Abstract
BackgroundAdoptive transfer of virus-specific T cells (VSTs) represents a prophylactic and curative approach for opportunistic viral infections and reactivations after transplantation. However, inadequate frequencies of circulating memory VSTs in the T-cell donor’s peripheral blood often result in insufficient enrichment efficiency and purity of the final T-cell product, limiting the effectiveness of this approach.MethodsThis pilot study was designed as a cross-over trial and compared the effect of a single bout (30 min) of high-intensity interval training (HIT) with that of 30 min of continuous exercise (CONT) on the frequency and function of circulating donor VSTs. To this end, we used established immunoassays to examine the donors’ cellular immune status, in particular, with respect to the frequency and specific characteristics of VSTs restricted against Cytomegalovirus (CMV)-, Epstein–Barr-Virus (EBV)- and Adenovirus (AdV)-derived antigens. T-cell function, phenotype, activation and proliferation were examined at different time points before and after exercise to identify the most suitable time for T-cell donation. The clinical applicability was determined by small-scale T-cell enrichment using interferon- (IFN-) γ cytokine secretion assay and virus-derived overlapping peptide pools.ResultsHIT proved to be the most effective exercise program with up to fivefold higher VST response. In general, donors with a moderate fitness level had higher starting and post-exercise frequencies of VSTs than highly fit donors, who showed significantly lower post-exercise increases in VST frequencies. Both exercise programs boosted the number of VSTs against less immunodominant antigens, specifically CMV (IE-1), EBV (EBNA-1) and AdV (Hexon, Penton), compared to VSTs against immunodominant antigens with higher memory T-cell frequencies.ConclusionThis study demonstrates that exercise before T-cell donation has a beneficial effect on the donor’s cellular immunity with respect to the proportion of circulating functionally active VSTs. We conclude that a single bout of HIT exercise 24 h before T-cell donation can significantly improve manufacturing of clinically applicable VSTs. This simple and economical adjuvant treatment proved to be especially efficient in enhancing virus-specific memory T cells with low precursor frequencies.
Highlights
Adoptive transfer of virus-specific T cells (VSTs) represents a prophylactic and curative approach for opportunistic viral infections and reactivations after transplantation
It is established that the delay in the reconstitution of virusspecific CD8+ and/or CD4+ T-cell responses is a critical factor in viral recrudescence and viral disease and that the permanent control and elimination of a virus depends on the presence of functional virus-specific T cells (VSTs) [18, 19]
Proof‐of concept: enrichment of antiviral T cells using small scale Cytokine Secretion Assay Encouraged by the positive effect of high-intensity interval training (HIT) on VST activation identified by the IFN-γ EliSpot assay, we examined its effect on IFN-γ-secreting T cells using the IFN-γ CSA, which revealed a similar outcome (Fig. 4)
Summary
Adoptive transfer of virus-specific T cells (VSTs) represents a prophylactic and curative approach for opportunistic viral infections and reactivations after transplantation. Inadequate frequencies of circulating memory VSTs in the T-cell donor’s peripheral blood often result in insufficient enrichment efficiency and purity of the final T-cell product, limiting the effectiveness of this approach. Latent herpes viruses such as Cytomegalovirus (CMV) and Epstein–Barr virus (EBV) as well as lytic viruses such as Adenovirus (AdV) remain an important cause of morbidity and mortality after hematopoietic stem cell transplantation (HSCT) and solid organ transplantation (SOT) in immunocompromised patients [1,2,3]. We demonstrated the successful use of EBV-specific T cells as a consolidating treatment for a patient suffering from EBVassociated PTLD of the central nervous system [27]
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