A New Generation of Cell Therapies Employing Regulatory T Cells (Treg) to Induce Immune Tolerance in Pediatric Transplantation

Abstract

Kidney transplantation is the most common solid organ transplant and the preferred treatment for pediatric patients with end-stage renal disease, but it is still not a definitive solution due to immune graft rejection. Regulatory T cells (Treg) and their control over effector T cells is a crucial and intrinsic tolerance mechanism in limiting excessive immune responses. In the case of transplants, Treg are important for the survival of the transplanted organ, and their dysregulation could increase the risk of rejection in transplanted children. Chronic immunosuppression to prevent rejection, for which Treg are especially sensitive, have a detrimental effect on Treg counts, decreasing the Treg/T-effector balance. Cell therapy with Treg cells is a promising approach to restore this imbalance, promoting tolerance and thus increasing graft survival. However, the strategies used to date that employ peripheral blood as a Treg source have shown limited efficacy. Moreover, it is not possible to use this approach in pediatric patients due to the limited volume of blood that can be extracted from children. Here, we outline our innovative strategy that employs the thymus removed during pediatric cardiac surgeries as a source of therapeutic Treg that could make this therapy accessible to transplanted children. The advantageous properties and the massive amount of Treg cells obtained from pediatric thymic tissue (thyTreg) opens a new possibility for Treg therapies to prevent rejection in pediatric kidney transplants. We are recruiting patients in a clinical trial to prevent rejection in heart-transplanted children through the infusion of autologous thyTreg cells (NCT04924491). If its efficacy is confirmed, thyTreg therapy may establish a new paradigm in preventing organ rejection in pediatric transplants, and their allogeneic use would extend its application to other solid organ transplantation.

Treg in inborn errors of immunity: gaps, knowns and future perspectives

“…With the first human treated with Treg in 2009, ACT using Treg is a rapidly expanding field that offers substantial advantages and holds great promise for medical applications ( 140 ). Numerous clinical trials are currently being carried out with Treg cell-based therapies to manage GVHD ( 39 ), T1D ( 141 ) and transplant rejection ( 142 ). As highlighted throughout this review, Tregs exhibit suppressive and immunoregulatory functions that render them ideal for addressing diseases characterized by immune activation.…”

“…An important limitation in approaches that use peripheral blood as the Treg source is the low number of Treg cells that can be obtained, making it challenging to achieve sufficient cell numbers for therapy. Additionally, the expansion process itself can lead to an exhausted phenotype of the Treg, potentially impacting functionality, stability, and efficacy ( 39 ).…”

“…As direct mechanisms, Tregs secrete suppressive cytokines such as IL-10, TGF-β, and IL-35 that act directly on effector T cells (Teff). They also produce perforin and granzyme-inducing apoptosis in target cells ( 39 ). Besides these secreted proteins, Tregs express a number of surface molecules that enable them to perform their inhibitory functions: through CTLA-4 and lymphocyte activation gene 3 (LAG-3) they can inhibit dendritic cells (DCs) ( 5 ) and through programmed cell death 1 (PD-1) they directly inhibit B cells ( 39 ).…”

“…They also produce perforin and granzyme-inducing apoptosis in target cells ( 39 ). Besides these secreted proteins, Tregs express a number of surface molecules that enable them to perform their inhibitory functions: through CTLA-4 and lymphocyte activation gene 3 (LAG-3) they can inhibit dendritic cells (DCs) ( 5 ) and through programmed cell death 1 (PD-1) they directly inhibit B cells ( 39 ). Moreover, the high levels of CD25 allow Tregs to highjack IL-2 preventing it from stimulating T and natural killer (NK) cells ( 2 ).…”

“…As indirect mechanisms, Tregs also present ectoenzymes on their membrane, specifically CD39 and CD73, that are responsible for ATP metabolism and control Teff activation. ATP acts as an inflammatory molecule when it is cleaved, AMP acts as an anti-inflammatory signal ( 5 , 39 ).…”