Successful expansion of functional and stable regulatory T cells for immunotherapy in liver transplantation

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// Niloufar Safinia 1,* , Trishan Vaikunthanathan 1,* , Henrieta Fraser 1 , Sarah Thirkell 1 , Katie Lowe 1 , Laura Blackmore 2 , Gavin Whitehouse 2 , Marc Martinez-Llordella 2 , Wayel Jassem 2 , Alberto Sanchez-Fueyo 2 , Robert I. Lechler 1 and Giovanna Lombardi 1 1 MRC Centre for Transplantation, Division of Transplantation Immunology and Mucosal Biology, King’s College London, Guy’s Hospital, London, UK 2 Institute of Liver Studies, King’s College Hospital, London, UK * Co-first author Correspondence to: Niloufar Safinia, email: // Giovanna Lombardi, email: // Keywords : regulatory T cells, tolerance, immunotherapy, immunosuppression, liver transplantation, Immunology and Microbiology Section, Immune response, Immunity Received : July 26, 2015 Accepted : January 01, 2016 Published : January 17, 2016 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.