Non-uniform in vivo Expansion of Epstein-Barr Virus-Specific T-Cells Following Donor Lymphocyte Infusion for Post-transplant Lymphoproliferative Disease
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 establi...
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| Format: | Article |
| Language: | English |
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Frontiers Media S.A.
2019-10-01
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| Series: | Frontiers in Immunology |
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| Online Access: | https://www.frontiersin.org/article/10.3389/fimmu.2019.02489/full |
| _version_ | 1818142788943872000 |
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| author | David M. Burns Gordon B. Ryan Gordon B. Ryan Caroline M. Harvey Eszter Nagy Eszter Nagy Simon Hughes Paul G. Murray Paul G. Murray Nigel H. Russell Christopher P. Fox Heather M. Long Heather M. Long |
| author_facet | David M. Burns Gordon B. Ryan Gordon B. Ryan Caroline M. Harvey Eszter Nagy Eszter Nagy Simon Hughes Paul G. Murray Paul G. Murray Nigel H. Russell Christopher P. Fox Heather M. Long Heather M. Long |
| author_sort | David M. Burns |
| collection | DOAJ |
| description | 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 whom were successfully rescued with 1 × 106/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. |
| first_indexed | 2024-12-11T11:21:21Z |
| format | Article |
| id | doaj.art-907bed34adb54dc59ab39d277e93efd3 |
| institution | Directory Open Access Journal |
| issn | 1664-3224 |
| language | English |
| last_indexed | 2024-12-11T11:21:21Z |
| publishDate | 2019-10-01 |
| publisher | Frontiers Media S.A. |
| record_format | Article |
| series | Frontiers in Immunology |
| spelling | doaj.art-907bed34adb54dc59ab39d277e93efd32022-12-22T01:09:10ZengFrontiers Media S.A.Frontiers in Immunology1664-32242019-10-011010.3389/fimmu.2019.02489475384Non-uniform in vivo Expansion of Epstein-Barr Virus-Specific T-Cells Following Donor Lymphocyte Infusion for Post-transplant Lymphoproliferative DiseaseDavid M. Burns0Gordon B. Ryan1Gordon B. Ryan2Caroline M. Harvey3Eszter Nagy4Eszter Nagy5Simon Hughes6Paul G. Murray7Paul G. Murray8Nigel H. Russell9Christopher P. Fox10Heather M. Long11Heather M. Long12Institute for Immunology and Immunotherapy, University of Birmingham, Birmingham, United KingdomInstitute for Immunology and Immunotherapy, University of Birmingham, Birmingham, United KingdomCancer Immunology and Immunotherapy Centre, University of Birmingham, Birmingham, United KingdomDepartment of Clinical Haematology, Nottingham University Hospitals NHS Trust, Nottingham, United KingdomInstitute for Immunology and Immunotherapy, University of Birmingham, Birmingham, United KingdomCancer Immunology and Immunotherapy Centre, University of Birmingham, Birmingham, United KingdomDepartment of Radiology, Nottingham University Hospitals NHS Trust, Nottingham, United KingdomInstitute for Immunology and Immunotherapy, University of Birmingham, Birmingham, United KingdomCancer Immunology and Immunotherapy Centre, University of Birmingham, Birmingham, United KingdomDepartment of Clinical Haematology, Nottingham University Hospitals NHS Trust, Nottingham, United KingdomDepartment of Clinical Haematology, Nottingham University Hospitals NHS Trust, Nottingham, United KingdomInstitute for Immunology and Immunotherapy, University of Birmingham, Birmingham, United KingdomCancer Immunology and Immunotherapy Centre, University of Birmingham, Birmingham, United KingdomEpstein-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 whom were successfully rescued with 1 × 106/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.https://www.frontiersin.org/article/10.3389/fimmu.2019.02489/fullpost-transplant lymphoproliferative diseasePTLDEpstein-Barr virusadoptive T-cell therapydonor lymphocyte infusionT-cells |
| spellingShingle | David M. Burns Gordon B. Ryan Gordon B. Ryan Caroline M. Harvey Eszter Nagy Eszter Nagy Simon Hughes Paul G. Murray Paul G. Murray Nigel H. Russell Christopher P. Fox Heather M. Long Heather M. Long Non-uniform in vivo Expansion of Epstein-Barr Virus-Specific T-Cells Following Donor Lymphocyte Infusion for Post-transplant Lymphoproliferative Disease Frontiers in Immunology post-transplant lymphoproliferative disease PTLD Epstein-Barr virus adoptive T-cell therapy donor lymphocyte infusion T-cells |
| title | Non-uniform in vivo Expansion of Epstein-Barr Virus-Specific T-Cells Following Donor Lymphocyte Infusion for Post-transplant Lymphoproliferative Disease |
| title_full | Non-uniform in vivo Expansion of Epstein-Barr Virus-Specific T-Cells Following Donor Lymphocyte Infusion for Post-transplant Lymphoproliferative Disease |
| title_fullStr | Non-uniform in vivo Expansion of Epstein-Barr Virus-Specific T-Cells Following Donor Lymphocyte Infusion for Post-transplant Lymphoproliferative Disease |
| title_full_unstemmed | Non-uniform in vivo Expansion of Epstein-Barr Virus-Specific T-Cells Following Donor Lymphocyte Infusion for Post-transplant Lymphoproliferative Disease |
| title_short | Non-uniform in vivo Expansion of Epstein-Barr Virus-Specific T-Cells Following Donor Lymphocyte Infusion for Post-transplant Lymphoproliferative Disease |
| title_sort | non uniform in vivo expansion of epstein barr virus specific t cells following donor lymphocyte infusion for post transplant lymphoproliferative disease |
| topic | post-transplant lymphoproliferative disease PTLD Epstein-Barr virus adoptive T-cell therapy donor lymphocyte infusion T-cells |
| url | https://www.frontiersin.org/article/10.3389/fimmu.2019.02489/full |
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