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.

Keywords: Vascularized composite allotransplantation; animal models; rodent; swine; tolerance induction.

FIGURE 1

Figure shows cell-based tolerance induction approaches in VCA. Bone marrow transplantation with donor-derived stem cells can induce mixed chimerism and thereby induce tolerance (A), vascularized bone marrow as continuous source for donor derived hematopoietic cells might be able to help minimize immunosuppressants (B) and mesenchymal stem cells extracted from adipose tissue (C) are already tested in VCA to induce tolerance through mixed chimerism and direct effects on the graft. The extraction of Treg cells (D), modification into CAR-Tcells using CRISPR/C9 and infusion into humans is tested in clinical trials with SOT so far and seems to be a promising approach to induce tolerance in VCA. CAR-Tcells can recognize MHC-I on donor cells and block their interaction with the recipient´s immune system to prevent rejection (Figure created with BioRender.com).

FIGURE 2

Left (A) demonstrates physiologic naïve T-cell activation. Antigen presenting cells (APC) interact with the CD28 surface receptor of naïve T-cells with their ligands CD80/86 while the antigen is presented to the T-cell. This interaction will promote T-cell proliferation and activation of cellular inflammatory pathways. (B) With the use of Belatacept (second-generation CTLA4-Ig) the costimulatory interaction between APC and T-cell can be altered. Belatacept blocks the interaction of CD28 with CD80/86 by binding to CD80/86. This interaction limits the activation of T-cells and was shown to reduce alloreactivity and thereby prolong allograft survival (Figure created with BioRender.com).