Ex vivo generation of regulatory T cells from liver transplant recipients using costimulation blockade

Abstract

The potential of adoptive cell therapy with regulatory T cells (Tregs) to promote transplant tolerance is under active exploration. However, the impact of specific transplant settings and protocols on Treg manufacturing is not well‐delineated. Here, we compared the use of peripheral blood mononuclear cells (PBMCs) from patients before or after liver transplantation to the use of healthy control PBMCs to determine their suitability for Treg manufacture using ex vivo costimulatory blockade with belatacept. Despite liver failure or immunosuppressive therapy, the capacity for Treg expansion during the manufacturing process was preserved. These experiments did not identify performance or quality issues that disqualified the use of posttransplant PBMCs—the currently favored protocol design. However, as Treg input correlated with output, significant CD4‐lymphopenia in both pre‐ and posttransplant patients limited Treg yield. We therefore turned to leukapheresis posttransplant to improve absolute yield. To make deceased donor use feasible, we also developed protocols to substitute splenocytes for PBMCs as allostimulators. In addition to demonstrating that this Treg expansion strategy works in a liver transplant context, this preclinical study illustrates how characterizing cellular input populations and their performance can both inform and respond to clinical trial design and Treg manufacturing requirements.

Emerging translational strategies and challenges for enhancing regulatory T cell therapy for graft-versus-host disease

“…A platform has been developed for solid organ transplant in which allo(donor)-specific Tregs from healthy donors or recipients post-transplantation are expanded in the presence of co-stimulatory blockade. Such Tregs maintain Foxp3 demethylation status which strongly correlates with stability ( 181 , 182 ).…”

Transcriptomic analysis of graft liver provides insight into the immune response of rat liver transplantation

“…Studies have also shown that costimulatory pathways blockade could limit the activation of T cells reversely ( 12 ), which may alter the immune response against allograft and attenuate rejection, prolonging graft survival time ( 13 ). Currently, the potential for adoptive cell therapy with Tregs to promote transplant tolerance is being actively explored ( 14 ). Although most results of these trials are optimistic, many experimental and clinical unanswered questions are slowing the progression of this new therapeutic alternative ( 15 ).…”

Moving the Goalpost: From “Alive” to “Ideal”

“…End-stage renal disease is also more permissive than end stage liver disease of harsh conditioning regimens that underpin some tolerance protocols. 8 Delayed protocols for immunosuppression withdrawal that do not involve intense conditioning are being developed, particularly in liver, 9 and as the practice of tolerance advances, it is important to keep in mind the pediatric liver transplant population.…”