Treg-Centric View of Immunosuppressive Drugs in Transplantation: A Balancing Act

Abstract

Regulatory CD4+ Foxp3+ T cells (Tregs) are critical in controlling immunity and tolerance. Thus, preserving Treg numbers and function in transplanted patients is essential for the successful minimization of maintenance immunosuppression. Multiple cellular signals control the development, differentiation, and function of Tregs. Many of these signals are shared with conventional Foxp3 T cells (Tconv) and are targeted by immunosuppressive drugs, negatively affecting both Tregs and Tconv. Because intracellular signals vary in optimal intensity in different T cell subsets, improved specificity in immunosuppressive regimens must occur to benefit long-term transplant outcomes. In this regard, recent advances are gradually uncovering differences in the signals required in Tregs and Tconv biology, opening the door to new potential therapeutic approaches to either enhance or spare Tregs. In this review, we will explain the prominent cell signaling pathways critical for Treg maintenance and function, while reporting the effects of immunosuppressive drugs targeting these signaling pathways in clinical transplantation settings.

Transplant trials with Tregs: perils and promises

“…CNIs produce effective immunosuppression early after transplantation, but have adverse long-term effects for both the patient and the renal allograft (6). CNIs impede the emergence of tolerogenic immune responses, propagating the dependence on maintenance drugs for immunosuppression (7,8). Unlike currently used experimental stem cell regimens, Treg therapies do not require drastic conditioning regimens and do not pose a risk of GVHD (4,9); however, the promising results obtained with Treg infusions in experimental transplantation and autoimmunity models have yet to be fully tested in humans.…”

Induction of immunological tolerance to myelinogenic glial-restricted progenitor allografts

“…Although Tregs are important regulators for alloimmune responses (Adams et al, 2016) in organ and cell transplantation (Camirand and Riella, 2017), the effects of costimulation blockade on Tregs is still unclear. It was assumed that co-stimulation blockade inhibits Treg survival and function (Adams et al, 2016), and an in-vitro study showed that CTLA4-Ig inhibited Treg proliferation (Levitsky et al, 2013).…”

Impact of TBX21, GATA3, and FOXP3 gene polymorphisms on acute cellular rejection after liver transplantation

“…An alternative explanation why there is only an association with l‐BPACR liver transplant recipients and not with e‐BPACR liver transplant recipients may be because of the immunosuppressive treatment. It has been reported that calcineurin inhibitors significantly reduce Treg numbers and Treg development in transplanted patients . Often the dose of calcineurin inhibitors is minimized at a later post‐transplant time point in order to reduce side effects.…”

“…It has been reported that calcineurin inhibitors significantly reduce Treg numbers and Treg development in transplanted patients. 24,25 Often the dose of calcineurin inhibitors is minimized at a later post-transplant time point in order to reduce side effects. This may be the reason why the SNP rs3761548 shows only an association in the late post-transplant phase.…”