Successful Expansion of Functional and Stable Regulatory T Cells for Immunotherapy in Liver Transplantation

Oncotarget. 2016 Feb 16;7(7):7563-77. doi: 10.18632/oncotarget.6927.

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.

Keywords: Immune response; Immunity; Immunology and Microbiology Section; immunosuppression; immunotherapy; liver transplantation; regulatory T cells; tolerance.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Alcohol-Related Disorders / immunology
  • Alcohol-Related Disorders / therapy*
  • Cells, Cultured
  • Enzyme-Linked Immunosorbent Assay
  • Flow Cytometry
  • Follow-Up Studies
  • Humans
  • Immune Tolerance / drug effects
  • Immune Tolerance / immunology
  • Immunosuppressive Agents / therapeutic use
  • Immunotherapy*
  • Liver Cirrhosis / immunology
  • Liver Cirrhosis / therapy*
  • Liver Transplantation*
  • Prospective Studies
  • T-Lymphocytes / cytology*
  • T-Lymphocytes / drug effects
  • T-Lymphocytes / immunology
  • T-Lymphocytes, Regulatory / cytology*
  • T-Lymphocytes, Regulatory / drug effects
  • T-Lymphocytes, Regulatory / immunology
  • Th17 Cells / cytology*
  • Th17 Cells / drug effects
  • Th17 Cells / immunology

Substances

  • Immunosuppressive Agents