Regulatory T Cells: Liquid and Living Precision Medicine for the Future of VCA

Abstract

Transplant rejection remains a challenge especially in the field of vascularized composite allotransplantation (VCA). To blunt the alloreactive immune response‚ stable levels of maintenance immunosupression are required. However‚ the need for lifelong immunosuppression poses the risk of severe side effects, such as increased risk of infection, metabolic complications, and malignancies. To balance therapeutic efficacy and medication side effects, immunotolerance promoting immune cells (especially regulatory T cells [Treg]) have become of great scientific interest. This approach leverages immune system mechanisms that usually ensure immunotolerance toward self-antigens and prevent autoimmunopathies. Treg can be bioengineered to express a chimeric antigen receptor or a T-cell receptor. Such bioengineered Treg can target specific antigens and thereby reduce unwanted off-target effects. Treg have demonstrated beneficial clinical effects in solid organ transplantation and promising in vivo data in VCAs. In this review, we summarize the functional, phenotypic, and immunometabolic characteristics of Treg and outline recent advancements and current developments regarding Treg in the field of VCA and solid organ transplantation.

Cellular activation pathways and interaction networks in vascularized composite allotransplantation

“…demonstrated the beneficial effect of T regs cells in preventing skin allograft rejection utilizing humanized mouse models ( 172 ). T regs can be equipped with a chimeric antigen receptor (CAR) representing another, yet bioengineered cell type in VCA grafts ( 173 ). Such CAR-T regs are not MHC-dependent in their activation process and instead specifically migrate to the rejection site, where they unleash more potent immunosuppression than conventional polyclonal T regs ( 3 ).…”

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

“…: CAR-Tregs) might be a promising supplementary treatment of rejection in the future. CAR-T cells are typically designed to recognize donor MHC molecules, thus localizing to donor tissues and exerting their regulatory effects in a precise and targeted manner (21). Pharmaceutical therapy regimens are the current gold standard in VCA and are mostly modifications of regimens that have already been established in SOT (23).…”

“…Tregs exert their immunosuppressive effects via cell-to-cell interaction with target immune cells, via removal of IL-2 (potent factor in T cell survival and growth), via anti-inflammatory molecules (TGF-beta) or through costimulatory pathways such as binding to cytotoxic T-lymphocyte-associated protein 4. Nevertheless, irregularity in Tregs can lead to autoimmune disorders, reduced disease tolerance or higher risk for cancer( 21 ). Recent studies have investigated the potential therapeutic value of genetically modified patient-derived Tregs, such as antigen-specific Chimeric Antigen Receptor (CAR)-Tregs, targeting for example MHC-class I expressed by donor cells.…”

“…: CAR-Tregs) might be a promising supplementary treatment of rejection in the future. CAR-T cells are typically designed to recognize donor MHC molecules, thus localizing to donor tissues and exerting their regulatory effects in a precise and targeted manner ( 21 ).…”

“…However, stable macro or micro chimerism has not been documented in human VCA. Further studies are necessary, for example on how to enhance the ability of vascularized bone marrow to induce chimerism, e.g., via Treg modulative strategies to increase acceptance of donor derived hematopoietic stem cells ( 21 ).…”