Improving the Safety of Tolerance Induction: Chimerism and Cellular Co-Treatment Strategies Applied to Vascularized Composite Allografts

Abstract

Although vascularized composite allografts (VCAs) have been performed clinically for a variety of indications, potential complications from long-term immunosuppression and graft-versus-host disease remain important barriers to widespread applications. Recently it has been demonstrated that VCAs incorporating a vascularized long bone in a rat model provide concurrent vascularized bone marrow transplantation that, itself, functions to establish hematopoietic chimerism and donor-specific tolerance following non-myeloablative conditioning of recipients. Advances such as this, which aim to improve the safety profile of tolerance induction, will help usher in an era of wider clinical VCA application for nonlife-saving reconstructions.

A novel rat full-thickness hemi-abdominal wall/hindlimb osteomyocutaneous combined flap: influence of allograft mass and vascularized bone marrow content on vascularized composite allograft survival

“…Such differences are in part explained by the highest chimerism level of the single HLOMC group determined at 4 weeks post-transplantation before rejection was observed clinically for all treated subjects. These results are in accordance with previous literature, which stated that chimerism is associated with induction of tolerance [26][27][28]. However, when AM was doubled using the HAW/HLOMC flap, allograft survival time was closer to that of the single HAW despite the presence of VBMT.…”

“…Engraftment and reconstitution of multiple hematopoietic lineages following allotransplantation may be critical for induction of tolerance to VCAs . In the current study, the higher degree of chimerism in HLOMC recipients was reflected by the increased level of donor‐derived CD161 + NK cells as well as CD4 + cells relative to the other cell types.…”

The Impact of Mesenchymal Stem Cell Source on Proliferation, Differentiation, Immunomodulation and Therapeutic Efficacy

“…Furthermore, when allografts containing multiple types of tissues, termed vascularized composite allotransplant (VCA such as face transplants or limb transplants), were transplanted, MSCs were shown to induce donor-specific tolerance and prolong VCA survival [75][76][77][78][79]. BM-MSCs and AT-MSCs were the two types that were mostly utilized, although they have not yet been compared side-by-side in terms of influencing VCA survival.…”

Developing an Optimal Experimental Model for Immunological Studies in VCA: Vascularized Composite Allotransplants Based on Femoral Vessels in Rats

“…Since 1998, when first hand transplant was performed, vascularized composite allotransplantation became a new clinical entity, with different types of reconstructive transplants performed for various anatomic locations including: upper and lower extremities, face, larynx, tongue, trachea, abdominal wall, uterus, penis. Reported short-and long-term outcomes have been excellent thus far, reconstructive transplantation is now a reality, and basic and translational research in this field is advancing on many fronts, in order to overcome the immunological challenge (2)(3)(4)(5)(6).…”

“…The long-term goal is to induce donor-specific tolerance in order to avoid the toxicity of immunosuppressive drugs. Acceptance of the graft in absence of immunosuppressive therapy have been termed the "holy grail" in transplantation and would represent a transformational achievement for using vascularized composite allotransplantation as reconstructive option for extensive defects, allowing unlimited potential for tissue repair (3)(4)(5)8).…”