Abstract
Cytomegalovirus (CMV) and Epstein-Barr virus (EBV) infections remain a major cause of morbidity and mortality after allogeneic hematopoietic stem cell transplantation (HSCT). The adoptive transfer of donor-derived viral-specific cytotoxic T-cells (VSTs) is an effective treatment for controlling CMV and EBV infections after HSCT; however, new practical methods are required to augment the ex vivo manufacture of multi-VSTs from healthy donors. This study investigated the effects of a single exercise bout on the ex vivo manufacture of multi-VSTs. PBMCs isolated from healthy CMV/EBV seropositive participants before (PRE) and immediately after (POST) 30-minutes of cycling exercise were stimulated with CMV (pp65 and IE1) and EBV (LMP2A and BMLF1) peptides and expanded over 8 days. The number (fold difference from PRE) of T-cells specific for CMV pp65 (2.6), EBV LMP2A (2.5), and EBV BMLF1 (4.4) was greater among the VSTs expanded POST. VSTs expanded PRE and POST had similar phenotype characteristics and were equally capable of MHC-restricted killing of autologous target cells. We conclude that a single exercise bout enhances the manufacture of multi-VSTs from healthy donors without altering their phenotype or function and may serve as a simple and economical adjuvant to boost the production of multi-VSTs for allogeneic adoptive transfer immunotherapy.
Highlights
Cytomegalovirus (CMV) and Epstein-Barr virus (EBV) infections remain a major cause of morbidity and mortality after allogeneic hematopoietic stem cell transplantation (HSCT)
This study shows for the first time that a single bout of dynamic exercise markedly increases the production of CMV- and EBV-specific T-cells from healthy donors following a single exposure to clinically relevant viral peptides
We hypothesized that the exercise-induced mobilization of these viral-specific cytotoxic T-cells (VSTs) into the blood compartment would augment the production of cells lines with T-cells specific to multiple viruses for use in the allogeneic adoptive transfer immunotherapy setting
Summary
Cytomegalovirus (CMV) and Epstein-Barr virus (EBV) infections remain a major cause of morbidity and mortality after allogeneic hematopoietic stem cell transplantation (HSCT). The adoptive transfer of donor-derived viral-specific cytotoxic T-cells (VSTs) is an effective treatment for controlling CMV and EBV infections after HSCT; new practical methods are required to augment the ex vivo manufacture of multi-VSTs from healthy donors. VSTs are often directly isolated from donor blood samples using MHC class I multimers (i.e. pentamers or tetramers) that are loaded with synthetic virus specific peptide HLA molecules allowing them to bind to cognate receptors on the T-cells. This approach has limitations as it requires prior knowledge of immunodominant epitopes and is restricted by donor HLA type[10]. New methods are required to increase the frequency of VSTs within the final product to be clinically efficacious
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