Tolerance Induction in Vascularized Composite Allotransplantation—A Brief Review of Preclinical Models

Abstract

Pre-clinical studies are an obligatory tool to develop and translate novel therapeutic strategies into clinical practice. Acute and chronic rejection mediated by the recipient’s immune system remains an important limiting factor for the (long-term) survival of vascularized composite allografts (VCA). Furthermore, high intensity immunosuppressive (IS) protocols are needed to mitigate the immediate and long-term effects of rejection. These IS regiments can have significant side-effects such as predisposing transplant recipients to infections, organ dysfunction and malignancies. To overcome these problems, tolerance induction has been proposed as one strategy to reduce the intensity of IS protocols and to thereby mitigate long-term effects of allograft rejection. In this review article, we provide an overview about animal models and strategies that have been used to induce tolerance. The induction of donor-specific tolerance was achieved in preclinical animal models and clinical translation may help improve short and long-term outcomes in VCAs in the future.

Efficacy of Engraftment and Safety of Human Umbilical Di-Chimeric Cell (HUDC) Therapy after Systemic Intraosseous Administration in an Experimental Model

“…Given the intricate nature of cell-based therapy within the transplantation field, a variety of animal models have been investigated to gain valuable insights into the immunomodulation, induction of graft tolerance, and factors influencing tissue regeneration. Among these models, rodent models have emerged as the most popular choice for preclinical studies due to the relatively low housing cost, ease of maintenance, and extensive genetic and physiological similarities to humans [14,68,69].…”

“…Nevertheless, the translation of these cell-based therapies from preclinical models to clinical practice requires assessment of the maintenance of both donor-specific phenotypes and safety profile. These confirmations are crucial for expanding the clinical applicability of cellular therapies and propelling advancements in the field of regenerative medicine [13,14].…”

Hedgehog costimulation during ischemia-reperfusion injury potentiates cytokine and homing responses of CD4+ T cells

“…While toleragenic strategies have been proposed, including CAR T and autologous Treg therapies ( 37 , 43 , 45 ), targeted therapies toward Tmem showing enhanced peripheral tissue homing, inclusive of Ptch Hi Tmem, have not been explored in the setting of VCAs. Blockade of EC-mediated anti-VCAM1 interactions via biologics, including natalizumab and vedolizumab, has proven effective in ameliorating T-cell homing to inflamed tissues in autoimmune disease and may show promise in blocking immune complications attendant to VCAs.…”

Sub-Zero Non-Freezing of Vascularized Composite Allografts Preservation in Rodents

“…Additionally, these grafts contain skin tissue, which is known to be highly immunogenic [ 9 ]. Recent research focuses on developing tolerance induction protocols through mixed chimerism that aim to reduce the need for immunosuppressive treatments [ 10 , 11 ]. However, for VCAs live donation is not an option [ 12 ] and tolerance protocols require 48h of patient preparation prior to transplantation (conditioning period), thereby making extended organ storage a priority.…”