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Original Research ARTICLE Provisionally accepted The full-text will be published soon. Notify me

Front. Immunol. | doi: 10.3389/fimmu.2019.02489

Non-Uniform In Vivo Expansion of Epstein-Barr Virus-Specific T-cells Following Donor Lymphocyte Infusion for Post-Transplant Lymphoproliferative Disease

 David M. Burns1, Gordon B. Ryan1, Caroline M. Harvey2, Eszter Nagy1, Simon Hughes3,  Paul G. Murray1, Nigel H. Russell2, Christopher P. Fox2 and  Heather M. Long1*
  • 1Institute of Immunology and Immunotherapy, College of Medical and Dental Sciences, University of Birmingham, United Kingdom
  • 2Department of Clinical Haematology, Nottingham University Hospitals NHS Trust, United Kingdom
  • 3Department of Radiology, Nottingham University Hospitals NHS Trust, United Kingdom

Epstein-Barr virus (EBV)-associated post-transplant lymphoproliferative disease (PTLD) is a life-threatening complication of T-lymphocyte deplete allogeneic hematopoietic stem cell transplantation (allo-HSCT). For patients with PTLD refractory to Rituximab, donor lymphocyte infusion (DLI) is established as a successful option for salvage therapy. However, although in vivo lymphocyte expansion has been correlated with good clinical outcome following DLI, the specificity and functional characteristics of EBV-specific T-cell responses remain poorly characterized. Here we describe two patients with Rituximab-refractory PTLD complicating T-cell deplete allo-HSCT, both of which were successfully rescued with 1x106/Kg unselected stem cell donor-derived DLI. Prospective analyses revealed that complete clinical and radiological responses were associated with in vivo expansion of T and NK cells. Furthermore, EBV MHC tetramer and interferon gamma analyses revealed a marked increase in EBV-specific T-cell frequency from 4 weeks after DLI. Reactivity was demonstrated against a range of EBV latent and lytic antigens, including those detected in tumor biopsy material. The immunodominant EBV-specific T cell response expanding in vivo following infusion matched the dominant response present in the DLI preparations prior to administration. Furthermore, differences in the repertoire of subdominant antigen-specific T-cells were also detected, suggesting that antigen-encounter in vivo can shape the immune response. These results demonstrate the value of prospectively studying in vivo T-cell responses, by facilitating the identification of important specificities required for clinical efficacy. Applying this approach on a larger scale promises to yield data which may be essential for the optimization of future adoptive immunotherapeutic strategies for PTLD.

Keywords: post-transplant lymphoproliferative disease, Epstein - Barr virus, Adoptive T Cell Therapy, PTLD, Donor lymphocyte infusion (DLI), T cells, flow cytmetry, Tetramers

Received: 30 May 2019; Accepted: 04 Oct 2019.

Copyright: © 2019 Burns, Ryan, Harvey, Nagy, Hughes, Murray, Russell, Fox and Long. This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.

* Correspondence: Dr. Heather M. Long, Institute of Immunology and Immunotherapy, College of Medical and Dental Sciences, University of Birmingham, Birmingham, B15 2TT, England, United Kingdom,