Abstract

Strategies to prevent organ transplant rejection whilst minimizing long-term immunosuppression are currently under intense investigation with regulatory T cells (Tregs) nearing clinical application. The clinical trial, ThRIL, recently commenced at King's College London, proposes to use Treg cell therapy to induce tolerance in liver transplant recipients, the success of which has the potential to revolutionize the management of these patients and enable a future of drug-free transplants. This is the first report of the manufacture of clinical grade Tregs from prospective liver transplant recipients via a CliniMACS-based GMP isolation technique and expanded using anti-CD3/CD28 beads, IL-2 and rapamycin. We report the enrichment of a pure, stable population of Tregs (>95% CD4+CD25+FOXP3+), reaching adequate numbers for their clinical application. Our protocol proved successful in, influencing the expansion of superior functional Tregs, as compared to freshly isolated cells, whilst also preventing their conversion to Th17 cells under pro-inflammatory conditions. We conclude with the manufacture of the final Treg product in the clinical research facility (CRF), a prerequisite for the clinical application of these cells. The data presented in this manuscript together with the much-anticipated clinical results from ThRIL, will undoubtedly inform the improved management of the liver transplant recipient.

Highlights

  • Liver transplantation remains the treatment of choice for patients with end stage liver disease

  • We further present the successful manufacture of the final drug product in the Biomedical Research Centre Clinical Research Facility (BRC clinical research facility (CRF)) at Guy’s Hospital (King’s College London) as a prelude for ThRIL

  • In preparation for ThRIL, clinical grade autologous Tregs were isolated from 9 patients with alcohol related cirrhosis (ARC), awaiting transplantation, and 9 age and sex matched healthy controls (HCs)

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Summary

Introduction

Liver transplantation remains the treatment of choice for patients with end stage liver disease. There have been reports of a variable proportion of liver transplant recipients developing a state of ‘operational’ tolerance forgoing the requirements of therapeutic immunosuppression [1]. This phenomenon, only occurs late after transplantation and in a minority of patients [2]. It is, necessary to find novel strategies to allow for the development of tolerance early after transplantation and in turn negate the use of lifelong immunosuppression

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