Clinical and preclinical tolerance protocols for vascularized composite allograft transplantation

Abstract

The field of vascularized composite allografts (VCAs) has undergone significant advancement in recent decades, and VCAs are increasingly common and accepted in the clinical setting, bringing hope of functional recovery to patients with debilitating injuries. A major obstacle facing the widespread application of VCAs is the side effect profile associated with the current immunosuppressive regimen, which can cause a wide array of complications such as infection, malignancy, and even death. Significant concerns remain regarding whether the treatment outweighs the risk. The potential solution to this dilemma would be achieving VCA tolerance, which would allow recipients to receive allografts without significant immunosuppression and its sequelae. Promising tolerance protocols are being studied in kidney transplantation; four major trials have attempted to withdraw immunosuppressive treatment with various successes. The common theme in all four trials is the use of radiation treatment and donor cell transplantation. The knowledge gained from these trials can provide valuable insight into the development of a VCA tolerance protocol. Despite similarities, VCAs present additional barriers compared to kidney allografts regarding tolerance induction. VCA donors are likely to be deceased, which limits the time for significant pre-conditioning. VCA donors are also more likely to be human leukocyte antigen–mismatched, which means that tolerance must be induced across major immunological barriers. This review also explores adjunct therapies studied in large animal models that could be the missing element in establishing a safe and stable tolerance induction method.

Regulatory T cells in skin regeneration and wound healing

“…For allograft survival, it is necessary that patients receive highly toxic but effective immunosuppressants, such as tacrolimus, mycophenolate mofetil (MMF), and steroids. Despite this, acute rejection of the skin portion of the allograft occurs in more than 85% of VCA patients within the first year and often multiple times thereafter [ 172 , 173 ]. Given the non-life-saving nature of this procedure, it is particularly important to search for novel avenues that optimize the risk–benefit ratio of VCAs.…”

Immune modulation in transplant medicine: a comprehensive review of cell therapy applications and future directions

“…Despite the adoption of SOT triple therapy as the standard maintenance regimen for the majority of VCA patients, the occurrence of acute rejection within the first-year post-transplant remains high, exceeding 80% ( 23 ). Furthermore, while chronic rejection rates in VCA patients have not been definitively established, approximately 85% of VCA recipients experience at least one episode of acute rejection during their first year of transplantation ( 24 , 25 ).…”

Novel cell-based strategies for immunomodulation in vascularized composite allotransplantation

“…Donor specific tolerance induction which aims for long-term immunosuppression-free graft acceptance without clinical or histological evidence of rejection, is the goal of many preclinical and clinical studies [14,15]. This tolerant state prevents acute allograft rejection, slows the development of CR, which is the primary long-term cause of graft loss [16,17]. Tolerance induction strategies can be cellbased, pharmaceutical-based or a combination of both.…”