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Bozhkova M, Gardzheva P, Rangelova V, Taskov H, Murdjeva M. Cutting-edge assessment techniques for B cell immune memory: an overview. BIOTECHNOL BIOTEC EQ 2024; 38. [DOI: 10.1080/13102818.2024.2345119] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/06/2023] [Revised: 04/02/2024] [Accepted: 04/15/2024] [Indexed: 10/31/2024] Open
Affiliation(s)
- Martina Bozhkova
- Department of Medical Microbiology and Immunology “Prof. Elisey Yanev, MD”, Medical University–Plovdiv, Plovdiv, Bulgaria
- Research Institute, Medical University–Plovdiv, Plovdiv, Bulgaria
- Laboratory of Clinical Immunology, University Hospital “St. George”, Plovdiv, Bulgaria
| | - Petya Gardzheva
- Department of Medical Microbiology and Immunology “Prof. Elisey Yanev, MD”, Medical University–Plovdiv, Plovdiv, Bulgaria
- Research Institute, Medical University–Plovdiv, Plovdiv, Bulgaria
- Laboratory of Clinical Immunology, University Hospital “St. George”, Plovdiv, Bulgaria
| | - Vanya Rangelova
- Department of Epidemiology and Disaster Medicine, Faculty of Public Health, Medical University–Plovdiv, Plovdiv, Bulgaria
| | - Hristo Taskov
- Research Institute, Medical University–Plovdiv, Plovdiv, Bulgaria
- Laboratory of Clinical Immunology, University Hospital “St. George”, Plovdiv, Bulgaria
| | - Marianna Murdjeva
- Department of Medical Microbiology and Immunology “Prof. Elisey Yanev, MD”, Medical University–Plovdiv, Plovdiv, Bulgaria
- Research Institute, Medical University–Plovdiv, Plovdiv, Bulgaria
- Laboratory of Clinical Immunology, University Hospital “St. George”, Plovdiv, Bulgaria
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Ikegame K, Fukunaga K, Osugi Y, Kaida K, Teramoto M, Inoue T, Okada M, Yoshihara K, Tamaki H, Yoshihara S, Fujiwara H. Donor-derived cytomegalovirus-specific CD8 + T cells restricted to shared, donor-specific, or host-specific HLA after HLA mismatched hematopoietic stem cell transplantation. Transpl Immunol 2024; 87:102099. [PMID: 39111366 DOI: 10.1016/j.trim.2024.102099] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/02/2023] [Revised: 05/17/2024] [Accepted: 07/24/2024] [Indexed: 09/14/2024]
Abstract
Immune reconstitution after human leukocyte antigen (HLA)-mismatched (haploidentical) hematopoietic stem cell transplantation (haplo-HCT) can significantly influence long-term outcomes. The three possible HLA haplotypes after transplantation are: one carried by both the patient and the donor (shared HLA), one by donor only (donor-specific HLA), and one by patient only (host-specific HLA), and the donor T cells remain restricted to one of these three haplotypes. Understanding the presence of donor T cells restricted to each haplotype may provide more detailed insights into post-transplant immune response and potentially provide valuable information for the development of chimeric antigen receptor T cell or T cell receptor T cell constructs. In this study, patients or donors with HLA-A24 or HLA-A2 were tested with HLA-A*24:02- and A*02:01-restricted cytomegalovirus (CMV)-specific tetramers for detecting the respective HLA-restricted T cells. Sixty-four samples from 40 patients were assayed. More than half of the patients at day 90 and all patients by day 900 had shared HLA-restricted T cells. After day 90, half of the patients had donor-specific HLA-restricted T cells, but no host-specific HLA-restricted T cells were found. In the comparative analysis of the transplant types, shared HLA-restricted T cells were positive in all three categories: haplo-HCT (50%), 2-haplo-mis-HCT (75%), and spousal HCT (67%). Furthermore, donor-specific HLA-restricted T cells demonstrated positivity in haplo-HCT at 57% and in 2-haplo-mis-HCT at 60%, with a threshold of 0.01%. Donor-specific HLA-restricted T cells for spousal HCT were not examined due to the lack of an appropriate HLA combination for the tetramers. The presence of shared HLA-restricted T cells explains the host defense after HLA-haploidentical transplantation, while the presence of donor-specific HLA-restricted T cells may account for host defense against hematotropic viruses, such as CMV. However, this study failed to detect host-specific HLA-restricted T cells, leaving the host defense against epitheliotropic viruses unresolved, thus requiring further investigation.
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Affiliation(s)
- Kazuhiro Ikegame
- Department of Hematology, Hyogo Medical University, Hyogo, Japan; Hematopoietic Cell Transplantation Center, Aichi Medical University of School of Medicine, Aichi, Japan.
| | - Keiko Fukunaga
- Department of Hematology, Hyogo Medical University, Hyogo, Japan; Department of Hematology, Nippon Medical school, Tokyo, Japan.
| | - Yuko Osugi
- Department of Hematology, Hyogo Medical University, Hyogo, Japan.
| | - Katsuji Kaida
- Department of Hematology, Hyogo Medical University, Hyogo, Japan.
| | | | - Takayuki Inoue
- Department of Hematology, Hyogo Medical University, Hyogo, Japan.
| | - Masaya Okada
- Department of Hematology, Hyogo Medical University, Hyogo, Japan; First Department of Internal Medicine, Kansai Medical University Medical Center, Osaka, Japan.
| | - Kyoko Yoshihara
- Department of Hematology, Hyogo Medical University, Hyogo, Japan.
| | - Hiroya Tamaki
- Department of Hematology, Hyogo Medical University, Hyogo, Japan.
| | | | - Hiroshi Fujiwara
- Department of Personalized Cancer Immunotherapy, Mie University Graduate School of Medicine, Mie, Japan.
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Liang H, Gong S, Gui G, Wang H, Jiang L, Li X, Fan J. Secretion of IFN-γ by specific T cells in HCMV infection. Heliyon 2024; 10:e28177. [PMID: 38533049 PMCID: PMC10963622 DOI: 10.1016/j.heliyon.2024.e28177] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/27/2023] [Revised: 03/13/2024] [Accepted: 03/13/2024] [Indexed: 03/28/2024] Open
Abstract
One major risk for recipients undergoing allogeneic hematopoietic stem cell transplants (allo-HSCTs) is infection with the human cytomegalovirus (HCMV). For HCMV treatment, it is especially crucial to be able to differentiate between recipients who are at high risk of reactivation and those who are not. In this study, HCMV-DNA was collected from 60 HLA-A*02 allo-HSCT recipients before and after transplantation. After transplantation, the release of interferon (IFN)-γ by T cells specific to HCMV was assessed using the enzyme-linked immunospot assay (ELISPOT). The results show that the median viral load (VL) was significantly higher in the HCMV persistent-infection group compared to the non-persistent-infection group (p = 0.002), and that the late-infection rate was considerably higher in the high-VL group compared to the low-VL group (p = 0.014). The uninfected group had a considerably higher median IFN-γ spot-forming cell (SFC) count than the persistent-infection group (p = 0.001), and IFN-γ SFC counts correlated negatively and linearly with VLs (r = -0.397, p = 0.002). The immune-response groups showed significantly difference in median VL (p = 0.018), and the high immune response group had a reduced late-infection rate than the no/low immune response groups (p = 0.049). Our study showed that allo-HSCT recipients with a high VL at an early transplantation stage were at high risk for late HCMV infection. Further HCMV reactivation can be prevented by HCMV-specific T cells secreting enough IFN-γ.
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Affiliation(s)
- Hanying Liang
- State Key Laboratory for Diagnosis and Treatment of Infectious Diseases, The First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, 310003, Zhejiang, PR China
| | - Shengnan Gong
- State Key Laboratory for Diagnosis and Treatment of Infectious Diseases, The First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, 310003, Zhejiang, PR China
| | - Genyong Gui
- State Key Laboratory for Diagnosis and Treatment of Infectious Diseases, The First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, 310003, Zhejiang, PR China
| | - Huiqi Wang
- State Key Laboratory for Diagnosis and Treatment of Infectious Diseases, The First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, 310003, Zhejiang, PR China
| | - Lili Jiang
- State Key Laboratory for Diagnosis and Treatment of Infectious Diseases, The First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, 310003, Zhejiang, PR China
| | - Xuejie Li
- State Key Laboratory for Diagnosis and Treatment of Infectious Diseases, The First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, 310003, Zhejiang, PR China
| | - Jun Fan
- State Key Laboratory for Diagnosis and Treatment of Infectious Diseases, The First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, 310003, Zhejiang, PR China
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Hu X, Wang HY, Otero CE, Jenks JA, Permar SR. Lessons from Acquired Natural Immunity and Clinical Trials to Inform Next-Generation Human Cytomegalovirus Vaccine Development. Annu Rev Virol 2022; 9:491-520. [PMID: 35704747 PMCID: PMC10154983 DOI: 10.1146/annurev-virology-100220-010653] [Citation(s) in RCA: 12] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/09/2022]
Abstract
Human cytomegalovirus (HCMV) infection, the most common cause of congenital disease globally, affecting an estimated 1 million newborns annually, can result in lifelong sequelae in infants, such as sensorineural hearing loss and brain damage. HCMV infection also leads to a significant disease burden in immunocompromised individuals. Hence, an effective HCMV vaccine is urgently needed to prevent infection and HCMV-associated diseases. Unfortunately, despite more than five decades of vaccine development, no successful HCMV vaccine is available. This review summarizes what we have learned from acquired natural immunity, including innate and adaptive immunity; the successes and failures of HCMV vaccine human clinical trials; the progress in related animal models; and the analysis of protective immune responses during natural infection and vaccination settings. Finally, we propose novel vaccine strategies that will harness the knowledge of protective immunity and employ new technology and vaccine concepts to inform next-generation HCMV vaccine development.
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Affiliation(s)
- Xintao Hu
- Department of Pediatrics, Weill Cornell Medicine, New York, New York, USA;
| | - Hsuan-Yuan Wang
- Department of Pediatrics, Weill Cornell Medicine, New York, New York, USA;
- Duke Human Vaccine Institute, Duke University Medical Center, Durham, North Carolina, USA
| | - Claire E Otero
- Department of Pediatrics, Weill Cornell Medicine, New York, New York, USA;
- Duke Human Vaccine Institute, Duke University Medical Center, Durham, North Carolina, USA
| | - Jennifer A Jenks
- Duke Human Vaccine Institute, Duke University Medical Center, Durham, North Carolina, USA
| | - Sallie R Permar
- Department of Pediatrics, Weill Cornell Medicine, New York, New York, USA;
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Boccard M, Conrad A, Mouton W, Valour F, Roure-Sobas C, Frobert E, Rohmer B, Alcazer V, Labussière-Wallet H, Ghesquières H, Venet F, Brengel-Pesce K, Trouillet-Assant S, Ader F. A Simple-to-Perform ifn-γ mRNA Gene Expression Assay on Whole Blood Accurately Appraises Varicella Zoster Virus-Specific Cell-Mediated Immunity After Allogeneic Hematopoietic Stem Cell Transplantation. Front Immunol 2022; 13:919806. [PMID: 35967359 PMCID: PMC9363621 DOI: 10.3389/fimmu.2022.919806] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/13/2022] [Accepted: 06/20/2022] [Indexed: 11/22/2022] Open
Abstract
Herpes zoster, which is due to the reactivation of Varicella zoster virus (VZV), is a leading cause of morbidity after allogeneic hematopoietic stem cell transplantation (allo-HSCT). While cell-mediated immunity (CMI) is critical to inhibiting VZV reactivation, CMI is not routinely assessed due to a lack of reliable tests. In this study, we aimed to evaluate VZV-specific CMI among allo-HSCT recipients (n = 60) and healthy individuals (HI, n = 17) through a panel of three immune functional assays after ex vivo stimulation by VZV antigen: quantification of (i) IFN-γ release in the supernatants, (ii) T-cell proliferation after a 7-day stimulation of peripheral blood mononuclear cells (PBMC), and (iii) measurement of the ifn-γ mRNA gene expression level after 24 h of stimulation of a whole-blood sample. VZV responsiveness was defined according to IFN-γ release from VZV-stimulated PBMC. Upon VZV stimulation, we found that allo-HSCT recipients at a median time of 6 [5-8] months post-transplant had lower IFN-γ release (median [IQR], 0.34 [0.12–8.56] vs. 409.5 [143.9–910.2] pg/ml, P <.0001) and fewer proliferating T cells (0.05 [0.01–0.57] % vs. 8.74 [3.12–15.05] %, P <.0001) than HI. A subset of allo-HSCT recipients (VZV-responders, n = 15/57, 26%) distinguished themselves from VZV-non-responders (n = 42/57, 74%; missing data, n = 3) by higher IFN-γ release (80.45 [54.3–312.8] vs. 0.22 [0.12–0.42] pg/ml, P <.0001) and T-cell proliferation (2.22 [1.18–7.56] % vs. 0.002 [0.001–0.11] %, P <.0001), suggesting recovery of VZV-specific CMI. Interestingly, VZV responders had a significant fold increase in ifn-γ gene expression, whereas ifn-γ mRNA was not detected in whole blood of VZV-non-responders (P <.0001). This study is the first to suggest that measurement of ifn-γ gene expression in 24-h-stimulated whole blood could be an accurate test of VZV-specific CMI. The routine use of this immune functional assay to guide antiviral prophylaxis at an individual level remains to be evaluated.
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Affiliation(s)
- Mathilde Boccard
- Centre International de Recherche en Infectiologie (CIRI), Inserm U1111, Université Claude Bernard Lyon 1, CNRS, UMR5308, Ecole Normale Supérieure de Lyon, Univ Lyon, Lyon, France
- Département des Maladies infectieuses et tropicales, Hôpital de la Croix-Rousse, Hospices Civils de Lyon, Lyon, France
| | - Anne Conrad
- Centre International de Recherche en Infectiologie (CIRI), Inserm U1111, Université Claude Bernard Lyon 1, CNRS, UMR5308, Ecole Normale Supérieure de Lyon, Univ Lyon, Lyon, France
- Département des Maladies infectieuses et tropicales, Hôpital de la Croix-Rousse, Hospices Civils de Lyon, Lyon, France
| | - William Mouton
- Centre International de Recherche en Infectiologie (CIRI), Inserm U1111, Université Claude Bernard Lyon 1, CNRS, UMR5308, Ecole Normale Supérieure de Lyon, Univ Lyon, Lyon, France
- Laboratoire de Recherche Commun (LCR), Hospices Civils de Lyon/BioMérieux, Pierre-Bénite, France
| | - Florent Valour
- Centre International de Recherche en Infectiologie (CIRI), Inserm U1111, Université Claude Bernard Lyon 1, CNRS, UMR5308, Ecole Normale Supérieure de Lyon, Univ Lyon, Lyon, France
- Département des Maladies infectieuses et tropicales, Hôpital de la Croix-Rousse, Hospices Civils de Lyon, Lyon, France
| | - Chantal Roure-Sobas
- Institut des Agents Infectieux, Hôpital de la Croix-Rousse, Hospices Civils de Lyon, Lyon, France
| | - Emilie Frobert
- Centre International de Recherche en Infectiologie (CIRI), Inserm U1111, Université Claude Bernard Lyon 1, CNRS, UMR5308, Ecole Normale Supérieure de Lyon, Univ Lyon, Lyon, France
- Institut des Agents Infectieux, Hôpital de la Croix-Rousse, Hospices Civils de Lyon, Lyon, France
| | - Barbara Rohmer
- Service d’Hépatologie Gastro-Entérologie et Nutrition Pédiatriques, Hôpital Femme Mère Enfant, Hospices Civils de Lyon, Bron, France
| | - Vincent Alcazer
- Centre International de Recherche en Infectiologie (CIRI), Inserm U1111, Université Claude Bernard Lyon 1, CNRS, UMR5308, Ecole Normale Supérieure de Lyon, Univ Lyon, Lyon, France
- Département d’Hématologie clinique, Centre Hospitalier Lyon Sud, Hospices Civils de Lyon, Pierre-Bénite, France
| | - Hélène Labussière-Wallet
- Département d’Hématologie clinique, Centre Hospitalier Lyon Sud, Hospices Civils de Lyon, Pierre-Bénite, France
| | - Hervé Ghesquières
- Centre International de Recherche en Infectiologie (CIRI), Inserm U1111, Université Claude Bernard Lyon 1, CNRS, UMR5308, Ecole Normale Supérieure de Lyon, Univ Lyon, Lyon, France
- Département d’Hématologie clinique, Centre Hospitalier Lyon Sud, Hospices Civils de Lyon, Pierre-Bénite, France
| | - Fabienne Venet
- Centre International de Recherche en Infectiologie (CIRI), Inserm U1111, Université Claude Bernard Lyon 1, CNRS, UMR5308, Ecole Normale Supérieure de Lyon, Univ Lyon, Lyon, France
- Laboratoire de Recherche Commun (LCR), Hospices Civils de Lyon/BioMérieux, Pierre-Bénite, France
- Laboratoire d’Immunologie, Hospices Civils de Lyon, Lyon, France
- EA7426 UCBL1-HCL-bioMérieux Pathophysiology of Injury-induced Immunosuppression, Lyon, France
| | - Karen Brengel-Pesce
- Laboratoire de Recherche Commun (LCR), Hospices Civils de Lyon/BioMérieux, Pierre-Bénite, France
| | - Sophie Trouillet-Assant
- Centre International de Recherche en Infectiologie (CIRI), Inserm U1111, Université Claude Bernard Lyon 1, CNRS, UMR5308, Ecole Normale Supérieure de Lyon, Univ Lyon, Lyon, France
- Laboratoire de Recherche Commun (LCR), Hospices Civils de Lyon/BioMérieux, Pierre-Bénite, France
| | - Florence Ader
- Centre International de Recherche en Infectiologie (CIRI), Inserm U1111, Université Claude Bernard Lyon 1, CNRS, UMR5308, Ecole Normale Supérieure de Lyon, Univ Lyon, Lyon, France
- Département des Maladies infectieuses et tropicales, Hôpital de la Croix-Rousse, Hospices Civils de Lyon, Lyon, France
- *Correspondence: Florence Ader,
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Comparable anti-CMV responses of transplant donor and third-party CMV-specific T cells for treatment of CMV infection after allogeneic stem cell transplantation. Cell Mol Immunol 2022; 19:482-491. [PMID: 35017718 PMCID: PMC8975930 DOI: 10.1038/s41423-021-00829-y] [Citation(s) in RCA: 14] [Impact Index Per Article: 4.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/12/2021] [Accepted: 12/08/2021] [Indexed: 11/08/2022] Open
Abstract
Adoptive transfer of cytomegalovirus (CMV)-specific cytotoxic T lymphocytes (CMV-CTLs) from original transplant donors or third-party donors was effective for the treatment of CMV infection after allogenic stem cell transplantation (allo-SCT), but the antiviral activity of CMV-CTL types has not been compared. To determine whether third-party CMV-CTLs provide comparable long-term antiviral efficacy to transplant donor CMV-CTLs, we first compared the antiviral abilities of transplant donors and third-party CMV-CTLs for treatment of CMV infection in two mouse models, compared the in vivo recovery of CMV-specific immunity, and analyzed the underlying mechanisms driving sustained antiviral immunity. The results showed that both donor and third-party CMV-CTLs effectively combated systemic CMV infection by reducing CMV pathology and tumor burden 28 days postinfusion. The in vivo recovery of CMV-specific immunity after CMV-CTL infusion was comparable in both groups. A detailed analysis of the source of recovered CMV-CTLs showed the proliferation and expansion of graft-derived endogenous CMV-CTLs in both groups. Our clinical study, which enrolled 31 patients who received third-party CMV-CTLs and 62 matched pairs of individuals who received transplant donor CMV-CTLs for refractory CMV infection, further showed that adoptive therapy with donor or third-party CMV-CTLs had comparable clinical responses without significant therapy-related toxicity. We observed strong expansion of CD8+ tetramer+ T cells and proliferation of recipient endogenous CMV-CTLs after CMV-CTL infusion, which were associated with a reduced or cleared viral load. Our data confirmed that adoptive therapy with third-party or transplant donor CMV-CTLs triggered comparable antiviral responses to CMV infection that might be mediated by restoration of endogenous CMV-specific immunity.
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Gabanti E, Borsani O, Colombo AA, Zavaglio F, Binaschi L, Caldera D, Sciarra R, Cassinelli G, Alessandrino EP, Bernasconi P, Ferretti VV, Lilleri D, Baldanti F. Human cytomegalovirus-specific T-cell reconstitution and late-onset cytomegalovirus infection in hematopoietic stem cell transplant recipients following letermovir prophylaxis. Transplant Cell Ther 2022; 28:211.e1-211.e9. [PMID: 35042012 DOI: 10.1016/j.jtct.2022.01.008] [Citation(s) in RCA: 26] [Impact Index Per Article: 8.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/06/2021] [Revised: 12/28/2021] [Accepted: 01/09/2022] [Indexed: 11/26/2022]
Abstract
BACKGROUND Letermovir (LTV), recently approved for the prophylaxis of human Citomegalovirus (HCMV) reactivation after hematopoietic stem cell transplantation (HSCT), has decreased the rate of infection in the first months post-transplant. OBJECTIVE The aim of this study was to evaluate the impact of LTV prophylaxis on immune reconstitution and late-onset infection. STUDY DESIGN We studied HCMV infection and HCMV-specific T-cell reconstitution in two matched groups of HSCT recipients receiving LTV prophylaxis (N=30, LTV group) vs pre-emptive therapy (N=31, PET group). Rate of GvHD, neutropenia, baseline disease recurrence and overall survival were analyzed. RESULTS Clinically significant infections requiring pre-emptive therapy showed a similar rate in the PET (21/31, 68%) vs the LTV group (17/30, 57%; P=0.434), but occurred significantly later (after prophylaxis discontinuation) in the LTV group. No difference was found in peak HCMV DNAemia levels (P=0.232). HCMV-specific T-cell recovery was delayed by about 100 days in the LTV group. HCMV-specific CD4 and CD8 T cells were significantly lower in the LTV group between days 120-360 and 90-120, respectively. A lower rate of chronic GvHD (P=0.024) was found in the LTV-group. Time to engraftment, rate of disease relapse and one-year survival were not different in the two groups, whereas a trend towards a lower occurrence of neutropenia (P=0.124) and higher occurrence of acute GvHD grade III-IV (P=0.103) was observed in the LTV group. CONCLUSIONS LTV prophylaxis delays HCMV infection and HCMV-specific immune reconstitution, therefore immunological and virological monitoring should be implemented post-prophylaxis discontinuation. The potential effect of LTV prophylaxis in reducing chronic GvHD should be evaluated by prospective studies.
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Affiliation(s)
- Elisa Gabanti
- Microbiology and Virology Unit, IRCCS Policlinico San Matteo, Pavia, Italy
| | - Oscar Borsani
- Molecular Medicine Department, University of Pavia, Pavia, Italy
| | - Anna Amelia Colombo
- Hematology Department, Fondazione IRCCS Policlinico San Matteo, Pavia, Italy
| | - Federica Zavaglio
- Microbiology and Virology Unit, IRCCS Policlinico San Matteo, Pavia, Italy
| | - Luana Binaschi
- Microbiology and Virology Unit, IRCCS Policlinico San Matteo, Pavia, Italy
| | - Daniela Caldera
- Hematology Department, Fondazione IRCCS Policlinico San Matteo, Pavia, Italy
| | - Roberta Sciarra
- Hematology Department, Fondazione IRCCS Policlinico San Matteo, Pavia, Italy
| | | | | | - Paolo Bernasconi
- Hematology Department, Fondazione IRCCS Policlinico San Matteo, Pavia, Italy
| | | | - Daniele Lilleri
- Microbiology and Virology Unit, IRCCS Policlinico San Matteo, Pavia, Italy.
| | - Fausto Baldanti
- Microbiology and Virology Unit, IRCCS Policlinico San Matteo, Pavia, Italy; Department of Clinical, Surgical, Diagnostic and Pediatric Sciences, University of Pavia, Pavia Italy
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8
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Suàrez-Fernández P, Utrero-Rico A, Sandonis V, García-Ríos E, Arroyo-Sánchez D, Fernández-Ruiz M, Andrés A, Polanco N, González-Cuadrado C, Almendro-Vázquez P, Pérez-Romero P, Aguado JM, Paz-Artal E, Laguna-Goya R. Circulatory follicular helper T lymphocytes associate with lower incidence of CMV infection in kidney transplant recipients. Am J Transplant 2021; 21:3946-3957. [PMID: 34153157 DOI: 10.1111/ajt.16725] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/03/2021] [Revised: 06/08/2021] [Accepted: 06/10/2021] [Indexed: 01/25/2023]
Abstract
Primary infection and/or reactivation of cytomegalovirus (CMV) in kidney transplant recipients (KTR) favor rejection and mortality. T follicular helper cells (TFH) could contribute to protection against CMV. Circulatory TFH (cTFH) were studied pretransplant and early posttransplant in 90 CMV seropositive KTR not receiving antithymocyte globulin or antiviral prophylaxis, followed-up for 1 year. Patients who presented CMV infection had significantly lower cTFH and activated cTFH pretransplant and early posttransplant. Pretransplant activated cTFH were also lower within patients who developed CMV disease. Pre- and 14 days posttransplant activated cTFH were an independent protective factor for CMV infection (HR 0.41, p = .01; and 0.52, p = .02, respectively). KTR with low cTFH 7 days posttransplant (<11.9%) had lower CMV infection-free survival than patients with high cTFH (28.2% vs. 67.6%, p = .002). cTFH were associated with CMV-specific neutralizing antibodies (Nabs). In addition, IL-21 increased interferon-γ secretion by CMV-specific CD8+ T cells in healthy controls. Thus, we show an association between cTFH and lower incidence of CMV infection, probably through their cooperation in CMV-specific Nab production and IL-21-mediated enhancement of CD8+ T cell activity. Moreover, monitoring cTFH pre- and early posttransplant could improve CMV risk stratification and help select KTR catalogued at low/intermediate risk who could benefit from prophylaxis.
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Affiliation(s)
| | - Alberto Utrero-Rico
- Instituto de Investigación Biomédica Hospital 12 de Octubre (imas12), Madrid, Spain
| | - Virginia Sandonis
- National Center for Microbiology, Instituto de Salud Carlos III, Madrid, Majadahonda, Spain
| | - Estéfani García-Ríos
- National Center for Microbiology, Instituto de Salud Carlos III, Madrid, Majadahonda, Spain
| | - Daniel Arroyo-Sánchez
- Instituto de Investigación Biomédica Hospital 12 de Octubre (imas12), Madrid, Spain.,Department of Immunology, Hospital Universitario 12 de Octubre, Madrid, Spain
| | - Mario Fernández-Ruiz
- Instituto de Investigación Biomédica Hospital 12 de Octubre (imas12), Madrid, Spain.,Unit of Infectious Diseases, Hospital Universitario 12 de Octubre, Madrid, Spain
| | - Amado Andrés
- Department of Nephrology, Hospital Universitario 12 de Octubre, Madrid, Spain
| | - Natalia Polanco
- Department of Nephrology, Hospital Universitario 12 de Octubre, Madrid, Spain
| | | | | | - Pilar Pérez-Romero
- National Center for Microbiology, Instituto de Salud Carlos III, Madrid, Majadahonda, Spain
| | - José María Aguado
- Instituto de Investigación Biomédica Hospital 12 de Octubre (imas12), Madrid, Spain.,Unit of Infectious Diseases, Hospital Universitario 12 de Octubre, Madrid, Spain
| | - Estela Paz-Artal
- Instituto de Investigación Biomédica Hospital 12 de Octubre (imas12), Madrid, Spain.,Department of Immunology, Hospital Universitario 12 de Octubre, Madrid, Spain.,Department of Immunology, Universidad Complutense de Madrid, Madrid, Spain
| | - Rocío Laguna-Goya
- Instituto de Investigación Biomédica Hospital 12 de Octubre (imas12), Madrid, Spain.,Department of Immunology, Hospital Universitario 12 de Octubre, Madrid, Spain
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Consequence of Histoincompatibility beyond GvH-Reaction in Cytomegalovirus Disease Associated with Allogeneic Hematopoietic Cell Transplantation: Change of Paradigm. Viruses 2021; 13:v13081530. [PMID: 34452395 PMCID: PMC8402734 DOI: 10.3390/v13081530] [Citation(s) in RCA: 10] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/16/2021] [Revised: 07/23/2021] [Accepted: 07/28/2021] [Indexed: 02/06/2023] Open
Abstract
Hematopoietic cell (HC) transplantation (HCT) is the last resort to cure hematopoietic malignancies that are refractory to standard therapies. Hematoablative treatment aims at wiping out tumor cells as completely as possible to avoid leukemia/lymphoma relapse. This treatment inevitably co-depletes cells of hematopoietic cell lineages, including differentiated cells that constitute the immune system. HCT reconstitutes hematopoiesis and thus, eventually, also antiviral effector cells. In cases of an unrelated donor, that is, in allogeneic HCT, HLA-matching is performed to minimize the risk of graft-versus-host reaction and disease (GvHR/D), but a mismatch in minor histocompatibility antigens (minor HAg) is unavoidable. The transient immunodeficiency in the period between hematoablative treatment and reconstitution by HCT gives latent cytomegalovirus (CMV) the chance to reactivate from latently infected donor HC or from latently infected organs of the recipient, or from both. Clinical experience shows that HLA and/or minor-HAg mismatches increase the risk of complications from CMV. Recent results challenge the widespread, though never proven, view of a mechanistic link between GvHR/D and CMV. Instead, new evidence suggests that histoincompatibility promotes CMV disease by inducing non-cognate transplantation tolerance that inhibits an efficient reconstitution of high-avidity CD8+ T cells capable of recognizing and resolving cytopathogenic tissue infection.
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10
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Hyun YS, Jo HA, Lee YH, Kim SM, Baek IC, Sohn HJ, Cho HI, Kim TG. Comprehensive Analysis of CD4 + T Cell Responses to CMV pp65 Antigen Restricted by Single HLA-DR, -DQ, and -DP Allotype Within an Individual. Front Immunol 2021; 11:602014. [PMID: 33658991 PMCID: PMC7917246 DOI: 10.3389/fimmu.2020.602014] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/02/2020] [Accepted: 12/15/2020] [Indexed: 01/18/2023] Open
Abstract
Within an individual, six different HLA class II heterodimers are expressed co-dominantly by two alleles of HLA-DR, -DQ, and -DP loci. However, it remained unclear which HLA allotypes were used in T cell responses to a given antigen. For the measurement of the CD4+ T cell responses restricted by a single HLA allotype, we established a panel of artificial antigen-presenting cells (aAPCs) expressing each single HLA allele of 20 HLA-DRB1, 16 HLA-DQ, and 13 HLA-DP alleles. CD4+ T cell responses to cytomegalovirus (CMV) pp65 restricted by single HLA class II allotype defined in 45 healthy donors. The average magnitude of CD4+ T cell responses by HLA-DR allotypes was higher than HLA-DQ and HLA-DP allotypes. CD4+ T cell responses by DRA*01:01/DRB1*04:06, DQA1*01:02/DQB1*06:02, DPA1*02:02/DPB1*05:01 were higher among the other alleles in each HLA-DR, -DQ, and -DP locus. Interestingly, the frequencies of HLA-DR alleles and the positivity of specific allotypes showed an inverse correlation. One allotype within individuals is dominantly used in CD4+ T cell response in 49% of donors, and two allotypes showed that in 7% of donors, and any positive response was detected in 44% of donors. Even if one individual had several dominant alleles, CD4+ T cell responses tended to be restricted by only one of them. Furthermore, CD8+ and CD4+ T cell responses by HLA class I and class II were correlated. Our results demonstrate that the CD4+ T cell preferentially use a few dominant HLA class II allotypes within individuals, similar to CD8+ T cell response to CMV pp65.
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Affiliation(s)
- You-Seok Hyun
- Department of Microbiology, College of Medicine, The Catholic University of Korea, Seoul, South Korea.,Department of Biomedicine and Health Sciences, College of Medicine, The Catholic University of Korea, Seoul, South Korea
| | - Hyeong-A Jo
- Department of Microbiology, College of Medicine, The Catholic University of Korea, Seoul, South Korea.,Department of Biomedicine and Health Sciences, College of Medicine, The Catholic University of Korea, Seoul, South Korea
| | - Yong-Hun Lee
- Department of Microbiology, College of Medicine, The Catholic University of Korea, Seoul, South Korea.,Department of Biomedicine and Health Sciences, College of Medicine, The Catholic University of Korea, Seoul, South Korea
| | - Sun-Mi Kim
- Catholic Hematopoietic Stem Cell Bank, College of Medicine, The Catholic University of Korea, Seoul, South Korea
| | - In-Cheol Baek
- Catholic Hematopoietic Stem Cell Bank, College of Medicine, The Catholic University of Korea, Seoul, South Korea
| | - Hyun-Jung Sohn
- Translational and Clinical Division, ViGenCell Inc., Seoul, South Korea
| | - Hyun-Il Cho
- Translational and Clinical Division, ViGenCell Inc., Seoul, South Korea
| | - Tai-Gyu Kim
- Department of Microbiology, College of Medicine, The Catholic University of Korea, Seoul, South Korea.,Department of Biomedicine and Health Sciences, College of Medicine, The Catholic University of Korea, Seoul, South Korea.,Catholic Hematopoietic Stem Cell Bank, College of Medicine, The Catholic University of Korea, Seoul, South Korea
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11
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Early T cell reconstitution and cytokine profile may help to guide a personalized management of human cytomegalovirus infection after allogeneic hematopoietic stem cell transplantation. J Clin Virol 2021; 135:104734. [PMID: 33476929 DOI: 10.1016/j.jcv.2021.104734] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/09/2020] [Revised: 12/04/2020] [Accepted: 01/06/2021] [Indexed: 11/20/2022]
Abstract
Human cytomegalovirus (HCMV) infection is one of the major causes of mortality and morbidity after allo-hematopoietic stem cell transplantation (HSCT). Antiviral therapies are associated with toxicity and high economic burden. The aim of this retrospective study was to identify allo-HSCT HCMV-seropositive recipients at low risk of clinically significant HCMV infection who could avoid antiviral therapies. Sixty adult patients who underwent allo-HSCT were clustered in two groups: i) 22 (37%) spontaneously controlling HCMV reactivation (Controllers); ii) 38 (63%) developing clinically significant HCMV infection and receiving pre-emptive therapy (Non-Controllers). We analyzed several patient baseline characteristics, total/HCMV-specific CD4+ and CD8+ T-cell counts and their cytokine production (IFNγ, TNFα, IL2). Controllers presented a higher number of total/HCMV-specific CD4+ and CD8+ T-cells (P=0.001 and P=0.017 for total CD4+ and CD8+ T-cells respectively; P<0.001 for HCMV-specific T-cells) and a lower percentage of mono-functional IFNγ-producing HCMV-specific CD8+ T-cells (P=0.002). In bi-variable models, the prognostic impact of the percentage of mono-functional HCMV-specific CD8+ T-cells on treatment-free survival, adjusted for total/HCMVspecific CD4+ and CD8+ T-cells, was confirmed. An HCMV-seronegative donor was the only baseline characteristic associated with a clinically significant infection. These data, when confirmed by a larger prospective study, may provide information for guiding the personalized management of HCMV infection in allo-HSCT recipients.
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12
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Annaloro C, Serpenti F, Saporiti G, Galassi G, Cavallaro F, Grifoni F, Goldaniga M, Baldini L, Onida F. Viral Infections in HSCT: Detection, Monitoring, Clinical Management, and Immunologic Implications. Front Immunol 2021; 11:569381. [PMID: 33552044 PMCID: PMC7854690 DOI: 10.3389/fimmu.2020.569381] [Citation(s) in RCA: 31] [Impact Index Per Article: 7.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/03/2020] [Accepted: 11/30/2020] [Indexed: 12/12/2022] Open
Abstract
In spite of an increasing array of investigations, the relationships between viral infections and allogeneic hematopoietic stem cell transplantation (HSCT) are still controversial, and almost exclusively regard DNA viruses. Viral infections per se account for a considerable risk of morbidity and mortality among HSCT recipients, and available antiviral agents have proven to be of limited effectiveness. Therefore, an optimal management of viral infection represents a key point in HSCT strategies. On the other hand, viruses bear the potential of shaping immunologic recovery after HSCT, possibly interfering with control of the underlying disease and graft-versus-host disease (GvHD), and eventually with HSCT outcome. Moreover, preliminary data are available about the possible role of some virome components as markers of immunologic recovery after HSCT. Lastly, HSCT may exert an immunotherapeutic effect against some viral infections, notably HIV and HTLV-1, and has been considered as an eradicating approach in these indications.
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Affiliation(s)
- Claudio Annaloro
- Hematology-BMT Center, Fondazione IRCCS Ca' Granda Ospedale Maggiore Policlinico, University of Milan, Milano, Italy
| | - Fabio Serpenti
- Hematology-BMT Center, Fondazione IRCCS Ca' Granda Ospedale Maggiore Policlinico, University of Milan, Milano, Italy
| | - Giorgia Saporiti
- Hematology-BMT Center, Fondazione IRCCS Ca' Granda Ospedale Maggiore Policlinico, University of Milan, Milano, Italy
| | - Giulia Galassi
- Hematology-BMT Center, Fondazione IRCCS Ca' Granda Ospedale Maggiore Policlinico, University of Milan, Milano, Italy
| | - Francesca Cavallaro
- Hematology-BMT Center, Fondazione IRCCS Ca' Granda Ospedale Maggiore Policlinico, University of Milan, Milano, Italy
| | - Federica Grifoni
- Hematology-BMT Center, Fondazione IRCCS Ca' Granda Ospedale Maggiore Policlinico, University of Milan, Milano, Italy
| | - Maria Goldaniga
- Hematology-BMT Center, Fondazione IRCCS Ca' Granda Ospedale Maggiore Policlinico, University of Milan, Milano, Italy
| | - Luca Baldini
- Hematology-BMT Center, Fondazione IRCCS Ca' Granda Ospedale Maggiore Policlinico, University of Milan, Milano, Italy
| | - Francesco Onida
- Hematology-BMT Center, Fondazione IRCCS Ca' Granda Ospedale Maggiore Policlinico, University of Milan, Milano, Italy
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13
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Boppana SB, Britt WJ. Recent Approaches and Strategies in the Generation of Anti-human Cytomegalovirus Vaccines. Methods Mol Biol 2021; 2244:403-463. [PMID: 33555597 DOI: 10.1007/978-1-0716-1111-1_19] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/23/2022]
Abstract
Human cytomegalovirus is the largest human herpesvirus and shares many core features of other herpesviruses such as tightly regulated gene expression during genome replication and latency as well as the establishment of lifelong persistence following infection. In contrast to stereotypic clinical syndromes associated with alpha-herpesvirus infections, almost all primary HCMV infections are asymptomatic and acquired early in life in most populations in the world. Although asymptomatic in most individuals, HCMV is a major cause of disease in hosts with deficits in adaptive and innate immunity such as infants who are infected in utero and allograft recipients following transplantation. Congenital HCMV is a commonly acquired infection in the developing fetus that can result in a number of neurodevelopmental abnormalities. Similarly, HCMV is a major cause of disease in allograft recipients in the immediate and late posttransplant period and is thought to be a major contributor to chronic allograft rejection. Even though HCMV induces robust innate and adaptive immune responses, it also encodes a vast array of immune evasion functions that are thought aid in its persistence. Immune correlates of protective immunity that prevent or modify intrauterine HCMV infection remain incompletely defined but are thought to consist primarily of adaptive responses in the pregnant mother, thus making congenital HCMV a potentially vaccine modifiable disease. Similarly, HCMV infection in allograft recipients is often more severe in recipients without preexisting adaptive immunity to HCMV. Thus, there has been a considerable effort to modify HCMV specific immunity in transplant recipient either through active immunization or passive transfer of adaptive effector functions. Although efforts to develop an efficacious vaccine and/or passive immunotherapy to limit HCMV disease have been underway for nearly six decades, most have met with limited success at best. In contrast to previous efforts, current HCMV vaccine development has relied on observations of unique properties of HCMV in hopes of reproducing immune responses that at a minimum will be similar to that following natural infection. However, more recent findings have suggested that immunity following naturally acquired HCMV infection may have limited protective activity and almost certainly, is not sterilizing. Such observations suggest that either the induction of natural immunity must be specifically tailored to generate protective activity or alternatively, that providing targeted passive immunity to susceptible populations could be prove to be more efficacious.
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Affiliation(s)
- Suresh B Boppana
- Departments of Pediatrics, The University of Alabama at Birmingham, Birmingham, AL, USA.,Departments of Microbiology, The University of Alabama at Birmingham, Birmingham, AL, USA
| | - William J Britt
- Departments of Pediatrics, The University of Alabama at Birmingham, Birmingham, AL, USA. .,Departments of Microbiology, The University of Alabama at Birmingham, Birmingham, AL, USA. .,Departments of Neurobiology, The University of Alabama at Birmingham, Birmingham, AL, USA.
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14
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Forlanini F, Dara J, Dvorak CC, Cowan MJ, Puck JM, Dorsey MJ. Unknown cytomegalovirus serostatus in primary immunodeficiency disorders: A new category of transplant recipients. Transpl Infect Dis 2020; 23:e13504. [PMID: 33169931 DOI: 10.1111/tid.13504] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/25/2020] [Revised: 10/15/2020] [Accepted: 10/25/2020] [Indexed: 11/30/2022]
Abstract
BACKGROUND Cytomegalovirus (CMV) serostatus of recipient (R) and donor (D) influences hematopoietic stem cell transplant (HSCT) outcome. However, it is not a reliable indicator of CMV infection in primary immunodeficiency disorder (PIDD) recipients who are unable to make adequate antigen-specific immunoglobulin (Ig) or who receive intravenous Ig (IVIg) prior to testing. OBJECTIVE Since no data exist on PIDD with unknown CMV serostatus, we aimed to evaluate the relationship between pre-HSCT recipient and donor serostatus and incidence of CMV infection in recipients with unknown serostatus. METHODS A retrospective analysis of all pediatric PIDD HSCTs (2007-2018) was performed at University of California San Francisco. Recipients were separated into categories based on pre-transplant serostatus: 1) seropositive (R(+)), 2) seronegative (R(-)), and 3) unknown serostatus (R(x)). Patients with pre-HSCT active CMV viremia were excluded. RESULTS A total of 90 patients were included, 69% male. The overall incidence of CMV infection was 20%, but varied in R(+), R(-), and R(x) at 80%, 0%, and 14%, (P-value = .0001). Similarly, 5-year survival differed among groups, 60% R(+), 100% R(-), and 90% of R(x) (P-value = .0045). There was no difference in CMV reactivation by donor serostatus (P-value = .29), however, faster time to clearance of CMV was observed for R(x)/D(+) group (median 9.5 days (IQR 2.5-18), P-value = .024). CONCLUSION We identify a novel group of recipients, R(x), with an intermediate level of survival and CMV incidence post-HSCT, when compared to seropositive and seronegative recipients. No evidence of CMV transmission from D(+) in R(-) and R(x) was observed. We believe R(x) should be considered as a separate category in future studies to better delineate recipient risk status.
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Affiliation(s)
- Federica Forlanini
- Division of Pediatric Allergy, Immunology and Bone Marrow Transplantation, UCSF Benioff Children's Hospital, University of California, San Francisco, CA, USA.,Department of Pediatrics, Vittore Buzzi Children's Hospital, University of Milan, Milan, Italy
| | - Jasmeen Dara
- Division of Pediatric Allergy, Immunology and Bone Marrow Transplantation, UCSF Benioff Children's Hospital, University of California, San Francisco, CA, USA
| | - Christopher C Dvorak
- Division of Pediatric Allergy, Immunology and Bone Marrow Transplantation, UCSF Benioff Children's Hospital, University of California, San Francisco, CA, USA
| | - Morton J Cowan
- Division of Pediatric Allergy, Immunology and Bone Marrow Transplantation, UCSF Benioff Children's Hospital, University of California, San Francisco, CA, USA
| | - Jennifer M Puck
- Division of Pediatric Allergy, Immunology and Bone Marrow Transplantation, UCSF Benioff Children's Hospital, University of California, San Francisco, CA, USA
| | - Morna J Dorsey
- Division of Pediatric Allergy, Immunology and Bone Marrow Transplantation, UCSF Benioff Children's Hospital, University of California, San Francisco, CA, USA
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15
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Impact of CMV Reactivation, Treatment Approaches, and Immune Reconstitution in a Nonmyeloablative Tolerance Induction Protocol in Cynomolgus Macaques. Transplantation 2020; 104:270-279. [PMID: 31385931 DOI: 10.1097/tp.0000000000002893] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/25/2022]
Abstract
BACKGROUND Cytomegalovirus (CMV) infection is a serious complication in immunosuppressed patients, specifically transplant recipients. Here, we describe the development and use of an assay to monitor the incidence and treatment of CMV viremia in a Cynomolgus macaque model of bone marrow transplantation (BMT) for tolerance induction. We address the correlation between the course of viremia and immune reconstitution. METHODS Twenty-one animals received a nonmyeloablative conditioning regimen. Seven received cyclosporine A for 28 days and 14 received rapamycin. A CMV polymerase chain reaction assay was developed and run twice per week to monitor viremia. Nineteen recipients were CMV seropositive before BMT. Immune reconstitution was monitored through flow cytometry and CMV viremia was tracked via quantitative polymerase chain reaction. RESULTS Recipients developed CMV viremia during the first month post-BMT. Two animals developed uncontrollable CMV disease. CMV reactivation occurred earlier in cyclosporine A-treated animals compared with those receiving rapamycin. Post-BMT, T-cell counts remained significantly lower compared with pretransplant levels until CMV reactivation, at which point they increased during the viremic phase and approached pretransplant levels 3 months post-BMT. Management of CMV required treatment before viremia reached 10 000 copies/mL; otherwise clinical symptoms were observed. High doses of ganciclovir resolved the viremia, which could subsequently be controlled with valganciclovir. CONCLUSIONS We developed an assay to monitor CMV in Cynomolgus macaques. CMV reactivation occurred in 100% of seropositive animals in this model. Rapamycin delayed CMV reactivation and ganciclovir treatment was effective at high doses. As in humans, CD8 T cells proliferated during CMV viremia.
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16
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Bewarder M, Held G, Thurner L, Stilgenbauer S, Smola S, Preuss KD, Carbon G, Bette B, Christofyllakis K, Bittenbring JT, Felbel A, Hasse A, Murawski N, Kaddu-Mulindwa D, Neumann F. Characterization of an HLA-restricted and human cytomegalovirus-specific antibody repertoire with therapeutic potential. Cancer Immunol Immunother 2020; 69:1535-1548. [PMID: 32300857 PMCID: PMC7347513 DOI: 10.1007/s00262-020-02564-1] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/01/2019] [Accepted: 04/02/2020] [Indexed: 01/04/2023]
Abstract
With an infection rate of 60-90%, the human cytomegalovirus (HCMV) is very common among adults but normally causes no symptoms. When T cell-mediated immunity is compromised, HCMV reactivation can lead to increased morbidity and mortality. HCMV antigens are processed and presented as peptides on the cell surface via HLA I complexes to the T cell receptor (TCR) of T cells. The generation of antibodies against HCMV peptides presented on HLA complexes (TCR-like antibodies) has been described, but is without therapeutic applications to date due to the polygenic and polymorphic nature of HLA genes. We set out to obtain antibodies specific for HLA/HCMV-peptides, covering the majority of HLA alleles present in European populations. Using phage display technology, we selected 10 Fabs, able to bind to HCMV-peptides presented in the 6 different HLA class I alleles A*0101, A*0201, A*2402, B*0702, B*0801 and B*3501. We demonstrate specific binding of all selected Fabs to HLA-typed lymphoblastoid cell lines (EBV-transformed B cells) and lymphocytes loaded with HCMV-peptides. After infection with HCMV, 4/10 tetramerized Fabs restricted to the alleles HLA-A*0101, HLA-A*0201 and HLA-B*0702 showed binding to infected primary fibroblasts. When linked to the pseudomonas exotoxin A, these Fab antibodies induce highly specific cytotoxicity in HLA matched cell lines loaded with HCMV peptides. TCR-like antibody repertoires therefore represent a promising new treatment modality for viral infections and may also have applications in the treatment of cancers.
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Affiliation(s)
- Moritz Bewarder
- Internal Medicine I, Saarland University Medical Center, 66421, Homburg, Germany.
- José Carreras Center, Saarland University Medical Center, Homburg, Germany.
| | - Gerhard Held
- Internal Medicine I, Westpfalz-Klinikum Kaiserslautern, Kaiserslautern, Germany
| | - Lorenz Thurner
- Internal Medicine I, Saarland University Medical Center, 66421, Homburg, Germany
- José Carreras Center, Saarland University Medical Center, Homburg, Germany
| | - Stephan Stilgenbauer
- Internal Medicine I, Saarland University Medical Center, 66421, Homburg, Germany
- José Carreras Center, Saarland University Medical Center, Homburg, Germany
| | - Sigrun Smola
- Institute of Virology, Saarland University Medical Center, Homburg, Germany
| | | | - Gabi Carbon
- José Carreras Center, Saarland University Medical Center, Homburg, Germany
| | - Birgit Bette
- José Carreras Center, Saarland University Medical Center, Homburg, Germany
| | | | | | - Arne Felbel
- Internal Medicine I, Saarland University Medical Center, 66421, Homburg, Germany
| | - Alexander Hasse
- Internal Medicine I, Saarland University Medical Center, 66421, Homburg, Germany
| | - Niels Murawski
- Internal Medicine I, Saarland University Medical Center, 66421, Homburg, Germany
| | | | - Frank Neumann
- José Carreras Center, Saarland University Medical Center, Homburg, Germany
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17
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The Identity Card of T Cells-Clinical Utility of T-cell Receptor Repertoire Analysis in Transplantation. Transplantation 2020; 103:1544-1555. [PMID: 31033649 DOI: 10.1097/tp.0000000000002776] [Citation(s) in RCA: 10] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/18/2022]
Abstract
There is a clear medical need to change the current strategy of "one-size-fits-all" immunosuppression for controlling transplant rejection to precision medicine and targeted immune intervention. As T cells play a key role in both undesired graft rejection and protection, a better understanding of the fate and function of both alloreactive graft-deteriorating T cells and those protecting to infections is required. The T-cell receptor (TCR) is the individual identity card of each T cell clone and can help to follow single specificities. In this context, tracking of lymphocytes with certain specificity in blood and tissue in clinical follow up is of especial importance. After overcoming technical limitations of the past, novel molecular technologies opened new avenues of diagnostics. Using advantages of next generation sequencing, a method was established for T-cell tracing by detection of variable TCR region as identifiers of individual lymphocyte clones. The current review describes principles of laboratory and computational methods of TCR repertoire analysis, and gives an overview on applications for the basic understanding of transplant biology and immune monitoring. The review also delineates methodological pitfalls and challenges. With the outlook on prediction of antigens in immune-mediated processes including those of unknown causative pathogens, monitoring the fate and function of individual T cell clones, and the adoptive transfer of protective effector or regulatory T cells, this review highlights the current and future capability of TCR repertoire analysis.
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18
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Aldoss I, La Rosa C, Baden LR, Longmate J, Ariza-Heredia EJ, Rida WN, Lingaraju CR, Zhou Q, Martinez J, Kaltcheva T, Dagis A, Hardwick N, Issa NC, Farol L, Nademanee A, Al Malki MM, Forman S, Nakamura R, Diamond DJ. Poxvirus Vectored Cytomegalovirus Vaccine to Prevent Cytomegalovirus Viremia in Transplant Recipients: A Phase 2, Randomized Clinical Trial. Ann Intern Med 2020; 172:306-316. [PMID: 32040960 PMCID: PMC9074089 DOI: 10.7326/m19-2511] [Citation(s) in RCA: 55] [Impact Index Per Article: 11.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 11/22/2022] Open
Abstract
Background Triplex vaccine was developed to enhance cytomegalovirus (CMV)-specific T cells and prevent CMV reactivation early after hematopoietic stem cell transplant (HCT). Objective To determine the safety and efficacy of Triplex. Design First-in-patient, phase 2 trial. (ClinicalTrials.gov: NCT02506933). Setting 3 U.S. HCT centers. Participants 102 CMV-seropositive HCT recipients at high risk for CMV reactivation. Intervention Intramuscular injections of Triplex or placebo were given on days 28 and 56 after HCT. Triplex is a recombinant attenuated poxvirus (modified vaccinia Ankara) expressing immunodominant CMV antigens. Measurements The primary outcomes were CMV events (CMV DNA level ≥1250 IU/mL, CMV viremia requiring antiviral treatment, or end-organ disease), nonrelapse mortality, and severe (grade 3 or 4) graft-versus-host disease (GVHD), all evaluated through 100 days after HCT, and grade 3 or 4 adverse events (AEs) within 2 weeks after vaccination that were probably or definitely attributable to injection. Results A total of 102 patients (51 per group) received the first vaccination, and 91 (89.2%) received both vaccinations (46 Triplex and 45 placebo). Reactivation of CMV occurred in 5 Triplex (9.8%) and 10 placebo (19.6%) recipients (hazard ratio, 0.46 [95% CI, 0.16 to 1.4]; P = 0.075). No Triplex recipient died of nonrelapse causes during the first 100 days or had serious AEs, and no grade 3 or 4 AEs related to vaccination were observed within 2 weeks after vaccination. Incidence of severe acute GVHD after injection was similar between groups (hazard ratio, 1.1 [CI, 0.53 to 2.4]; P = 0.23). Levels of long-lasting, pp65-specific T cells with effector memory phenotype were significantly higher in Triplex than placebo recipients. Limitation The lower-than-expected incidence of CMV events in the placebo group reduced the power of the trial. Conclusion No vaccine-associated safety concerns were identified. Triplex elicited and amplified CMV-specific immune responses, and fewer Triplex-vaccinated patients had CMV viremia. Primary Funding Source National Cancer Institute and Helocyte.
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Affiliation(s)
- Ibrahim Aldoss
- Department of Hematology and Hematopoietic Cell Transplantation of the City of Hope Comprehensive Cancer Center and the Beckman Research Institute of City of Hope, Duarte, CA
| | - Corinna La Rosa
- Department of Hematology and Hematopoietic Cell Transplantation of the City of Hope Comprehensive Cancer Center and the Beckman Research Institute of City of Hope, Duarte, CA
| | - Lindsey R. Baden
- Division of Infectious Disease, Brigham and Women's Hospital & The Dana-Farber Cancer Institute, Boston, MA
| | - Jeffrey Longmate
- Division of Biostatistics of the City of Hope Comprehensive Cancer Center and the Beckman Research Institute of City of Hope, Duarte, CA
| | - Ella J. Ariza-Heredia
- Department of Infectious Diseases, Infection Control, and Employee Health, The University of Texas MD Anderson Cancer Center, Houston, TX
| | | | - Chetan Raj Lingaraju
- Department of Hematology and Hematopoietic Cell Transplantation of the City of Hope Comprehensive Cancer Center and the Beckman Research Institute of City of Hope, Duarte, CA
| | - Qiao Zhou
- Department of Hematology and Hematopoietic Cell Transplantation of the City of Hope Comprehensive Cancer Center and the Beckman Research Institute of City of Hope, Duarte, CA
| | - Joy Martinez
- Department of Hematology and Hematopoietic Cell Transplantation of the City of Hope Comprehensive Cancer Center and the Beckman Research Institute of City of Hope, Duarte, CA
| | - Teodora Kaltcheva
- Department of Hematology and Hematopoietic Cell Transplantation of the City of Hope Comprehensive Cancer Center and the Beckman Research Institute of City of Hope, Duarte, CA
| | - Andy Dagis
- Division of Biostatistics of the City of Hope Comprehensive Cancer Center and the Beckman Research Institute of City of Hope, Duarte, CA
| | - Nicola Hardwick
- Department of Hematology and Hematopoietic Cell Transplantation of the City of Hope Comprehensive Cancer Center and the Beckman Research Institute of City of Hope, Duarte, CA
| | - Nicolas C. Issa
- Division of Infectious Disease, Brigham and Women's Hospital & The Dana-Farber Cancer Institute, Boston, MA
| | - Len Farol
- Department of Hematology and Hematopoietic Cell Transplantation of the City of Hope Comprehensive Cancer Center and the Beckman Research Institute of City of Hope, Duarte, CA
| | - Auayporn Nademanee
- Department of Hematology and Hematopoietic Cell Transplantation of the City of Hope Comprehensive Cancer Center and the Beckman Research Institute of City of Hope, Duarte, CA
| | - Monzr M. Al Malki
- Department of Hematology and Hematopoietic Cell Transplantation of the City of Hope Comprehensive Cancer Center and the Beckman Research Institute of City of Hope, Duarte, CA
| | - Stephen Forman
- Department of Hematology and Hematopoietic Cell Transplantation of the City of Hope Comprehensive Cancer Center and the Beckman Research Institute of City of Hope, Duarte, CA
| | - Ryotaro Nakamura
- Department of Hematology and Hematopoietic Cell Transplantation of the City of Hope Comprehensive Cancer Center and the Beckman Research Institute of City of Hope, Duarte, CA
| | - Don J. Diamond
- Department of Hematology and Hematopoietic Cell Transplantation of the City of Hope Comprehensive Cancer Center and the Beckman Research Institute of City of Hope, Duarte, CA
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19
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Yan CH, Wang Y, Mo XD, Sun YQ, Wang FR, Fu HX, Chen Y, Han TT, Kong J, Cheng YF, Zhang XH, Xu LP, Liu KY, Huang XJ. Incidence, risk factors, and outcomes of cytomegalovirus retinitis after haploidentical hematopoietic stem cell transplantation. Bone Marrow Transplant 2020; 55:1147-1160. [PMID: 31992849 DOI: 10.1038/s41409-020-0790-z] [Citation(s) in RCA: 18] [Impact Index Per Article: 3.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/09/2019] [Revised: 12/24/2019] [Accepted: 01/13/2020] [Indexed: 12/15/2022]
Abstract
This study investigated the epidemiological characteristics of cytomegalovirus retinitis (CMVR) after haploidentical hematopoietic stem cell transplantation (HSCT). We studied a cohort of 1466 consecutive patients who had undergone haploidentical HSCT between 2013 and 2017. We documented 34 episodes of CMVR in 31 patients, with a median onset of 167 days after the transplant. The cumulative incidence of CMVR was 2.3% 1 year after the transplant. Multivariate analysis suggested that platelet engraft failure at 100 days, EBV DNAemia, refractory or recurrent CMV DNAemia, and acute graft-versus-host disease were related to the development of CMVR in patients with CMV DNAemia. Patients with ≥3 risk factors (high risk) had a higher 1-year incidence of CMVR than patients with ≤2 risk factors (low risk) (26.2% vs. 0.6%, P < 0.001). In patients with CMVR, visual acuity (VA) improved in 16 episodes, remained stable in 10 episodes, and worsened in 8 episodes. The variable related to the improvement of VA was VA ≥ 0.1 at time of CMVR diagnosis. Our study showed that CMVR was a rare complication after haploidentical HSCT but that the risk was greater in patients with multiple risk factors.
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Affiliation(s)
- Chen-Hua Yan
- Peking University People's Hospital, Peking University Institute of Hematology, Beijing Key Laboratory of Hematopoietic Stem Cell Transplantation, Xi Zhimen South Street No. 11, Beijing, 100044, China.,Collaborative Innovation Center of Hematology, Suzhou, China
| | - Yu Wang
- Peking University People's Hospital, Peking University Institute of Hematology, Beijing Key Laboratory of Hematopoietic Stem Cell Transplantation, Xi Zhimen South Street No. 11, Beijing, 100044, China.,Collaborative Innovation Center of Hematology, Suzhou, China
| | - Xiao-Dong Mo
- Peking University People's Hospital, Peking University Institute of Hematology, Beijing Key Laboratory of Hematopoietic Stem Cell Transplantation, Xi Zhimen South Street No. 11, Beijing, 100044, China
| | - Yu-Qian Sun
- Peking University People's Hospital, Peking University Institute of Hematology, Beijing Key Laboratory of Hematopoietic Stem Cell Transplantation, Xi Zhimen South Street No. 11, Beijing, 100044, China
| | - Feng-Rong Wang
- Peking University People's Hospital, Peking University Institute of Hematology, Beijing Key Laboratory of Hematopoietic Stem Cell Transplantation, Xi Zhimen South Street No. 11, Beijing, 100044, China
| | - Hai-Xia Fu
- Peking University People's Hospital, Peking University Institute of Hematology, Beijing Key Laboratory of Hematopoietic Stem Cell Transplantation, Xi Zhimen South Street No. 11, Beijing, 100044, China
| | - Yao Chen
- Peking University People's Hospital, Peking University Institute of Hematology, Beijing Key Laboratory of Hematopoietic Stem Cell Transplantation, Xi Zhimen South Street No. 11, Beijing, 100044, China
| | - Ting-Ting Han
- Peking University People's Hospital, Peking University Institute of Hematology, Beijing Key Laboratory of Hematopoietic Stem Cell Transplantation, Xi Zhimen South Street No. 11, Beijing, 100044, China
| | - Jun Kong
- Peking University People's Hospital, Peking University Institute of Hematology, Beijing Key Laboratory of Hematopoietic Stem Cell Transplantation, Xi Zhimen South Street No. 11, Beijing, 100044, China
| | - Yi-Fei Cheng
- Peking University People's Hospital, Peking University Institute of Hematology, Beijing Key Laboratory of Hematopoietic Stem Cell Transplantation, Xi Zhimen South Street No. 11, Beijing, 100044, China
| | - Xiao-Hui Zhang
- Peking University People's Hospital, Peking University Institute of Hematology, Beijing Key Laboratory of Hematopoietic Stem Cell Transplantation, Xi Zhimen South Street No. 11, Beijing, 100044, China.,Collaborative Innovation Center of Hematology, Suzhou, China
| | - Lan-Ping Xu
- Peking University People's Hospital, Peking University Institute of Hematology, Beijing Key Laboratory of Hematopoietic Stem Cell Transplantation, Xi Zhimen South Street No. 11, Beijing, 100044, China
| | - Kai-Yan Liu
- Peking University People's Hospital, Peking University Institute of Hematology, Beijing Key Laboratory of Hematopoietic Stem Cell Transplantation, Xi Zhimen South Street No. 11, Beijing, 100044, China
| | - Xiao-Jun Huang
- Peking University People's Hospital, Peking University Institute of Hematology, Beijing Key Laboratory of Hematopoietic Stem Cell Transplantation, Xi Zhimen South Street No. 11, Beijing, 100044, China.
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20
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Wu L, Seung E, Xu L, Rao E, Lord DM, Wei RR, Cortez-Retamozo V, Ospina B, Posternak V, Ulinski G, Piepenhagen P, Francesconi E, El-Murr N, Beil C, Kirby P, Li A, Fretland J, Vicente R, Deng G, Dabdoubi T, Cameron B, Bertrand T, Ferrari P, Pouzieux S, Lemoine C, Prades C, Park A, Qiu H, Song Z, Zhang B, Sun F, Chiron M, Rao S, Radošević K, Yang ZY, Nabel GJ. Trispecific antibodies enhance the therapeutic efficacy of tumor-directed T cells through T cell receptor co-stimulation. ACTA ACUST UNITED AC 2019; 1:86-98. [DOI: 10.1038/s43018-019-0004-z] [Citation(s) in RCA: 84] [Impact Index Per Article: 14.0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/24/2019] [Accepted: 10/23/2019] [Indexed: 12/26/2022]
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21
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Stern L, Withers B, Avdic S, Gottlieb D, Abendroth A, Blyth E, Slobedman B. Human Cytomegalovirus Latency and Reactivation in Allogeneic Hematopoietic Stem Cell Transplant Recipients. Front Microbiol 2019; 10:1186. [PMID: 31191499 PMCID: PMC6546901 DOI: 10.3389/fmicb.2019.01186] [Citation(s) in RCA: 93] [Impact Index Per Article: 15.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/31/2019] [Accepted: 05/09/2019] [Indexed: 12/14/2022] Open
Abstract
Human cytomegalovirus (HCMV) reactivation is a major infectious cause of morbidity and mortality after allogeneic hematopoietic stem cell transplantation (HSCT). HCMV is a ubiquitous beta-herpesvirus which asymptomatically infects immunocompetent individuals but establishes lifelong latency, with the potential to reactivate to a life-threatening productive infection when the host immune system is suppressed or compromised. Opportunistic HCMV reactivation is the most common viral complication following engraftment after HSCT and is associated with a marked increase in non-relapse mortality, which appears to be linked to complex effects on post-transplant immune recovery. This minireview explores the cellular sites of HCMV latency and reactivation in HSCT recipients and provides an overview of the risk factors for HCMV reactivation post-HSCT. The impact of HCMV in shaping post-transplant immune reconstitution and its relationship with patient outcomes such as relapse and graft-versus-host disease will be discussed. Finally, we survey current and emerging strategies to prevent and control HCMV reactivation in HSCT recipients, with recent developments including adoptive T cell therapies to accelerate HCMV-specific T cell reconstitution and new anti-HCMV drug therapy for HCMV reactivation after HSCT.
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Affiliation(s)
- Lauren Stern
- Discipline of Infectious Diseases and Immunology, Sydney Medical School, Charles Perkins Centre, University of Sydney, Sydney, NSW, Australia
| | - Barbara Withers
- Department of Haematology, St Vincent's Hospital, Darlinghurst, NSW, Australia
| | - Selmir Avdic
- Westmead Institute of Medical Research, University of Sydney, Sydney, NSW, Australia.,Sydney Cellular Therapies Laboratory, Westmead, NSW, Australia
| | - David Gottlieb
- Westmead Institute of Medical Research, University of Sydney, Sydney, NSW, Australia.,Sydney Cellular Therapies Laboratory, Westmead, NSW, Australia.,Blood and Marrow Transplant Unit, Westmead Hospital, Sydney, NSW, Australia
| | - Allison Abendroth
- Discipline of Infectious Diseases and Immunology, Sydney Medical School, Charles Perkins Centre, University of Sydney, Sydney, NSW, Australia
| | - Emily Blyth
- Westmead Institute of Medical Research, University of Sydney, Sydney, NSW, Australia.,Sydney Cellular Therapies Laboratory, Westmead, NSW, Australia.,Blood and Marrow Transplant Unit, Westmead Hospital, Sydney, NSW, Australia
| | - Barry Slobedman
- Discipline of Infectious Diseases and Immunology, Sydney Medical School, Charles Perkins Centre, University of Sydney, Sydney, NSW, Australia
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22
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Zhang YL, Zhu Y, Xiao Q, Wang L, Liu L, Luo XH. Cytomegalovirus infection is associated with AML relapse after allo-HSCT: a meta-analysis of observational studies. Ann Hematol 2019; 98:1009-1020. [PMID: 30666434 DOI: 10.1007/s00277-018-3585-1] [Citation(s) in RCA: 12] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/10/2018] [Accepted: 12/11/2018] [Indexed: 12/12/2022]
Abstract
Cytomegalovirus (CMV) infection and primary disease relapse remain challenging problems after allogeneic hematopoietic stem cell transplantation (allo-HSCT). We sought to assess the association between CMV infection and disease relapse after transplantation. PubMed, EMBASE, the Cochrane Library, SCI, and Chinese Biomedicine Databases were searched up to July 1, 2018, for all studies that investigate pre-transplant CMV serostatus, CMV replication, and primary disease relapse in allo-HSCT patients with hematologic malignancies. Meta-analysis of 24 eligible cohort studies showed a significantly lower relapse risk after allo-HSCT in patients with CMV replication in acute myeloid leukemia (AML) (HR = 0.64, 95% CI, 0.50-0.83; P < 0.001) subgroup. However, CMV replication was associated with increased non-relapse mortality (NRM) in AML patients (HR = 1.64, 95% CI, 1.46-1.85; P < 0.001), but not associated with overall survival (OS) or graft-versus-host disease for AML patients (P > 0.05). There was no association between pre-transplant CMV serostatus and disease relapse, although D-/R- was associated with better OS in acute leukemia patients (HR = 0.89, 95% CI, 0.83-0.96; P = 0.003). In AML patients, CMV replication may be a protective predictor against disease relapse, although the potential benefit of CMV replication is offset by increased NRM.
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Affiliation(s)
- Yu-Lin Zhang
- Department of Hematology, The First Affiliated Hospital of Chongqing Medical University, 1 Youyi Road, Yuzhong District, Chongqing, 400016, China
| | - Yan Zhu
- Department of Hematology, Southwest Hospital, Third Military Medical University (Army Medical University), Chongqing, 400038, China
| | - Qing Xiao
- Department of Hematology, The First Affiliated Hospital of Chongqing Medical University, 1 Youyi Road, Yuzhong District, Chongqing, 400016, China
| | - Li Wang
- Department of Hematology, The First Affiliated Hospital of Chongqing Medical University, 1 Youyi Road, Yuzhong District, Chongqing, 400016, China
| | - Lin Liu
- Department of Hematology, The First Affiliated Hospital of Chongqing Medical University, 1 Youyi Road, Yuzhong District, Chongqing, 400016, China
| | - Xiao-Hua Luo
- Department of Hematology, The First Affiliated Hospital of Chongqing Medical University, 1 Youyi Road, Yuzhong District, Chongqing, 400016, China.
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23
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Huth A, Liang X, Krebs S, Blum H, Moosmann A. Antigen-Specific TCR Signatures of Cytomegalovirus Infection. THE JOURNAL OF IMMUNOLOGY 2018; 202:979-990. [PMID: 30587531 DOI: 10.4049/jimmunol.1801401] [Citation(s) in RCA: 25] [Impact Index Per Article: 3.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Received: 10/17/2018] [Accepted: 11/19/2018] [Indexed: 11/19/2022]
Abstract
CMV is a prevalent human pathogen. The virus cannot be eliminated from the body, but is kept in check by CMV-specific T cells. Patients with an insufficient T cell response, such as transplant recipients, are at high risk of developing CMV disease. However, the CMV-specific T cell repertoire is complex, and it is not yet clear which T cells protect best against virus reactivation and disease. In this study, we present a highly resolved characterization of CMV-specific human CD8+ T cells based on enrichment by specific peptide stimulation and mRNA sequencing of their TCR β-chains (TCRβ). Our analysis included recently identified T cell epitopes restricted through HLA-C, whose presentation is resistant to viral immunomodulation, and well-studied HLA-B-restricted epitopes. In eight healthy virus carriers, we identified a total of 1052 CMV-specific TCRβ sequences. HLA-C-restricted, CMV-specific TCRβ clonotypes dominated the ex vivo T cell response and contributed the highest-frequency clonotype of the entire repertoire in two of eight donors. We analyzed sharing and similarity of CMV-specific TCRβ sequences and identified 63 public or related sequences belonging to 17 public TCRβ families. In our cohort, and in an independent cohort of 352 donors, the cumulative frequency of these public TCRβ family members was a highly discriminatory indicator of carrying both CMV infection and the relevant HLA type. Based on these findings, we propose CMV-specific TCRβ signatures as a biomarker for an antiviral T cell response to identify patients in need of treatment and to guide future development of immunotherapy.
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Affiliation(s)
- Alina Huth
- German Center for Infection Research Group Host Control of Viral Latency and Reactivation, Research Unit Gene Vectors, Helmholtz Center Munich, 81377 Munich, Germany.,Deutsches Zentrum für Infektionsforschung, 81377 Munich, Germany; and
| | - Xiaoling Liang
- German Center for Infection Research Group Host Control of Viral Latency and Reactivation, Research Unit Gene Vectors, Helmholtz Center Munich, 81377 Munich, Germany
| | - Stefan Krebs
- Laboratory for Functional Genome Analysis, Gene Center, Ludwig Maximilian University of Munich, 81377 Munich, Germany
| | - Helmut Blum
- Laboratory for Functional Genome Analysis, Gene Center, Ludwig Maximilian University of Munich, 81377 Munich, Germany
| | - Andreas Moosmann
- German Center for Infection Research Group Host Control of Viral Latency and Reactivation, Research Unit Gene Vectors, Helmholtz Center Munich, 81377 Munich, Germany; .,Deutsches Zentrum für Infektionsforschung, 81377 Munich, Germany; and
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24
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La Rosa C, Longmate J, Lingaraju CR, Zhou Q, Kaltcheva T, Hardwick N, Aldoss I, Nakamura R, Diamond DJ. Rapid Acquisition of Cytomegalovirus-Specific T Cells with a Differentiated Phenotype, in Nonviremic Hematopoietic Stem Transplant Recipients Vaccinated with CMVPepVax. Biol Blood Marrow Transplant 2018; 25:771-784. [PMID: 30562587 DOI: 10.1016/j.bbmt.2018.12.070] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/18/2018] [Accepted: 12/10/2018] [Indexed: 12/12/2022]
Abstract
Early cytomegalovirus (CMV) reactivation remains a significant cause of morbidity and mortality in allogeneic hematopoietic cell transplant (HCT) recipients. CMVPepVax is an investigational peptide vaccine designed to control CMV infection in HCT recipients seropositive for CMV by stimulating the expansion of T cell subsets that target the CMV tegument protein pp65. In a randomized Phase Ib pilot trial (ClinicalTrials.gov NCT01588015), two injections of CMVPepVax (at days 28 and 56 post-HCT) demonstrated safety, immunogenicity, increased relapse-free survival, and reduced CMV reactivation and use of antivirals. In the present study, we assessed the phenotypes and time courses of the pp65-specific CD8 T cell subsets that expanded in response to CMVPepVax vaccination. The functionality and antiviral role of CMV-specific T cells have been linked to immune reconstitution profiles characterized predominantly by differentiated effector memory T (TEM) subsets that have lost membrane expression of the costimulatory molecule CD28 and often reexpress the RA isoform of CD45 (TEMRA). Major histocompatibility complex class I pp65495-503 multimers, as well as CD28 and CD45 memory markers, were used to detect immune reconstitution in blood specimens from HCT recipients enrolled in the Phase Ib clinical trial. Specimens from the 10 (out of 18) vaccinated patients who had adequate (≥.2%) multimer binding to allow for memory analysis showed highly differentiated TEM and TEMRA phenotypes for pp65495-503-specific CD8 T cells during the first 100days post-transplantation. In particular, by day 70, during the period of highest risk for CMV reactivation, combined TEM and TEMRA phenotypes constituted a median of 90% of pp65495-503-specific CD8 T cells in these vaccinated patients. CMV viremia was not detectable in the patients who received CMVPepVax, although their pp65495-503-specific CD8 T cell profiles were strikingly similar to those observed in viremic patients who did not receive the vaccine. Collectively, our findings indicate that in the absence of clinically relevant viremia, CMVPepVax reconstituted significant levels of differentiated pp65495-503-specific CD8 TEMs early post-HCT. Our data indicate that the rapid reconstitution of CMV-specific T cells with marked levels of effector phenotypes may have been key to the favorable outcomes of the CMVPepVax clinical trial.
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Affiliation(s)
- Corinna La Rosa
- Department of Experimental Therapeutics, Beckman Research Institute of City of Hope, City of Hope Comprehensive Cancer Center, Duarte, California
| | - Jeffrey Longmate
- Division of Biostatistics, Beckman Research Institute of City of Hope, City of Hope Comprehensive Cancer Center, Duarte, California
| | - Chetan Raj Lingaraju
- Department of Experimental Therapeutics, Beckman Research Institute of City of Hope, City of Hope Comprehensive Cancer Center, Duarte, California
| | - Qiao Zhou
- Department of Experimental Therapeutics, Beckman Research Institute of City of Hope, City of Hope Comprehensive Cancer Center, Duarte, California
| | - Teodora Kaltcheva
- Department of Experimental Therapeutics, Beckman Research Institute of City of Hope, City of Hope Comprehensive Cancer Center, Duarte, California
| | - Nicola Hardwick
- Department of Experimental Therapeutics, Beckman Research Institute of City of Hope, City of Hope Comprehensive Cancer Center, Duarte, California
| | - Ibrahim Aldoss
- Department of Hematology and Hematopoietic Cell Transplantation, City of Hope Comprehensive Cancer Center, Duarte, California
| | - Ryotaro Nakamura
- Department of Hematology and Hematopoietic Cell Transplantation, City of Hope Comprehensive Cancer Center, Duarte, California
| | - Don J Diamond
- Department of Experimental Therapeutics, Beckman Research Institute of City of Hope, City of Hope Comprehensive Cancer Center, Duarte, California.
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25
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Tanimura K, Yamada H. Potential Biomarkers for Predicting Congenital Cytomegalovirus Infection. Int J Mol Sci 2018; 19:ijms19123760. [PMID: 30486359 PMCID: PMC6321102 DOI: 10.3390/ijms19123760] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/17/2018] [Revised: 11/22/2018] [Accepted: 11/23/2018] [Indexed: 12/12/2022] Open
Abstract
Early diagnosis and treatment of infants with symptomatic congenital cytomegalovirus (CMV) infection may improve neurological outcomes. For this reason, prenatal detection of newborns at high risk for congenital CMV infection is important. A polymerase chain reaction (PCR) assay for CMV DNA in the amniotic fluid is the gold standard for the diagnosis of intrauterine CMV infection; however, amniocentesis is an invasive procedure. Recently, we have found that the presence of CMV DNA in the maternal uterine cervical secretion is predictive of the occurrence of congenital CMV infection in CMV immunoglobulin M (IgM)-positive pregnant women. In contrast, we have suggested that maternal serological screening for primary CMV infection using CMV-specific immunoglobulin G (IgG), the IgG avidity index, or CMV-specific IgM overlooks a number of newborns with congenital CMV infection. We will review current knowledge of the potential biomarkers for predicting congenital CMV infection.
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Affiliation(s)
- Kenji Tanimura
- Department of Obstetrics and Gynecology, Kobe University Graduate School of Medicine, Kobe 650-0017, Japan.
| | - Hideto Yamada
- Department of Obstetrics and Gynecology, Kobe University Graduate School of Medicine, Kobe 650-0017, Japan.
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26
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Nam M, Shin S, Park KU, Kim I, Yoon SS, Kwon TK, Song EY. Association of FOXP3 Single Nucleotide Polymorphisms With Clinical Outcomes After Allogenic Hematopoietic Stem Cell Transplantation. Ann Lab Med 2018; 38:591-598. [PMID: 30027704 PMCID: PMC6056380 DOI: 10.3343/alm.2018.38.6.591] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/27/2017] [Revised: 01/16/2018] [Accepted: 06/22/2018] [Indexed: 01/04/2023] Open
Abstract
BACKGROUND Forkhead box P3 (FOXP3) is an important marker of regulatory T cells. FOXP3 polymorphisms are associated with autoimmune diseases, cancers, and allograft outcomes. We examined whether single nucleotide polymorphisms (SNPs) at the FOXP3 locus are associated with clinical outcomes after allogenic hematopoietic stem cell transplantation (HSCT). METHODS Five FOXP3 SNPs (rs5902434, rs3761549, rs3761548, rs2232365, and rs2280883) were analyzed by PCR-sequencing of 172 DNA samples from allogenic HSCT patients. We examined the relationship between each SNP and the occurrence of graft-versus-host disease (GVHD), post-HSCT infection, relapse, and patient survival. RESULTS Patients with acute GVHD (grades II-IV) showed higher frequencies of the rs3761549 T/T genotype, rs5902434 ATT/ATT genotype, and rs2232365 G/G genotype than did patients without acute GVHD (P=0.017, odds ratio [OR]=5.3; P=0.031, OR=2.4; and P=0.023, OR=2.6, respectively). Multivariate analysis showed that the TT genotype of rs3761549 was an independent risk factor for occurrence of acute GVHD (P=0.032, hazard ratio=5.6). In contrast, the genotype frequencies of rs3761549 T/T, rs5902434 ATT/ATT, and rs2232365 G/G were lower in patients with post-HSCT infection than in patients without infection (P=0.026, P=0.046, and P=0.031, respectively). CONCLUSIONS rs3761549, rs5902434, and rs2232365 are associated with an increased risk of acute GVHD and decreased risk of post-HSCT infection.
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Affiliation(s)
- Minjeong Nam
- Department of Laboratory Medicine, Seoul National University College of Medicine, Seoul, Korea
| | - Sue Shin
- Department of Laboratory Medicine, Seoul National University College of Medicine, Seoul, Korea
| | - Kyoung Un Park
- Department of Laboratory Medicine, Seoul National University College of Medicine, Seoul, Korea
| | - Inho Kim
- Department of Internal Medicine, Seoul National University College of Medicine, Seoul, Korea
| | - Sung Soo Yoon
- Department of Internal Medicine, Seoul National University College of Medicine, Seoul, Korea
| | - Tack Kyun Kwon
- Department of Otorhinolaryngology, Seoul National University College of Medicine, Seoul, Korea.
| | - Eun Young Song
- Department of Laboratory Medicine, Seoul National University College of Medicine, Seoul, Korea.
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27
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Navarro D, Fernández-Ruiz M, Aguado JM, Sandonís V, Pérez-Romero P. Going beyond serology for stratifying the risk of CMV infection in transplant recipients. Rev Med Virol 2018; 29:e2017. [PMID: 30358016 DOI: 10.1002/rmv.2017] [Citation(s) in RCA: 19] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/05/2018] [Revised: 10/02/2018] [Accepted: 10/03/2018] [Indexed: 12/12/2022]
Abstract
Knowledge of donor and recipient (D/R) cytomegalovirus (CMV) serostatus is critical for risk stratification of CMV infection and disease in transplant recipients, particularly in the solid organ transplantation (SOT) setting. Despite its broad availability and the success of it use, the risk stratification based on the D/R serostatus is not free of limitations since there are a nondepreciable number of patients that are not accurately categorized by this approach. In fact, up to 20% of seropositive SOT recipients, classically considered at intermediate risk, develop episodes of CMV infection and disease after transplantation. Here, we provide an overview of additional donor and recipient factors that may have utility in identifying patients at risk for post-transplant CMV infection. Specifically, we summarize our current understanding regarding the potential use of use CMV-specific T-cell-mediated immunity, neutralizing antibodies and host genetics that may influence the risk of CMV infection and disease. We provide an overview of the benefits and limitations associated with using these immunological factors in risk stratification and propose specific variables that could be analyzed at the pretransplant evaluation to improve the identification of patients with increased individual susceptibility.
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Affiliation(s)
- David Navarro
- Microbiology Service, Hospital Clínico Universitario, Fundación INCLIVA, Valencia, Spain
| | - Mario Fernández-Ruiz
- Unit of Infectious Diseases, Hospital Universitario "12 de Octubre", Instituto de Investigación Hospital,"12 de Octubre" (i+12), School of Medicine, Universidad Complutense, Madrid, Spain
| | - José María Aguado
- Unit of Infectious Diseases, Hospital Universitario "12 de Octubre", Instituto de Investigación Hospital,"12 de Octubre" (i+12), School of Medicine, Universidad Complutense, Madrid, Spain
| | - Virginia Sandonís
- Unit of Infectious Diseases, Hospital Universitario "12 de Octubre", Instituto de Investigación Hospital,"12 de Octubre" (i+12), School of Medicine, Universidad Complutense, Madrid, Spain
| | - Pilar Pérez-Romero
- National Center of Microbiology, Instituto de Salud Carlos III, Majadahonda, Madrid, Spain
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28
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van der Heiden P, Marijt E, Falkenburg F, Jedema I. Control of Cytomegalovirus Viremia after Allogeneic Stem Cell Transplantation: A Review on CMV-Specific T Cell Reconstitution. Biol Blood Marrow Transplant 2018; 24:1776-1782. [DOI: 10.1016/j.bbmt.2018.03.028] [Citation(s) in RCA: 21] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/09/2017] [Accepted: 03/29/2018] [Indexed: 12/20/2022]
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29
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Suárez-Lledó M, Martínez-Cibrián N, Gutiérrez-García G, Dimova-Svetoslavova V, Marcos MA, Martín-Antonio B, Martínez-Trillos A, Villamor N, Rosiñol L, Martínez C, Fernández-Avilés F, García-Vidal C, Urbano-Ispizua Á, Rovira M. Deleterious Effect of Steroids on Cytomegalovirus Infection Rate after Allogeneic Stem Cell Transplantation Depends on Pretransplant Cytomegalovirus Serostatus of Donors and Recipients. Biol Blood Marrow Transplant 2018; 24:2088-2093. [PMID: 29753162 DOI: 10.1016/j.bbmt.2018.05.001] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/22/2018] [Accepted: 05/01/2018] [Indexed: 10/16/2022]
Abstract
This study examined the impact of prednisone (PDN) on cytomegalovirus (CMV) infection after allogeneic stem cell transplantation (allo-SCT) according to donor and recipient CMV serostatus. Seventy-five patients underwent allo-SCT from June 2010 to July 2012. The risk of CMV infection according to donor and recipient serostatus was defined as follows: high risk (HR; D-/R+), intermediate risk (IR; D+/R+ and D+/R-), and low risk (D-/R-). Forty-five patients (60%) developed CMV infection, and 46 patients (61%) received steroids (PDN ≥ 1 mg/kg/day) to treat acute graft-versus-host disease. CMV infection was more common in those treated with steroids than in those not treated with steroids (70% versus 44%, respectively, P < .05). Overall, 40% of patients had recurrent CMV infection (50% PDN versus 24% no PDN, P < .05). Steroids had no impact on the incidence of CMV infection or its recurrence in HR patients; however, steroids did prolong the need for antiviral treatment. The incidence of CMV infection in IR patients was higher in those receiving PDN (80% PDN versus 41% no PDN, P = .01); recurrence rates were also higher (55% PDN versus 18% no PDN, P = .02). We analyzed CMV-specific immune reconstitution in the first 22 patients of the series and observed that patients on steroids had lower levels of CMV-specific lymphocytes TCD8 (P < .05 on days +60, +100, and +180) and that CMV-specific immune reconstitution (defined as lymphocytes CD8/IFN ≥ 1 cell/µL) was achieved later (after day +100 post-SCT) in the steroid group.
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Affiliation(s)
| | | | | | | | - Ma Angeles Marcos
- Clinical Microbiology Department, Hospital Clínic Barcelona, Barcelona, Spain
| | - Beatriz Martín-Antonio
- Institut d'Investigació Biomèdica August Pi I Sunyer (IDIBAPS), University of Barcelona, Barcelona, Spain; Institut Josep Carreras, Barcelona, Spain
| | | | - Neus Villamor
- Institut d'Investigació Biomèdica August Pi I Sunyer (IDIBAPS), University of Barcelona, Barcelona, Spain; Hematopathology Department, Hospital Clinic Barcelona, Barcelona, Spain
| | - Laura Rosiñol
- Hematology Department, Hospital Clínic Barcelona, Barcelona, Spain; Institut d'Investigació Biomèdica August Pi I Sunyer (IDIBAPS), University of Barcelona, Barcelona, Spain
| | - Carmen Martínez
- Hematology Department, Hospital Clínic Barcelona, Barcelona, Spain; Institut d'Investigació Biomèdica August Pi I Sunyer (IDIBAPS), University of Barcelona, Barcelona, Spain; Institut Josep Carreras, Barcelona, Spain
| | - Francesc Fernández-Avilés
- Hematology Department, Hospital Clínic Barcelona, Barcelona, Spain; Institut d'Investigació Biomèdica August Pi I Sunyer (IDIBAPS), University of Barcelona, Barcelona, Spain; Institut Josep Carreras, Barcelona, Spain
| | | | - Álvaro Urbano-Ispizua
- Hematology Department, Hospital Clínic Barcelona, Barcelona, Spain; Institut d'Investigació Biomèdica August Pi I Sunyer (IDIBAPS), University of Barcelona, Barcelona, Spain; Institut Josep Carreras, Barcelona, Spain
| | - Montserrat Rovira
- Hematology Department, Hospital Clínic Barcelona, Barcelona, Spain; Institut d'Investigació Biomèdica August Pi I Sunyer (IDIBAPS), University of Barcelona, Barcelona, Spain; Institut Josep Carreras, Barcelona, Spain
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30
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Donskow-Łysoniewska K, Krawczak K, Kozłowska E, Doligalska M. The intestinal nematode inhibits T-cell reactivity by targeting P-GP activity. Parasite Immunol 2018; 39. [PMID: 29063624 DOI: 10.1111/pim.12497] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/02/2017] [Accepted: 10/17/2017] [Indexed: 12/20/2022]
Abstract
Host immunosuppression occurs during chronic nematode infection, partly due to effector T-cell hyporesponsiveness. The role of P-glycoprotein (P-gp), a member of the ABC transporter family, has been assessed in T-cell activity. This study assesses the possible role of P-gp in T-cell activity during nematode infection. Our findings indicate that blockade of P-gp in vivo increased protection against Heligmosomoides polygyrus nematode infection and was associated with the enhanced T-cell activity. Three P-gp-inhibitors, verapamil (VRP), cyclosporine (CsA) and tariquidar (XR9576), were used to determine the influence of nematode infection on the P-gp function of T cells. The influence of the nematode on the uptake, efflux and kinetics of extrusion in T-cell subsets CD4+ and CD8+ was assessed by the accumulation of Rho123 dye. The results indicate that H. polygyrus infection contributes to the inhibition of T-cell function by elevating P-gp activity. The blockade of P-gp in the T cells of infected mice led to an impressive increase in T-cell proliferation and IL-4 cytokine release through the upregulation of NF-κB activation. These results provide the first evidence that the P-gp function of T cells is altered during nematode infection to open the way for further studies aiming to explore the role of P-gp in host-parasite interactions.
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Affiliation(s)
- K Donskow-Łysoniewska
- Faculty of Biology, Department of Parasitology, Institute of Zoology, University of Warsaw, Warsaw, Poland
| | - K Krawczak
- Faculty of Biology, Department of Parasitology, Institute of Zoology, University of Warsaw, Warsaw, Poland
| | - E Kozłowska
- Faculty of Biology, Department of Immunology, Institute of Zoology, University of Warsaw, Warsaw, Poland
| | - M Doligalska
- Faculty of Biology, Department of Parasitology, Institute of Zoology, University of Warsaw, Warsaw, Poland
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31
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Pei XY, Zhao XY, Chang YJ, Liu J, Xu LP, Wang Y, Zhang XH, Han W, Chen YH, Huang XJ. Cytomegalovirus-Specific T-Cell Transfer for Refractory Cytomegalovirus Infection After Haploidentical Stem Cell Transplantation: The Quantitative and Qualitative Immune Recovery for Cytomegalovirus. J Infect Dis 2017; 216:945-956. [DOI: 10.1093/infdis/jix357] [Citation(s) in RCA: 76] [Impact Index Per Article: 9.5] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 08/30/2023] Open
Affiliation(s)
- Xu-Ying Pei
- Peking University People’s Hospital, Peking University Institute of Hematology, Beijing Key Laboratory of Hematopoietic Stem Cell Transplantation
| | - Xiang-Yu Zhao
- Peking University People’s Hospital, Peking University Institute of Hematology, Beijing Key Laboratory of Hematopoietic Stem Cell Transplantation
- Beijing Engineering Lab for Cell Therapy, Beijing, China
| | - Ying-Jun Chang
- Peking University People’s Hospital, Peking University Institute of Hematology, Beijing Key Laboratory of Hematopoietic Stem Cell Transplantation
| | - Jing Liu
- Peking University People’s Hospital, Peking University Institute of Hematology, Beijing Key Laboratory of Hematopoietic Stem Cell Transplantation
| | - Lan-Ping Xu
- Peking University People’s Hospital, Peking University Institute of Hematology, Beijing Key Laboratory of Hematopoietic Stem Cell Transplantation
| | - Yu Wang
- Peking University People’s Hospital, Peking University Institute of Hematology, Beijing Key Laboratory of Hematopoietic Stem Cell Transplantation
| | - Xiao-Hui Zhang
- Peking University People’s Hospital, Peking University Institute of Hematology, Beijing Key Laboratory of Hematopoietic Stem Cell Transplantation
| | - Wei Han
- Peking University People’s Hospital, Peking University Institute of Hematology, Beijing Key Laboratory of Hematopoietic Stem Cell Transplantation
| | - Yu-Hong Chen
- Peking University People’s Hospital, Peking University Institute of Hematology, Beijing Key Laboratory of Hematopoietic Stem Cell Transplantation
| | - Xiao-Jun Huang
- Peking University People’s Hospital, Peking University Institute of Hematology, Beijing Key Laboratory of Hematopoietic Stem Cell Transplantation
- Peking-Tsinghua Center for Life Sciences
- Beijing Engineering Lab for Cell Therapy, Beijing, China
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32
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Ma CKK, Clancy L, Simms R, Burgess J, Deo S, Blyth E, Micklethwaite KP, Gottlieb DJ. Adjuvant Peptide Pulsed Dendritic Cell Vaccination in Addition to T Cell Adoptive Immunotherapy for Cytomegalovirus Infection in Allogeneic Hematopoietic Stem Cell Transplantation Recipients. Biol Blood Marrow Transplant 2017; 24:71-77. [PMID: 28864137 DOI: 10.1016/j.bbmt.2017.08.028] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/03/2017] [Accepted: 08/23/2017] [Indexed: 01/21/2023]
Abstract
Adoptive cellular immunotherapy has been shown to be effective in the management of cytomegalovirus (CMV) reactivation and disease. Whether adjuvant dendritic cell (DC) vaccination will provide additional benefit in prophylaxis or treatment of CMV in hematoietic cell transplantation (HSCT) recipients is unknown. In this study, we administered prophylactic CMV-peptide specific T cell infusions, followed by 2 doses of intradermal CMV peptide-pulsed DC vaccine, to 4 HSCT recipients. There were no immediate adverse events associated with T cell infusion or DC vaccinations. One of the 4 patients developed grade III acute gut graft-versus-host disease. Immune reconstitution against CMV was detected in all 4 patients. Patients receiving CMV peptide-specific T cells and DC vaccination had peak immune reconstitution at least 10 days after the second DC vaccination. In summary, combining DC vaccine with T cell infusion appears feasible, although further study is required to ascertain its safety and efficacy in augmenting the effects of infusing donor-derived CMV-specific T cells.
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Affiliation(s)
- Chun K K Ma
- The Westmead Institute for Medical Research, The University of Sydney, Sydney, Australia
| | - Leighton Clancy
- The Westmead Institute for Medical Research, The University of Sydney, Sydney, Australia; Blood and Marrow Transplant Unit, Westmead Hospital, Sydney, Australia; Sydney Cell and Gene Therapy Laboratory, Westmead Hospital, Sydney, Australia
| | - Renee Simms
- The Westmead Institute for Medical Research, The University of Sydney, Sydney, Australia; Blood and Marrow Transplant Unit, Westmead Hospital, Sydney, Australia; Sydney Cell and Gene Therapy Laboratory, Westmead Hospital, Sydney, Australia
| | - Jane Burgess
- The Westmead Institute for Medical Research, The University of Sydney, Sydney, Australia; Blood and Marrow Transplant Unit, Westmead Hospital, Sydney, Australia; Sydney Cell and Gene Therapy Laboratory, Westmead Hospital, Sydney, Australia
| | - Shivashni Deo
- The Westmead Institute for Medical Research, The University of Sydney, Sydney, Australia
| | - Emily Blyth
- The Westmead Institute for Medical Research, The University of Sydney, Sydney, Australia; Blood and Marrow Transplant Unit, Westmead Hospital, Sydney, Australia; Sydney Cell and Gene Therapy Laboratory, Westmead Hospital, Sydney, Australia
| | - Kenneth P Micklethwaite
- The Westmead Institute for Medical Research, The University of Sydney, Sydney, Australia; Blood and Marrow Transplant Unit, Westmead Hospital, Sydney, Australia; Sydney Cell and Gene Therapy Laboratory, Westmead Hospital, Sydney, Australia
| | - David J Gottlieb
- The Westmead Institute for Medical Research, The University of Sydney, Sydney, Australia; Blood and Marrow Transplant Unit, Westmead Hospital, Sydney, Australia; Sydney Cell and Gene Therapy Laboratory, Westmead Hospital, Sydney, Australia.
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33
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Lilleri D, Gerna G. Strategies to control human cytomegalovirus infection in adult hematopoietic stem cell transplant recipients. Immunotherapy 2017; 8:1135-49. [PMID: 27485084 DOI: 10.2217/imt-2015-0028] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/24/2022] Open
Abstract
Human cytomegalovirus (HCMV) represents the major viral complication after hematopoietic stem cell transplantation. HCMV infection may be controlled by the reconstituting immune system and remain subclinical or can lead to severe systemic and/or organ disease (mainly pneumonia and gastroenteritis) when immune reconstitution is delayed or impaired. In order to prevent the occurrence of HCMV disease, a prompt diagnosis of HCMV infection is mandatory. The adoption of pre-emptive therapy strategies guided by virological monitoring dramatically reduced the occurrence of HCMV disease. However, late-onset end-organ disease may occur in some patients with apparent immune reconstitution. In the near future, introduction of immunological monitoring and immunotherapies could markedly improve management of HCMV infection.
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Affiliation(s)
- Daniele Lilleri
- Laboratori Sperimentali di Ricerca-Area Trapiantologica, Fondazione IRCCS Policlinico San Matteo, 27100 Pavia, Italy.,Università della Svizzera Italiana, Institute for Research in Biomedicine, 6500 Bellinzona, Switzerland
| | - Giuseppe Gerna
- Laboratori Sperimentali di Ricerca-Area Trapiantologica, Fondazione IRCCS Policlinico San Matteo, 27100 Pavia, Italy
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34
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Cytomegalovirus Immunity After Alemtuzumab Induction in Desensitized Kidney Transplant Patients. Transplantation 2017; 101:1720-1726. [DOI: 10.1097/tp.0000000000001573] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/08/2023]
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35
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Ogonek J, Verma K, Schultze-Florey C, Varanasi P, Luther S, Schweier P, Kühnau W, Göhring G, Dammann E, Stadler M, Ganser A, Koehl U, Koenecke C, Weissinger EM, Hambach L. Characterization of High-Avidity Cytomegalovirus-Specific T Cells with Differential Tetramer Binding Coappearing after Allogeneic Stem Cell Transplantation. THE JOURNAL OF IMMUNOLOGY 2017. [DOI: 10.4049/jimmunol.1601992] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 11/19/2022]
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36
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Abstract
Cytomegalovirus (CMV) and Epstein-Barr virus (EBV) infections following allogeneic hematopoietic stem cell transplantation (HSCT) are a major cause of morbidity and mortality. Early clinical trials demonstrate that adoptive transfer of donor-derived virus-specific T cells to restore virus-specific immunity is an effective strategy to control CMV and EBV infection after HSCT, conferring protection in 70%-90% of patients. The field has evolved rapidly to develop solutions to some of the manufacturing challenges identified in early clinical studies, such as prolonged in vitro culture, optimization of the purity of the virus-specific T cell product, the potential limitations of targeting a single viral antigen, and how to manage the patient with a virus-naive donor. This Review both discusses the seminal early studies and explores cutting-edge novel technologies that broaden the feasibility of and the scope for delivering virus-specific T cells to patients after HSCT.
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Affiliation(s)
- Claire Roddie
- Department of Haematology, University College London Cancer Institute, London, United Kingdom.,Department of Haematology, University College London Hospitals NHS Foundation Trust, London, United Kingdom
| | - Karl S Peggs
- Department of Haematology, University College London Cancer Institute, London, United Kingdom.,Department of Haematology, University College London Hospitals NHS Foundation Trust, London, United Kingdom
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37
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Matko S, Teichert M, Tunger A, Schmitz M, Bornhauser M, Tonn T, Odendahl M. Enumeration of WT1-specific CD8 + T cells for clinical application using an MHC Streptamer based no-wash single-platform flow-cytometric assay. Cytometry A 2017; 91:1001-1008. [PMID: 28544366 DOI: 10.1002/cyto.a.23146] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/20/2017] [Revised: 05/02/2017] [Accepted: 05/11/2017] [Indexed: 11/08/2022]
Abstract
The advent of novel strategies to generate leukemia-associated-antigen (LAA)-specific T cells for adoptive immunotherapies creates a demand for standardized good laboratory practice (GLP)-compliant enumeration assays to provide a secure clinical environment-whether it is to identify potential donors, define therapeutic doses for transplantation, or monitor clinical success. Here, we introduce a no-wash assay based on single-platform cell enumeration and Streptamer staining to determine the Wilms' tumor antigen 1 (WT1)-specific T cell immunity in clinical samples. We analyzed the performance of the WT1-specific MHC Streptamers in direct comparison to CMV- and EBV-specific MHC Streptamer staining by spiking antigen-specific T cells in PBMCs. The accuracy of the assay was high for all performed experiments with a mean recovery of 94% and a linear regression of 0.988. Differences were apparent regarding the limit of detection/quantification (LOD/LOQ). While results obtained for WT1 yielded an LOD/LOQ of 0.08 ± 0.04% and 0.11 ± 0.06% (1.33 ± 0.32 cells/µl and 1.9 ± 0.14 cells/µl), the overall LOD/LOQ was notably lower and accounted to 0.02 ± 0.02% and 0.05 ± 0.03% (0.60 ± 0.03 cells/µl and 1.27 ± 0.58 cells/µl). Subsequent screening of 22 healthy individuals revealed significantly higher values for WT1 (0.04 ± 0.02% and 1.5 ± 0.9 cells/µl) than for the irrelevant HIV pol (0.016 ± 0.01% and 0.5 ± 0.4 cells/µl). In contrast, no increased frequencies were observed for WT1-specific T cells compared to HIV-specific T cells using a classical wash-protocol. These findings strongly suggest the use of no-wash single-platform assays in combination with MHC Streptamer staining for the detection of low affinity LAA-specific T cells due to its high accuracy and sensitivity. © 2017 International Society for Advancement of Cytometry.
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Affiliation(s)
- Sarah Matko
- Department for Experimental Transfusion Medicine, German Red Cross Blood Donation Service North-East, Dresden, Germany.,Institute for Transfusion Medicine, Medical Faculty, Technical University (TU) Dresden, Germany
| | - Madeleine Teichert
- Department for Experimental Transfusion Medicine, German Red Cross Blood Donation Service North-East, Dresden, Germany
| | - Antje Tunger
- Institute of Immunology, Medical Faculty, TU Dresden, Germany.,National Center for Tumor Diseases, University Hospital Carl Gustav Carus, TU Dresden, Germany
| | - Marc Schmitz
- Institute of Immunology, Medical Faculty, TU Dresden, Germany.,National Center for Tumor Diseases, University Hospital Carl Gustav Carus, TU Dresden, Germany.,Center for Regenerative Therapies Dresden (CRTD), Germany.,German Consortium for Translational Cancer Research (DKTK) Dresden, Germany.,German Cancer Research Center (DKFZ), Heidelberg, Germany
| | - Martin Bornhauser
- National Center for Tumor Diseases, University Hospital Carl Gustav Carus, TU Dresden, Germany.,Center for Regenerative Therapies Dresden (CRTD), Germany.,German Consortium for Translational Cancer Research (DKTK) Dresden, Germany.,German Cancer Research Center (DKFZ), Heidelberg, Germany.,Department of Medicine I, University Hospital Carl Gustav Carus, TU Dresden, Germany
| | - Torsten Tonn
- Department for Experimental Transfusion Medicine, German Red Cross Blood Donation Service North-East, Dresden, Germany.,Institute for Transfusion Medicine, Medical Faculty, Technical University (TU) Dresden, Germany.,Center for Regenerative Therapies Dresden (CRTD), Germany.,German Consortium for Translational Cancer Research (DKTK) Dresden, Germany.,German Cancer Research Center (DKFZ), Heidelberg, Germany
| | - Marcus Odendahl
- Department for Experimental Transfusion Medicine, German Red Cross Blood Donation Service North-East, Dresden, Germany
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38
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Li Pira G, Di Cecca S, Biagini S, Girolami E, Cicchetti E, Bertaina V, Quintarelli C, Caruana I, Lucarelli B, Merli P, Pagliara D, Brescia LP, Bertaina A, Montanari M, Locatelli F. Preservation of Antigen-Specific Functions of αβ T Cells and B Cells Removed from Hematopoietic Stem Cell Transplants Suggests Their Use As an Alternative Cell Source for Advanced Manipulation and Adoptive Immunotherapy. Front Immunol 2017; 8:332. [PMID: 28386262 PMCID: PMC5362590 DOI: 10.3389/fimmu.2017.00332] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/20/2016] [Accepted: 03/08/2017] [Indexed: 12/20/2022] Open
Abstract
Hematopoietic stem cell transplantation is standard therapy for numerous hematological diseases. The use of haploidentical donors, sharing half of the HLA alleles with the recipient, has facilitated the use of this procedure as patients can rely on availability of a haploidentical donor within their family. Since HLA disparity increases the risk of graft-versus-host disease, T-cell depletion has been used to remove alloreactive lymphocytes from the graft. Selective removal of αβ T cells, which encompass the alloreactive repertoire, combined with removal of B cells to prevent EBV-related lymphoproliferative disease, proved safe and effective in clinical studies. Depleted αβ T cells and B cells are generally discarded as by-products. Considering the possible use of donor T cells for donor lymphocyte infusions or for generation of pathogen-specific T cells as mediators of graft-versus-infection effect, we tested whether cells in the discarded fractions were functionally intact. Response to alloantigens and to viral antigens comparable to that of unmanipulated cells indicated a functional integrity of αβ T cells, in spite of the manipulation used for their depletion. Furthermore, B cells proved to be efficient antigen-presenting cells, indicating that antigen uptake, processing, and presentation were fully preserved. Therefore, we propose that separated αβ T lymphocytes could be employed for obtaining pathogen-specific T cells, applying available methods for positive selection, which eventually leads to indirect allodepletion. In addition, these functional T cells could undergo additional manipulation, such as direct allodepletion or genetic modification.
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Affiliation(s)
- Giuseppina Li Pira
- Department of Pediatric Hematology and Oncology, IRCCS Bambino Gesù Children's Hospital , Rome , Italy
| | - Stefano Di Cecca
- Department of Pediatric Hematology and Oncology, IRCCS Bambino Gesù Children's Hospital , Rome , Italy
| | - Simone Biagini
- Department of Pediatric Hematology and Oncology, IRCCS Bambino Gesù Children's Hospital , Rome , Italy
| | - Elia Girolami
- Department of Pediatric Hematology and Oncology, IRCCS Bambino Gesù Children's Hospital , Rome , Italy
| | - Elisabetta Cicchetti
- Department of Pediatric Hematology and Oncology, IRCCS Bambino Gesù Children's Hospital , Rome , Italy
| | - Valentina Bertaina
- Department of Pediatric Hematology and Oncology, IRCCS Bambino Gesù Children's Hospital , Rome , Italy
| | - Concetta Quintarelli
- Department of Pediatric Hematology and Oncology, IRCCS Bambino Gesù Children's Hospital, Rome, Italy; Department of "Medicina Clinica e Chirurgia", University of Naples Federico II, Naples, Italy
| | - Ignazio Caruana
- Department of Pediatric Hematology and Oncology, IRCCS Bambino Gesù Children's Hospital , Rome , Italy
| | - Barbarella Lucarelli
- Department of Pediatric Hematology and Oncology, IRCCS Bambino Gesù Children's Hospital , Rome , Italy
| | - Pietro Merli
- Department of Pediatric Hematology and Oncology, IRCCS Bambino Gesù Children's Hospital , Rome , Italy
| | - Daria Pagliara
- Department of Pediatric Hematology and Oncology, IRCCS Bambino Gesù Children's Hospital , Rome , Italy
| | - Letizia Pomponia Brescia
- Department of Pediatric Hematology and Oncology, IRCCS Bambino Gesù Children's Hospital , Rome , Italy
| | - Alice Bertaina
- Department of Pediatric Hematology and Oncology, IRCCS Bambino Gesù Children's Hospital , Rome , Italy
| | - Mauro Montanari
- Department of Pediatric Hematology and Oncology, IRCCS Bambino Gesù Children's Hospital , Rome , Italy
| | - Franco Locatelli
- Department of Pediatric Hematology and Oncology, IRCCS Bambino Gesù Children's Hospital, Rome, Italy; Department of Pediatrics, University of Pavia, Pavia, Italy
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39
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Toyoda M, Shin BH, Ge S, Mirocha J, Thomas D, Chu M, Rodriguez E, Chao C, Petrosyan A, Galera OA, Vo A, Choi J, Peng A, Kahwaji J, Jordan SC. Impact of Desensitization on Antiviral Immunity in HLA-Sensitized Kidney Transplant Recipients. J Immunol Res 2017; 2017:5672523. [PMID: 28265581 PMCID: PMC5317146 DOI: 10.1155/2017/5672523] [Citation(s) in RCA: 24] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/17/2016] [Accepted: 12/15/2016] [Indexed: 12/15/2022] Open
Abstract
Viral infections represent significant morbidity and mortality factors in kidney transplant recipients, with CMV, EBV, and BKV infections being most common. Desensitization (DES) with IVIg and rituximab with/without plasma exchange followed by kidney transplantation with alemtuzumab induction increased successful transplant rates in HLA-sensitized patients but may represent an increased risk for viral infections due to severe lymphocyte depletion. Here, we report on the posttransplant viral infection status in 372 DES versus 538 non-DES patients. CMV and EBV viremia were significantly lower in DES patients, while BKV viremia was similar. This trend was observed primarily in CMV sero(-), EBV sero(+), and sero(-) patients. No patient developed PTLD. The incidence of BKAN, allograft, and patient survival was similar in both groups. These viral infections were not associated with subsequent allograft rejection which occurred within 6 months after the infection. Conclusions. The IVIg + rituximab desensitization combined with alemtuzumab induction with triple immunosuppression maintenance does not increase the risk for CMV, EBV, and BKV infections. Possible factors include, in addition to posttransplant antiviral prophylaxis and PCR monitoring, presence of memory T cells and antibodies specific to CMV and likely EBV, NK cell-mediated ADCC despite lymphocyte depletion, elimination of EBV and CMV reservoirs by rituximab and alemtuzumab, and use of IVIg with antiviral properties.
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Affiliation(s)
- Mieko Toyoda
- Transplant Immunology Laboratory, Cedars-Sinai Medical Center, Los Angeles, CA, USA
| | - Bong-Ha Shin
- Transplant Immunology Laboratory, Cedars-Sinai Medical Center, Los Angeles, CA, USA
| | - Shili Ge
- Transplant Immunology Laboratory, Cedars-Sinai Medical Center, Los Angeles, CA, USA
| | - James Mirocha
- Biostatistics Core, Cedars-Sinai Medical Center, Los Angeles, CA, USA
| | - David Thomas
- Transplant Immunology Laboratory, Cedars-Sinai Medical Center, Los Angeles, CA, USA
| | - Maggie Chu
- Transplant Immunology Laboratory, Cedars-Sinai Medical Center, Los Angeles, CA, USA
| | - Edgar Rodriguez
- Transplant Immunology Laboratory, Cedars-Sinai Medical Center, Los Angeles, CA, USA
| | - Christine Chao
- Transplant Immunology Laboratory, Cedars-Sinai Medical Center, Los Angeles, CA, USA
| | - Anna Petrosyan
- Transplant Immunology Laboratory, Cedars-Sinai Medical Center, Los Angeles, CA, USA
| | - Odette A. Galera
- Transplant Immunology Laboratory, Cedars-Sinai Medical Center, Los Angeles, CA, USA
| | - Ashley Vo
- Comprehensive Transplant Center, Cedars-Sinai Medical Center, Los Angeles, CA, USA
| | - Jua Choi
- Comprehensive Transplant Center, Cedars-Sinai Medical Center, Los Angeles, CA, USA
| | - Alice Peng
- Comprehensive Transplant Center, Cedars-Sinai Medical Center, Los Angeles, CA, USA
| | - Joseph Kahwaji
- Comprehensive Transplant Center, Cedars-Sinai Medical Center, Los Angeles, CA, USA
| | - Stanley C. Jordan
- Comprehensive Transplant Center, Cedars-Sinai Medical Center, Los Angeles, CA, USA
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40
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Han SH. Immunological Prediction of Cytomegalovirus (CMV) Replication Risk in Solid Organ Transplantation Recipients: Approaches for Regulating the Targeted Anti-CMV Prevention Strategies. Infect Chemother 2017; 49:161-175. [PMID: 29027383 PMCID: PMC5620383 DOI: 10.3947/ic.2017.49.3.161] [Citation(s) in RCA: 13] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/14/2022] Open
Abstract
The current cytomegalovirus (CMV) prevention strategies in solid organ transplantation (SOT) recipients have contributed towards overcoming the detrimental effects caused by CMV lytic infection, and improving the long-term success rate of graft survival. Although the quantification of CMV in peripheral blood is the standard method, and an excellent end-point for diagnosing CMV replication and modulating the anti-CMV prevention strategies in SOT recipients, a novel biomarker mimicking the CMV control mechanism is required. CMV-specific immune monitoring can be employed as a basic tool predicting CMV infection or disease after SOT, since uncontrolled CMV replication mostly originates from the impairment of immune responses against CMV under immunosuppressive conditions in SOT recipients. Several studies conducted during the past few decades have indicated the possibility of measuring the CMV-specific cell-mediated immune response in clinical situations. Among several analytical assays, the most advancing standardized tool is the QuantiFERON®-CMV assay. The T-Track® CMV kit that uses the standardized enzyme-linked immunospot assay is also widely employed. In addition to these assays, immunophenotyping and intracellular cytokine analysis using flow cytometry (with fluorescence-labeled monoclonal antibodies or peptide-major histocompatibility complex multimers) needs to be adequately standardized and validated for potential clinical applications.
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Affiliation(s)
- Sang Hoon Han
- Division of Infectious Diseases, Department of Internal Medicine, Yonsei University College of Medicine, Seoul, Korea.
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41
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Ogonek J, Kralj Juric M, Ghimire S, Varanasi PR, Holler E, Greinix H, Weissinger E. Immune Reconstitution after Allogeneic Hematopoietic Stem Cell Transplantation. Front Immunol 2016; 7:507. [PMID: 27909435 PMCID: PMC5112259 DOI: 10.3389/fimmu.2016.00507] [Citation(s) in RCA: 298] [Impact Index Per Article: 33.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/05/2016] [Accepted: 11/02/2016] [Indexed: 12/17/2022] Open
Abstract
The timely reconstitution and regain of function of a donor-derived immune system is of utmost importance for the recovery and long-term survival of patients after allogeneic hematopoietic stem cell transplantation (HSCT). Of note, new developments such as umbilical cord blood or haploidentical grafts were associated with prolonged immunodeficiency due to delayed immune reconstitution, raising the need for better understanding and enhancing the process of immune reconstitution and finding strategies to further optimize these transplant procedures. Immune reconstitution post-HSCT occurs in several phases, innate immunity being the first to regain function. The slow T cell reconstitution is regarded as primarily responsible for deleterious infections with latent viruses or fungi, occurrence of graft-versus-host disease, and relapse. Here we aim to summarize the major steps of the adaptive immune reconstitution and will discuss the importance of immune balance in patients after HSCT.
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Affiliation(s)
- Justyna Ogonek
- Transplantation Biology, Department of Hematology, Hemostasis, Oncology and Stem Cell Transplantation, Hannover Medical School, Hannover, Germany
| | - Mateja Kralj Juric
- BMT, Department of Internal Medicine I, Medical University of Vienna, Vienna, Austria
| | - Sakhila Ghimire
- Department of Hematology and Oncology, University of Regensburg, Regensburg, Germany
| | - Pavankumar Reddy Varanasi
- Transplantation Biology, Department of Hematology, Hemostasis, Oncology and Stem Cell Transplantation, Hannover Medical School, Hannover, Germany
| | - Ernst Holler
- Department of Hematology and Oncology, University of Regensburg, Regensburg, Germany
| | | | - Eva Weissinger
- Transplantation Biology, Department of Hematology, Hemostasis, Oncology and Stem Cell Transplantation, Hannover Medical School, Hannover, Germany
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42
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Vdovin AS, Filkin SY, Yefimova PR, Sheetikov SA, Kapranov NM, Davydova YO, Egorov ES, Khamaganova EG, Drokov MY, Kuzmina LA, Parovichnikova EN, Efimov GA, Savchenko VG. Recombinant MHC tetramers for isolation of virus-specific CD8+ cells from healthy donors: Potential approach for cell therapy of posttransplant cytomegalovirus infection. BIOCHEMISTRY (MOSCOW) 2016; 81:1371-1383. [DOI: 10.1134/s0006297916110146] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 11/23/2022]
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43
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Liu J, Chang YJ, Yan CH, Xu LP, Jiang ZF, Zhang XH, Liu KY, Huang XJ. Poor CMV-specific CD8+ T central memory subset recovery at early stage post-HSCT associates with refractory and recurrent CMV reactivation. J Infect 2016; 73:261-70. [DOI: 10.1016/j.jinf.2016.04.033] [Citation(s) in RCA: 12] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/08/2015] [Revised: 04/07/2016] [Accepted: 04/21/2016] [Indexed: 11/25/2022]
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44
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Zieliński M, Tarasewicz A, Zielińska H, Jankowska M, Moszkowska G, Dębska-Ślizień A, Rutkowski B, Trzonkowski P. CD28 positive, cytomegalovirus specific cytotoxic T lymphocytes as a novel biomarker associated with cytomegalovirus viremia in kidney allorecipients. J Clin Virol 2016; 83:17-25. [PMID: 27526103 DOI: 10.1016/j.jcv.2016.08.290] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/29/2016] [Revised: 07/12/2016] [Accepted: 08/10/2016] [Indexed: 12/29/2022]
Abstract
BACKGROUND CMV infection remains major complication after kidney transplantation, thus diagnostics tools that would improve identification of individuals at risk of development of CMV - related complications are useful. For this reason, searching for proper immunological biomarkers candidates gives hope to individualize antiviral therapy and minimize side effects of antiviral drugs. OBJECTIVES The purpose of this research was to assess immune assays that can be used to predict the likelihood of CMV viremia after kidney allotransplantation. STUDY DESIGN In the study, immunological markers of CMV viremia were assessed in 52 kidney transplant recipients during two years lasting follow-up. Immunological markers associated with viral infection, like lymphocytosis, cytotoxic T lymphocytes (CTL) and serum cytokines levels were compared with less common immunological assays, like activated T lymphocytes, CMV-specific CTL stratified according to naïve/memory phenotype. The test to assess expression of CD28 antigen on CTL, as a possible additional marker of CMV-specificity, was developed. RESULTS CD28-positive CMV-specific CTL have been found the most useful marker for CMV viremia prediction. Tested value of 3 cells/μl was found to be most suitable for CMV activation assessment with acceptable sensitivity and specificity. DISCUSSION This preliminary report suggests that CD28-positive CMV-specific CTL could be put at the first line, as possible novel marker associated with CMV viremia development.
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Affiliation(s)
- Maciej Zieliński
- Clinical Immunology and Transplantology Department, Medical University of Gdańsk, Poland.
| | - Agnieszka Tarasewicz
- Department of Nephrology, Transplantology and Internal Diseases, Medical University of Gdańsk, Poland
| | - Hanna Zielińska
- Clinical Immunology and Transplantology Department, Medical University of Gdańsk, Poland
| | - Magdalena Jankowska
- Department of Nephrology, Transplantology and Internal Diseases, Medical University of Gdańsk, Poland
| | - Grażyna Moszkowska
- Clinical Immunology and Transplantology Department, Medical University of Gdańsk, Poland
| | - Alicja Dębska-Ślizień
- Department of Nephrology, Transplantology and Internal Diseases, Medical University of Gdańsk, Poland
| | - Bolesław Rutkowski
- Department of Nephrology, Transplantology and Internal Diseases, Medical University of Gdańsk, Poland
| | - Piotr Trzonkowski
- Clinical Immunology and Transplantology Department, Medical University of Gdańsk, Poland
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45
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Drylewicz J, Schellens IMM, Gaiser R, Nanlohy NM, Quakkelaar ED, Otten H, van Dorp S, Jacobi R, Ran L, Spijkers S, Koning D, Schuurman R, Meijer E, Pietersma FL, Kuball J, van Baarle D. Rapid reconstitution of CD4 T cells and NK cells protects against CMV-reactivation after allogeneic stem cell transplantation. J Transl Med 2016; 14:230. [PMID: 27484705 PMCID: PMC4971638 DOI: 10.1186/s12967-016-0988-4] [Citation(s) in RCA: 25] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/04/2016] [Accepted: 07/26/2016] [Indexed: 12/22/2022] Open
Abstract
BACKGROUND Epstein-Barr virus and Cytomegalovirus reactivations frequently occur after allogeneic stem cell transplantation (SCT). METHODS Here we investigated the role of immune cell reconstitution in the onset and subsequent severity of EBV- and CMV-reactivation. To this end, 116 patients were prospectively sampled for absolute T cell (CD4 and CD8), B-cell (CD19) and NK-cell (CD16 and CD56) numbers weekly post-SCT during the first 3 months and thereafter monthly until 6 months post-SCT. Viral load was monitored in parallel. RESULTS In contrast to the general belief, we found that early T-cell reconstitution does not play a role in the onset of viral reactivation. CMV reactivation in the first 7 weeks after SCT however resulted in higher absolute CD8(+) T-cell numbers 6 months post-SCT in patients with high-level reactivation, many of which were CMV-specific. Interestingly, rapid reconstitution of CD4(+) T-cells, as well as NK cells and the presence of donor KIR3DL1, are associated with the absence of CMV-reactivation after SCT, suggestive of a protective role of these cells. In contrast, EBV-reactivations were not affected in any way by the level of immune reconstitution after SCT. CONCLUSION In conclusion, these data suggest that CD4(+) T-cells and NK cells, rather than CD8(+) T-cells, are associated with protection against CMV-reactivation.
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Affiliation(s)
- Julia Drylewicz
- Laboratory of Translational Immunology, Department of Immunology, Utrecht, The Netherlands.,Theoretical Biology and Bioinformatics, Department of Biology, Utrecht University, Utrecht, The Netherlands
| | - Ingrid M M Schellens
- Laboratory of Translational Immunology, Department of Immunology, Utrecht, The Netherlands
| | - Rogier Gaiser
- Laboratory of Translational Immunology, Department of Immunology, Utrecht, The Netherlands
| | - Nening M Nanlohy
- Laboratory of Translational Immunology, Department of Immunology, Utrecht, The Netherlands
| | - Esther D Quakkelaar
- Laboratory of Translational Immunology, Department of Immunology, Utrecht, The Netherlands
| | - Henny Otten
- Laboratory of Translational Immunology, Department of Immunology, Utrecht, The Netherlands
| | - Suzanne van Dorp
- Laboratory of Translational Immunology, Department of Immunology, Utrecht, The Netherlands.,Department of Haematology, Utrecht, The Netherlands
| | - Ronald Jacobi
- Laboratory of Translational Immunology, Department of Immunology, Utrecht, The Netherlands
| | - Leonie Ran
- Laboratory of Translational Immunology, Department of Immunology, Utrecht, The Netherlands
| | - Sanne Spijkers
- Laboratory of Translational Immunology, Department of Immunology, Utrecht, The Netherlands
| | - Dan Koning
- Laboratory of Translational Immunology, Department of Immunology, Utrecht, The Netherlands
| | | | - Ellen Meijer
- Department of Haematology, VUMC, Amsterdam, The Netherlands
| | - Floortje L Pietersma
- Laboratory of Translational Immunology, Department of Immunology, Utrecht, The Netherlands
| | - Jurgen Kuball
- Laboratory of Translational Immunology, Department of Immunology, Utrecht, The Netherlands.,Department of Haematology, Utrecht, The Netherlands
| | - Debbie van Baarle
- Laboratory of Translational Immunology, Department of Immunology, Utrecht, The Netherlands. .,Department of Internal Medicine and Infectious Diseases, University Medical Center Utrecht, Utrecht, The Netherlands. .,Department of Immune Mechanisms, National Institute for Public Health and the environment (RIVM), Center for Infectious Disease Control, Antonie van leeuwenhoeklaan 9, Bilthoven, The Netherlands.
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46
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Fuji S, Löffler J, Einsele H, Kapp M. Immunotherapy for opportunistic infections: Current status and future perspectives. Virulence 2016; 7:939-949. [PMID: 27385102 DOI: 10.1080/21505594.2016.1207038] [Citation(s) in RCA: 8] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/08/2023] Open
Abstract
The outcome after allogeneic haematopoietic stem cell transplantation (allo-HSCT) has significantly improved during the last decades. However, opportunistic infections such as viral and mold infections are still a major obstacle for cure. Within this field, adoptive T cell therapy against pathogens is a promising treatment approach. Recently, the techniques to develop T cell products including pathogen-specific T cells have been sophisticated and are now available in accordance to good manufacturing practice (GMP). Here, we aim to summarize current knowledge about adoptive T cell therapy against viral and mold infections.
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Affiliation(s)
- Shigeo Fuji
- a Department of Haematopoietic Stem Cell Transplantation , National Cancer Center Hospital , Tokyo , Japan.,b Department of Internal Medicine II , Division of Hematology/Oncology, University Hospital of Würzburg , Würzburg , Germany
| | - Jürgen Löffler
- b Department of Internal Medicine II , Division of Hematology/Oncology, University Hospital of Würzburg , Würzburg , Germany
| | - Hermann Einsele
- b Department of Internal Medicine II , Division of Hematology/Oncology, University Hospital of Würzburg , Würzburg , Germany
| | - Markus Kapp
- b Department of Internal Medicine II , Division of Hematology/Oncology, University Hospital of Würzburg , Würzburg , Germany
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47
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Torre-Cisneros J, Aguado J, Caston J, Almenar L, Alonso A, Cantisán S, Carratalá J, Cervera C, Cordero E, Fariñas M, Fernández-Ruiz M, Fortún J, Frauca E, Gavaldá J, Hernández D, Herrero I, Len O, Lopez-Medrano F, Manito N, Marcos M, Martín-Dávila P, Monforte V, Montejo M, Moreno A, Muñoz P, Navarro D, Pérez-Romero P, Rodriguez-Bernot A, Rumbao J, San Juan R, Vaquero J, Vidal E. Management of cytomegalovirus infection in solid organ transplant recipients: SET/GESITRA-SEIMC/REIPI recommendations. Transplant Rev (Orlando) 2016; 30:119-43. [DOI: 10.1016/j.trre.2016.04.001] [Citation(s) in RCA: 64] [Impact Index Per Article: 7.1] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/10/2016] [Revised: 04/02/2016] [Accepted: 04/04/2016] [Indexed: 02/06/2023]
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48
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Nemeckova S, Krystofova J, Babiarova K, Hainz P, Musil J, Sroller V, Maly M, Stastna-Markova M. Reconstitution of cytomegalovirus-specific T-cell response in allogeneic hematopoietic stem cell recipients: the contribution of six frequently recognized, virus-encoded ORFs. Transpl Infect Dis 2016; 18:381-9. [PMID: 27061389 DOI: 10.1111/tid.12540] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/02/2015] [Revised: 12/16/2015] [Accepted: 01/31/2016] [Indexed: 11/28/2022]
Abstract
BACKGROUND The reactivation of human cytomegalovirus (HCMV) in immunosuppressed patients is associated with significant morbidity. Testing HCMV-specific T-cell responses can help determine which patients are at high risk of HCMV disease. We optimized selection of HCMV antigens for detection of T-cell response of patients after allogeneic hematopoietic stem cell transplantation (HSCT) with the aim of identifying patients with insufficient control of HCMV reactivation. METHODS T-cell immune response to HCMV was monitored in 30 patients during the first year after HSCT. The HSCT recipients were classified according to their anti-HCMV T-cell response and the presence of HCMV DNA in the blood. RESULTS We observed an inverse relationship between the magnitude of HCMV-specific T-cell responses against CMV lysate, phosphoprotein (pp) 65, immediate early-1 (IE-1), UL36, and UL55, but not to US3 and US29 detected by interferon-gamma (IFNγ)- ELISPOT and the level of HCMV DNA in the blood of patients during the 30 days following sampling. The study has revealed that patients who received a graft from a seronegative donor have a lower T-cell response against HCMV and increased probability of HCMV reactivation in comparison to the patients who had received their graft from a seropositive donor. CONCLUSION The individual peptide pools and native HCMV antigens were useful for monitoring the time course of the anti-HCMV response by IFNγ-ELISPOT, which proved to have a prognostic value. Besides widely employed peptide pools of pp65 and IE-1, the use of antigens UL36 and UL55, but not US3 or US29, increased sensitivity of the test.
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Affiliation(s)
- S Nemeckova
- Department of Immunology, Institute of Hematology and Blood Transfusion, Prague, Czech Republic
| | - J Krystofova
- Department of Immunology, Institute of Hematology and Blood Transfusion, Prague, Czech Republic
| | - K Babiarova
- Department of Immunology, Institute of Hematology and Blood Transfusion, Prague, Czech Republic
| | - P Hainz
- Department of Immunology, Institute of Hematology and Blood Transfusion, Prague, Czech Republic
| | - J Musil
- Department of Immunology, Institute of Hematology and Blood Transfusion, Prague, Czech Republic
| | - V Sroller
- Department of Immunology, Institute of Hematology and Blood Transfusion, Prague, Czech Republic
| | - M Maly
- Department of Biostatistics, National Institute of Public Health, Prague, Czech Republic
| | - M Stastna-Markova
- Transplantation Ward, Institute of Hematology and Blood Transfusion, Prague, Czech Republic
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49
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Li Pira G, Di Cecca S, Montanari M, Moretta L, Manca F. Specific removal of alloreactive T-cells to prevent GvHD in hemopoietic stem cell transplantation: rationale, strategies and perspectives. Blood Rev 2016; 30:297-307. [PMID: 27066851 DOI: 10.1016/j.blre.2016.03.001] [Citation(s) in RCA: 17] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/14/2015] [Revised: 02/06/2016] [Accepted: 03/08/2016] [Indexed: 01/05/2023]
Abstract
Hemopoietic stem cell transplantation (HSCT) is a standard procedure for treatment of malignant and non-malignant hematological diseases. HSCT donors include HLA-identical siblings, matched or mismatched unrelated donors and haploidentical related donors. Graft-versus-host disease (GvHD), mediated by donor alloreactive T-cells in the graft, can be triggered by minor histocompatibility antigens in HLA-identical pairs, by alleles at loci not considered for MUD-matching or by the mismatched haplotype in haplo-HSCT. Therefore, removal of donor T-cells, that contain the alloreactive precursors, is required, but T-cell depletion associates with opportunistic infections and with reduced graft-versus-leukemia effect. Selective T-cell depletion strategies have been introduced, like removal of αβ T-lymphocytes and of naive T-cells, two subsets including the alloreactive precursors, but the ultimate goal is specific removal of alloreactive T-cells. Here we review the different approaches to deplete alloreactive T-cells only and discuss pros and cons, specificity, efficiency and efficacy. Combinations of different methods and innovative approaches are also proposed for depleting specific alloreactive T-cells with high efficiency.
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Affiliation(s)
- Giuseppina Li Pira
- Department of Pediatric Hematology and Oncology, IRCCS Bambino Gesù Children's Hospital, Piazza S. Onofrio 4, 00165 Rome, Italy; Unit of Immuno-hematology and Transfusion Medicine, IRCCS Bambino Gesù Children's Hospital, Piazza S. Onoforio 4, 00165 Rome, Italy.
| | - Stefano Di Cecca
- Department of Pediatric Hematology and Oncology, IRCCS Bambino Gesù Children's Hospital, Piazza S. Onofrio 4, 00165 Rome, Italy.
| | - Mauro Montanari
- Department of Pediatric Hematology and Oncology, IRCCS Bambino Gesù Children's Hospital, Piazza S. Onofrio 4, 00165 Rome, Italy; Unit of Immuno-hematology and Transfusion Medicine, IRCCS Bambino Gesù Children's Hospital, Piazza S. Onoforio 4, 00165 Rome, Italy.
| | - Lorenzo Moretta
- Immunology Area, IRCCS Bambino Gesù Children's Hospital, Piazza S. Onoforio 4, 00165 Rome, Italy.
| | - Fabrizio Manca
- Immunology Area, IRCCS Bambino Gesù Children's Hospital, Piazza S. Onoforio 4, 00165 Rome, Italy.
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50
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Hanley PJ, Melenhorst JJ, Nikiforow S, Scheinberg P, Blaney JW, Demmler-Harrison G, Cruz CR, Lam S, Krance RA, Leung KS, Martinez CA, Liu H, Douek DC, Heslop HE, Rooney CM, Shpall EJ, Barrett AJ, Rodgers JR, Bollard CM. CMV-specific T cells generated from naïve T cells recognize atypical epitopes and may be protective in vivo. Sci Transl Med 2016; 7:285ra63. [PMID: 25925682 DOI: 10.1126/scitranslmed.aaa2546] [Citation(s) in RCA: 85] [Impact Index Per Article: 9.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/01/2023]
Abstract
Adoptive transfer of cytomegalovirus (CMV)-specific T cells derived from adult seropositive donors can effectively restore antiviral immunity after transplantation. However, CMV-seronegative donors lack CMV-specific memory T cells, which restricts the availability of virus-specific T cells for immunoprophylaxis. We demonstrate the feasibility of deriving CMV-specific T cells from naïve cells for T cell therapy. Naïve T cells primed to recognize CMV were restricted to different, atypical epitopes than T cells derived from CMV-seropositive individuals; however, these two cell populations had similar avidities. CMV-seropositive individuals also had T cells recognizing these atypical epitopes, but these cells had a lower avidity than those derived from the seronegative subjects, which suggests that high-avidity T cells to these epitopes may be lost over time. Indeed, recipients of cord blood (CB) grafts who did not develop CMV were found by clonotypic analysis to have T cells recognizing atypical CMVpp65 epitopes. Therefore, we examined unmanipulated CB units and found that T cells with T cell receptors restricted by atypical epitopes were the most common, which may explain why these T cells expanded. When infused to recipients, naïve donor-derived virus-specific T cells that recognized atypical epitopes were associated with prolonged periods of CMV-free survival and complete remission. These data suggest that naïve-derived T cells from seronegative patients may be an additional source of cells for CMV immunoprophylaxis.
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Affiliation(s)
- Patrick J Hanley
- Center for Cell and Gene Therapy, Baylor College of Medicine, Texas Children's Hospital, and Houston Methodist Hospital, Houston, TX 77030, USA. Department of Pathology and Immunology, Baylor College of Medicine, Houston, TX 77030, USA. Program for Cell Enhancement and Technologies for Immunotherapy, The Sheikh Zayed Institute for Pediatric Surgical Innovation, the Center for Cancer and Immunology Research, and the Division of Blood and Marrow Transplantation, Children's National Health System and The George Washington University, Washington, DC 20052, USA
| | - Jan J Melenhorst
- Hematology Branch, National Heart, Lung, and Blood Institute, National Institutes of Health, Bethesda, MD 20892, USA
| | - Sarah Nikiforow
- Dana-Farber Cancer Institute, Harvard Medical School, 44 Binney St., Boston, MA 02115, USA
| | - Phillip Scheinberg
- Hematology Branch, National Heart, Lung, and Blood Institute, National Institutes of Health, Bethesda, MD 20892, USA
| | - James W Blaney
- Center for Cell and Gene Therapy, Baylor College of Medicine, Texas Children's Hospital, and Houston Methodist Hospital, Houston, TX 77030, USA
| | | | - C Russell Cruz
- Center for Cell and Gene Therapy, Baylor College of Medicine, Texas Children's Hospital, and Houston Methodist Hospital, Houston, TX 77030, USA. Program for Cell Enhancement and Technologies for Immunotherapy, The Sheikh Zayed Institute for Pediatric Surgical Innovation, the Center for Cancer and Immunology Research, and the Division of Blood and Marrow Transplantation, Children's National Health System and The George Washington University, Washington, DC 20052, USA
| | - Sharon Lam
- Center for Cell and Gene Therapy, Baylor College of Medicine, Texas Children's Hospital, and Houston Methodist Hospital, Houston, TX 77030, USA. Department of Pathology and Immunology, Baylor College of Medicine, Houston, TX 77030, USA. Program for Cell Enhancement and Technologies for Immunotherapy, The Sheikh Zayed Institute for Pediatric Surgical Innovation, the Center for Cancer and Immunology Research, and the Division of Blood and Marrow Transplantation, Children's National Health System and The George Washington University, Washington, DC 20052, USA
| | - Robert A Krance
- Center for Cell and Gene Therapy, Baylor College of Medicine, Texas Children's Hospital, and Houston Methodist Hospital, Houston, TX 77030, USA. Department of Pediatrics, Baylor College of Medicine, Houston, TX 77030, USA. Department of Medicine, Baylor College of Medicine, Houston, TX 77030, USA
| | - Kathryn S Leung
- Center for Cell and Gene Therapy, Baylor College of Medicine, Texas Children's Hospital, and Houston Methodist Hospital, Houston, TX 77030, USA. Department of Pediatrics, Baylor College of Medicine, Houston, TX 77030, USA
| | - Caridad A Martinez
- Center for Cell and Gene Therapy, Baylor College of Medicine, Texas Children's Hospital, and Houston Methodist Hospital, Houston, TX 77030, USA. Department of Pediatrics, Baylor College of Medicine, Houston, TX 77030, USA
| | - Hao Liu
- Center for Cell and Gene Therapy, Baylor College of Medicine, Texas Children's Hospital, and Houston Methodist Hospital, Houston, TX 77030, USA
| | - Daniel C Douek
- Human Immunology Section, Vaccine Research Center, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD 20892, USA
| | - Helen E Heslop
- Center for Cell and Gene Therapy, Baylor College of Medicine, Texas Children's Hospital, and Houston Methodist Hospital, Houston, TX 77030, USA. Department of Pediatrics, Baylor College of Medicine, Houston, TX 77030, USA. Department of Medicine, Baylor College of Medicine, Houston, TX 77030, USA
| | - Cliona M Rooney
- Center for Cell and Gene Therapy, Baylor College of Medicine, Texas Children's Hospital, and Houston Methodist Hospital, Houston, TX 77030, USA. Department of Pathology and Immunology, Baylor College of Medicine, Houston, TX 77030, USA. Department of Pediatrics, Baylor College of Medicine, Houston, TX 77030, USA. Department of Medicine, Baylor College of Medicine, Houston, TX 77030, USA. Department of Molecular Virology and Microbiology, Baylor College of Medicine, Houston, TX 77030, USA
| | - Elizabeth J Shpall
- Department of Stem Cell Transplantation and Cellular Therapy, MD Anderson Cancer Center, Houston, TX 77030, USA
| | - A John Barrett
- Hematology Branch, National Heart, Lung, and Blood Institute, National Institutes of Health, Bethesda, MD 20892, USA
| | - John R Rodgers
- Department of Pathology and Immunology, Baylor College of Medicine, Houston, TX 77030, USA
| | - Catherine M Bollard
- Center for Cell and Gene Therapy, Baylor College of Medicine, Texas Children's Hospital, and Houston Methodist Hospital, Houston, TX 77030, USA. Department of Pathology and Immunology, Baylor College of Medicine, Houston, TX 77030, USA. Program for Cell Enhancement and Technologies for Immunotherapy, The Sheikh Zayed Institute for Pediatric Surgical Innovation, the Center for Cancer and Immunology Research, and the Division of Blood and Marrow Transplantation, Children's National Health System and The George Washington University, Washington, DC 20052, USA. Department of Pediatrics, Baylor College of Medicine, Houston, TX 77030, USA. Department of Medicine, Baylor College of Medicine, Houston, TX 77030, USA.
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