Allografts Using Hematopoietic Cell Transplantation in Large Animal Models

“…Long-term tolerance to a VCA can be accomplished with either VCA transplantation several months after or coincident with HCT in the canine DLA-identical transplantation model [95,96]. In a more clinically relevant setting, we recently tested immune tolerance to DLA-haploidentical marrow or G-CSF-mobilized peripheral blood stem cells coincident with VCA transplantation [97]. Conditioning was done with 4.5 Gy TBI, and postgrafting immunosuppression was accomplished with a brief course of CSP and MMF (Figure 1).…”