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Article ; Online: ROCKing Chronic Graft-Versus-Host Disease.

Heine, Annkristin / Holderried, Tobias A W / Wolf, Dominik

Journal of clinical oncology : official journal of the American Society of Clinical Oncology

2021 Volume 39, Issue 29, Page(s) 3308

MeSH term(s)	Chronic Disease ; Graft vs Host Disease/etiology ; Hematopoietic Stem Cell Transplantation/adverse effects ; Humans
Language	English
Publishing date	2021-08-04
Publishing country	United States
Document type	Letter ; Comment
ZDB-ID	604914-x
ISSN	1527-7755 ; 0732-183X
ISSN (online)	1527-7755
ISSN	0732-183X
DOI	10.1200/JCO.21.01081
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Article ; Online: The Role of Immune Checkpoints after Cellular Therapy.

Schmitz, Friederike / Wolf, Dominik / Holderried, Tobias A W

International journal of molecular sciences

2020 Volume 21, Issue 10

Abstract: Cellular therapies utilize the powerful force of the human immune system to target malignant cells. Allogeneic hematopoietic stem cell transplantation (allo-HCT) is the most established cellular therapy, but chimeric antigen receptor (CAR) T cell ... ...

Abstract	Cellular therapies utilize the powerful force of the human immune system to target malignant cells. Allogeneic hematopoietic stem cell transplantation (allo-HCT) is the most established cellular therapy, but chimeric antigen receptor (CAR) T cell therapies have gained attention in recent years. While in allo-HCT an entirely novel allogeneic immune system facilitates a so-called Graft-versus-tumor, respectively, Graft-versus-leukemia (GvT/GvL) effect against high-risk hematologic malignancies, in CAR T cell therapies genetically modified autologous T cells specifically attack target molecules on malignant cells. These therapies have achieved high success rates, offering potential cures in otherwise detrimental diseases. However, relapse after cellular therapy remains a serious clinical obstacle. Checkpoint Inhibition (CI), which was recently designated as breakthrough in cancer treatment and consequently awarded with the Nobel prize in 2018, is a different way to increase anti-tumor immunity. Here, inhibitory immune checkpoints are blocked on immune cells in order to restore the immunological force against malignant diseases. Disease relapse after CAR T cell therapy or allo-HCT has been linked to up-regulation of immune checkpoints that render cancer cells resistant to the cell-mediated anti-cancer immune effects. Thus, enhancing immune cell function after cellular therapies using CI is an important treatment option that might re-activate the anti-cancer effect upon cell therapy. In this review, we will summarize current data on this topic with the focus on immune checkpoints after cellular therapy for malignant diseases and balance efficacy versus potential side effects.
MeSH term(s)	Graft vs Leukemia Effect ; Hematopoietic Stem Cell Transplantation/methods ; Humans ; Immune Checkpoint Inhibitors/therapeutic use ; Immunotherapy, Adoptive/methods ; Leukemia/drug therapy ; Leukemia/therapy
Chemical Substances	Immune Checkpoint Inhibitors
Language	English
Publishing date	2020-05-21
Publishing country	Switzerland
Document type	Journal Article ; Review
ZDB-ID	2019364-6
ISSN	1422-0067 ; 1422-0067 ; 1661-6596
ISSN (online)	1422-0067
ISSN	1422-0067 ; 1661-6596
DOI	10.3390/ijms21103650
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Article ; Online: The potential of eHealth for cancer patients-does COVID-19 pandemic change the attitude towards use of telemedicine services?

Holderried, Tobias A W / Hecker, Katharina / Reh, Laura / Kirschner, Martin / Walter, Jeanette / Brossart, Peter / Holderried, Martin

PloS one

2023 Volume 18, Issue 2, Page(s) e0280723

Abstract: Background: Internet penetration worldwide has increased rapidly over the recent years. With this growth, modern information and communication technologies (ICT) have become increasingly important. They do not only change daily life but also patient- ... ...

Abstract	Background: Internet penetration worldwide has increased rapidly over the recent years. With this growth, modern information and communication technologies (ICT) have become increasingly important. They do not only change daily life but also patient-physician interaction and health related information search, which can be summarized as electronic Health (eHealth). eHealth was already known before the emergence of the coronavirus disease 2019 (COVID-19), but this pandemic substantially challenged health systems, physicians and hospitals so profoundly that new services and methods of patient-physician interaction had to be implemented rapidly. This study investigates the attitude of cancer patients towards eHealth and the potential impact of COVID-19 on its use. Methods and findings: The study was a multicentered study carried out at the university hospitals Bonn and Aachen. Patients were asked to answer a structured questionnaire in the time span between September 2019 and February 2021. Due to the COVID-19 pandemic, no patients were addressed between March 2020 and July 2020. The questionnaire focused on socio-demographic data, the dissemination of internet-enabled devices, the patients' attitude towards eHealth and the use of modern ICT in daily life and for health-related information search. In total, 280 patients have filled the questionnaire of which 48% were female and 52% were male. Men have a slightly more positive attitude towards the overall potential of eHealth than women which was shown by a significant influence for receiving medical information via e-mail. Hematological-oncological patients with a higher education level reported a significantly higher willingness to send personal health information to their physician and health insurance. A frequency of medical consultation of more than 5 times during the previous year has a significantly positive impact regarding the use of online communication, online video consultation and treatment quality. Younger patients have more concerns about data security than older patients. The study shows a different attitude towards the influence of eHealth on the patient-physician relationship in different therapy situations. While there were no significant changes in patients' attitude towards eHealth after the start of the COVID-19 pandemic, there was a trend towards an increasingly embracing attitude in patients, who answered the questionnaire during COVID-19 pandemic situation. Conclusions: Overall, cancer patients had a positive attitude towards eHealth and the dissemination of internet-enabled devices was high. The study shows that the potential of eHealth is high among hematological-oncological patients. Further eHealth technologies and especially telemedically supported care processes should be implemented to improve patient-physician interaction and cross-sectoral care. COVID-19 pandemic led to a fast initiation and acceleration of new structures and routines for physicians, hospitals and patients. These new processes should be used to promote digitalization in hematological and oncological telemedicine. To successfully implement new eHealth technologies, future research should focus on patients' concerns about data privacy and data availability especially in the context of exchange of medical information in cross sectoral and interdisciplinary care processes.
MeSH term(s)	Humans ; Male ; Female ; COVID-19/epidemiology ; Pandemics ; Neoplasms/epidemiology ; Neoplasms/therapy ; Telemedicine/methods ; Hospitals, University ; Surveys and Questionnaires ; Internet
Language	English
Publishing date	2023-02-10
Publishing country	United States
Document type	Journal Article
ZDB-ID	2267670-3
ISSN	1932-6203 ; 1932-6203
ISSN (online)	1932-6203
ISSN	1932-6203
DOI	10.1371/journal.pone.0280723
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Article ; Online: Peripheral blood kinetics following total body irradiation and allogeneic hematopoietic stem cell transplantation: Timing matters.

Dejonckheere, Cas S / Böhner, Alexander M C / Schmitz, Eva / Holderried, Tobias A W / Schmeel, Leonard C / Brossart, Peter / Giordano, Frank A / Köksal, Mümtaz A

Cancer medicine

2022 Volume 12, Issue 6, Page(s) 7170–7174

Abstract: Total body irradiation (TBI) remains an important component in many conditioning regimens before allogeneic hematopoietic stem cell transplantation (allo-HSCT). Because of its frequent toxicity, patient selection is crucial, making it of interest to ... ...

Abstract	Total body irradiation (TBI) remains an important component in many conditioning regimens before allogeneic hematopoietic stem cell transplantation (allo-HSCT). Because of its frequent toxicity, patient selection is crucial, making it of interest to identify factors improving engraftment. In this retrospective single center analysis, the characteristics of 48 adult such patients were studied. Mean overall survival (OS) was 22.2 months after allo-HSCT. Interestingly, people with an interval ≥3 days between TBI completion and allo-HSCT showed improved OS, when compared to a shorter interval (p = 0.10). Peripheral blood kinetics after successful engraftment also differed, with a longer interval resulting in a higher platelet count and lower leukocyte and neutrophil (p < 0.05) count. These data suggest that the exact timing of TBI before allo-HSCT might directly impact a patient's survival and could help single out those at higher risk of graft failure who might benefit from an altered conditioning regimen.
MeSH term(s)	Adult ; Humans ; Retrospective Studies ; Whole-Body Irradiation ; Kinetics ; Hematopoietic Stem Cell Transplantation/methods ; Leukemia, Myeloid, Acute/complications ; Transplantation Conditioning/methods ; Graft vs Host Disease/etiology
Language	English
Publishing date	2022-11-20
Publishing country	United States
Document type	Journal Article
ZDB-ID	2659751-2
ISSN	2045-7634 ; 2045-7634
ISSN (online)	2045-7634
ISSN	2045-7634
DOI	10.1002/cam4.5452
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Article ; Online: ECP versus ruxolitinib in steroid-refractory chronic GVHD - a retrospective study by the EBMT transplant complications working party.

Penack, Olaf / Peczynski, Christophe / Boreland, William / Lemaitre, Jessica / Reinhardt, H Christian / Afanasyeva, Ksenia / Avenoso, Daniele / Holderried, Tobias A W / Kornblit, Brian Thomas / Gavriilaki, Eleni / Martinez, Carmen / Chiusolo, Patrizia / Mico, Maria Caterina / Dagunet, Elisabeth / Wichert, Stina / Ozdogu, Hakan / Piekarska, Agnieszka / Kinsella, Francesca / Basak, Grzegorz W /

Schoemans, Hélène / Koenecke, Christian / Moiseev, Ivan / Peric, Zinaida

Bone marrow transplantation

2024 Volume 59, Issue 3, Page(s) 380–386

Abstract: Ruxolitinib has become the new standard of care for steroid-refractory and steroid-dependent chronic GVHD (SR-cGVHD). Our aim was to collect comparative data between ruxolitinib and extracorporeal photophoresis (ECP). We asked EBMT centers if they were ... ...

Abstract	Ruxolitinib has become the new standard of care for steroid-refractory and steroid-dependent chronic GVHD (SR-cGVHD). Our aim was to collect comparative data between ruxolitinib and extracorporeal photophoresis (ECP). We asked EBMT centers if they were willing to provide detailed information on GVHD grading, -therapy, -dosing, -response and complications for each included patient. 31 centers responded positively and we included all patients between 1/2017-7/2019 treated with ECP or ruxolitinib for moderate or severe SR-cGVHD. We identified 84 and 57 patients with ECP and ruxolitinib, respectively. We performed multivariate analyses adjusted on grading and type of SR-cGVHD (steroid dependent vs. refractory vs. intolerant to steroids). At day+180 after initiation of treatment for SR-cGVHD the odds ratio in the ruxolitinib group to achieve overall response vs. the ECP group was 1.35 (95% CI = [0.64; 2.91], p = 0.43). In line, we detected no statistically significant differences in overall survival, progression-free survival, non-relapse mortality and relapse incidence. The clinical significance is limited by the retrospective study design and the current data can't replace prospective studies on ECP in SR-cGVHD. However, the present results contribute to the accumulating evidence on ECP as an effective treatment option in SR-cGVHD.
MeSH term(s)	Humans ; Retrospective Studies ; Prospective Studies ; Steroids/therapeutic use ; Graft vs Host Disease/etiology ; Photopheresis/methods ; Chronic Disease ; Hematopoietic Stem Cell Transplantation/adverse effects ; Nitriles ; Pyrazoles ; Pyrimidines
Chemical Substances	ruxolitinib (82S8X8XX8H) ; Steroids ; Nitriles ; Pyrazoles ; Pyrimidines
Language	English
Publishing date	2024-01-06
Publishing country	England
Document type	Journal Article
ZDB-ID	632854-4
ISSN	1476-5365 ; 0268-3369 ; 0951-3078
ISSN (online)	1476-5365
ISSN	0268-3369 ; 0951-3078
DOI	10.1038/s41409-023-02174-2
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Zs.A 2168: Show issues

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Article ; Online: Hospital sanitary facilities on wards with high antibiotic exposure play an important role in maintaining a reservoir of resistant pathogens, even over many years.

Neidhöfer, Claudio / Sib, Esther / Neuenhoff, Marcel / Schwengers, Oliver / Dummin, Tobias / Buechler, Christian / Klein, Niklas / Balks, Julian / Axtmann, Katharina / Schwab, Katjana / Holderried, Tobias A W / Feldmann, Georg / Brossart, Peter / Engelhart, Steffen / Mutters, Nico T / Bierbaum, Gabriele / Parčina, Marijo

Antimicrobial resistance and infection control

2023 Volume 12, Issue 1, Page(s) 33

Abstract: Background: Hospitals with their high antimicrobial selection pressure represent the presumably most important reservoir of multidrug-resistant human pathogens. Antibiotics administered in the course of treatment are excreted and discharged into the ... ...

Abstract	Background: Hospitals with their high antimicrobial selection pressure represent the presumably most important reservoir of multidrug-resistant human pathogens. Antibiotics administered in the course of treatment are excreted and discharged into the wastewater system. Not only in patients, but also in the sewers, antimicrobial substances exert selection pressure on existing bacteria and promote the emergence and dissemination of multidrug-resistant clones. In previous studies, two main clusters were identified in all sections of the hospital wastewater network that was investigated, one K. pneumoniae ST147 cluster encoding NDM- and OXA-48 carbapenemases and one VIM-encoding P. aeruginosa ST823 cluster. In the current study, we investigated if NDM- and OXA-48-encoding K. pneumoniae and VIM-encoding P. aeruginosa isolates recovered between 2014 and 2021 from oncological patients belonged to those same clusters. Methods: The 32 isolates were re-cultured, whole-genome sequenced, phenotypically tested for their antimicrobial susceptibility, and analyzed for clonality and resistance genes in silico. Results: Among these strains, 25 belonged to the two clusters that had been predominant in the wastewater, while two others belonged to a sequence-type less prominently detected in the drains of the patient rooms. Conclusion: Patients constantly exposed to antibiotics can, in interaction with their persistently antibiotic-exposed sanitary facilities, form a niche that might be supportive for the emergence, the development, the dissemination, and the maintenance of certain nosocomial pathogen populations in the hospital, due to antibiotic-induced selection pressure. Technical and infection control solutions might help preventing transmission of microorganisms from the wastewater system to the patient and vice versa, particularly concerning the shower and toilet drainage. However, a major driving force might also be antibiotic induced selection pressure and parallel antimicrobial stewardship efforts could be essential.
MeSH term(s)	Humans ; Anti-Bacterial Agents/pharmacology ; Wastewater ; Bacteria ; Hospitals ; Anti-Infective Agents ; Klebsiella pneumoniae
Chemical Substances	Anti-Bacterial Agents ; Wastewater ; Anti-Infective Agents
Language	English
Publishing date	2023-04-15
Publishing country	England
Document type	Journal Article
ZDB-ID	2666706-X
ISSN	2047-2994 ; 2047-2994
ISSN (online)	2047-2994
ISSN	2047-2994
DOI	10.1186/s13756-023-01236-w
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Article ; Online: Fecal microbiota transfer for refractory intestinal graft-versus-host disease - Experience from two German tertiary centers.

Goeser, Felix / Sifft, Barbara / Stein-Thoeringer, Christoph / Farowski, Fedja / Strassburg, Christian P / Brossart, Peter / Higgins, Paul G / Scheid, Christoph / Wolf, Dominik / Holderried, Tobias A W / Vehreschild, Maria J G T / Cruz Aguilar, Marta Rebeca

European journal of haematology

2021 Volume 107, Issue 2, Page(s) 229–245

Abstract: Rationale: Steroid refractory graft-vs-host disease (sr-GvHD) represents a challenging complication after allogeneic hematopoietic cell transplantation (allo-HCT). Intestinal microbiota (IM) diversity and dysbiosis were identified as influencing factors ...

Abstract	Rationale: Steroid refractory graft-vs-host disease (sr-GvHD) represents a challenging complication after allogeneic hematopoietic cell transplantation (allo-HCT). Intestinal microbiota (IM) diversity and dysbiosis were identified as influencing factors for the development of acute GvHD. Fecal microbiota transfer (FMT) is hypothesized to restore IM dysbiosis, but there is limited knowledge about the significance of FMT in the treatment of sr-GvHD. Objectives: We studied the effects of FMT on sr-GvHD in allo-HCT patients from two German tertiary clinical centers (n = 11 patients; period: March 2017 until July 2019). To assess safety and clinical efficacy, we analyzed clinical data pre- and post-FMT (day -14 to +30 relative to FMT). Moreover, IM were analyzed in donor samples and in a subset of patients pre- and post-FMT by 16S rRNA sequencing. Results: Post-FMT, we observed no intervention-associated, systemic inflammatory responses and only minor side effects (5/11 patients: abdominal pain and transformation of peristalsis-each 3/11 and vomiting-1/11). Stool frequencies and volumes were significantly reduced [pre- vs post-FMT (d14): P < .05, respectively] as well as clear attenuation regarding both grading and staging of sr-GvHD was present upon FMT. Moreover, IM analyses revealed an increase of alpha diversity as well as a compositional shifts toward the donor post-FMT. Conclusions: In our study, we observed positive effects on sr-GVHD after FMT without the occurrence of major adverse events. Although these findings are in line with published data on beneficial effects of FMT in sr-GvHD, further randomized clinical studies are urgently needed to better define the clinical validity including mode of action.
MeSH term(s)	Adult ; Aged ; Biodiversity ; Disease Management ; Fecal Microbiota Transplantation/methods ; Female ; Gastrointestinal Diseases/diagnosis ; Gastrointestinal Diseases/etiology ; Gastrointestinal Diseases/therapy ; Gastrointestinal Microbiome ; Germany ; Graft vs Host Disease/diagnosis ; Graft vs Host Disease/etiology ; Graft vs Host Disease/therapy ; Hematopoietic Stem Cell Transplantation/adverse effects ; Hematopoietic Stem Cell Transplantation/methods ; Humans ; Male ; Middle Aged ; Tertiary Care Centers ; Transplantation, Homologous ; Treatment Outcome
Language	English
Publishing date	2021-06-09
Publishing country	England
Document type	Journal Article
ZDB-ID	392482-8
ISSN	1600-0609 ; 0902-4441
ISSN (online)	1600-0609
ISSN	0902-4441
DOI	10.1111/ejh.13642
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Zs.A 323: Show issues

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Article ; Online: Selective ABO immunoadsorption in hematopoietic stem cell transplantation with major ABO incompatibility.

Crysandt, Martina / Soysal, Hatice / Jennes, Eva / Holtick, Udo / Mrotzek, Matthias / Rehnelt, Susanne / Holderried, Tobias A W / Wessiepe, Martina / Kunter, Uta / Wilop, Stefan / Silling, Gerda / Gecht, Judith / Beier, Fabian / Brümmendorf, Tim H / Jost, Edgar

European journal of haematology

2021 Volume 107, Issue 3, Page(s) 324–332

Abstract: Objective: ABO mismatch between donor and recipient occurs in 40% of allogeneic hematopoietic stem cell transplantations (HCT). Different strategies have been described to reduce isohemagglutinins (IHA) before HCT. We describe the effect of selective ... ...

Abstract	Objective: ABO mismatch between donor and recipient occurs in 40% of allogeneic hematopoietic stem cell transplantations (HCT). Different strategies have been described to reduce isohemagglutinins (IHA) before HCT. We describe the effect of selective ABO immunoadsorption (ABO IA) on erythrocyte transfusion rate and the development of post-transplant pure red cell aplasia (ptPRCA). Methods: 63 patients with major ABO incompatibility were retrospectively analyzed. Nine patients with major ABO incompatibility and high-IHA titer were treated by ABO IA before HCT. We analyzed the need for transfusion and the occurrence of ptPRCA. We compared the outcome with patients treated by other methods to reduce IHA. Results: In all nine patients treated by ABO IA, IHA decreased in a median four times. PtPRCA occurred in one patient. The median number of transfusions was 8 (range: 0-36) between d0 and d100. In 25 patients with high-IHA titer without treatment or treated by other methods to reduce IHA, the need for transfusions was comparable. No difference in the incidence of ptPRCA was observed. Conclusions: Selective ABO IA is a feasible, safe, and effective method to reduce IHA before HCT in major ABO incompatibility. No effect on transfusion rate or ptPRCA compared to other strategies could be observed.
MeSH term(s)	ABO Blood-Group System/immunology ; Blood Group Incompatibility/immunology ; Blood Group Incompatibility/mortality ; Blood Group Incompatibility/therapy ; Erythrocyte Transfusion/adverse effects ; Female ; Hematopoietic Stem Cell Transplantation/adverse effects ; Hematopoietic Stem Cell Transplantation/methods ; Humans ; Leukemia/immunology ; Leukemia/mortality ; Leukemia/therapy ; Male ; Middle Aged ; Myelodysplastic Syndromes/immunology ; Myelodysplastic Syndromes/mortality ; Myelodysplastic Syndromes/therapy ; Myeloproliferative Disorders/immunology ; Myeloproliferative Disorders/mortality ; Myeloproliferative Disorders/therapy ; Plasmapheresis/methods ; Red-Cell Aplasia, Pure/etiology ; Red-Cell Aplasia, Pure/immunology ; Red-Cell Aplasia, Pure/mortality ; Red-Cell Aplasia, Pure/prevention & control ; Retrospective Studies ; Survival Analysis ; Tissue Donors ; Transfusion Reaction/etiology ; Transfusion Reaction/immunology ; Transfusion Reaction/mortality ; Transfusion Reaction/prevention & control ; Transplantation, Homologous ; Treatment Outcome
Chemical Substances	ABO Blood-Group System
Language	English
Publishing date	2021-06-07
Publishing country	England
Document type	Journal Article
ZDB-ID	392482-8
ISSN	1600-0609 ; 0902-4441
ISSN (online)	1600-0609
ISSN	0902-4441
DOI	10.1111/ejh.13668
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Article ; Online: Treatment Response Monitoring in Patients with Advanced Malignancies Using Cell-Free SHOX2 and SEPT9 DNA Methylation in Blood: An Observational Prospective Study.

de Vos, Luka / Jung, Maria / Koerber, Ruth-Miriam / Bawden, Emma G / Holderried, Tobias A W / Dietrich, Jörn / Bootz, Friedrich / Brossart, Peter / Kristiansen, Glen / Dietrich, Dimo

The Journal of molecular diagnostics : JMD

2020 Volume 22, Issue 7, Page(s) 920–933

Abstract: Patients with incurable cancer usually receive palliative treatment with significant toxicity and limited efficacy. Methylation analysis of circulating cell-free DNA (ccfDNA) in blood from cancer patients represents a promising approach for minimally ... ...

Abstract	Patients with incurable cancer usually receive palliative treatment with significant toxicity and limited efficacy. Methylation analysis of circulating cell-free DNA (ccfDNA) in blood from cancer patients represents a promising approach for minimally invasive, real-time monitoring of treatment response. Short stature homeobox 2 (SHOX2) and septin 9 (SEPT9) methylation was analyzed in N = 8865 malignant and N = 746 normal adjacent tissues across 33 different malignancies from The Cancer Genome Atlas. Furthermore, we performed quantitative SHOX2 and SEPT9 ccfDNA methylation analysis in plasma obtained before and consecutively during treatment from prospectively enrolled N = 115 patients with various advanced cancers. SHOX2 and/or SEPT9 hypermethylation in malignant tissues is present in various carcinomas, sarcoma, melanoma, brain tumors, mesothelioma, and hematopoietic malignancies. Among the prospectively enrolled cancer patients, 61% (70/115) of patients had a baseline-positive blood cumulative ccfDNA methylation score (CMS) and were eligible for response monitoring. Dynamic changes of CMS during treatment were strongly associated with treatment response. A CMS increase indicated response up to 80 days before conventional monitoring. SHOX2 and SEPT9 ccfDNA methylation represents a pan-cancer biomarker and has the potential to be a powerful tool for monitoring treatment response in patients with solid tumors and lymphomas. The early identification of nonresponders might allow for a timely change of treatment regimen.
MeSH term(s)	Biomarkers, Tumor/blood ; Biomarkers, Tumor/genetics ; Cell-Free Nucleic Acids/blood ; Cell-Free Nucleic Acids/genetics ; DNA Methylation ; Feasibility Studies ; Homeodomain Proteins/blood ; Homeodomain Proteins/genetics ; Humans ; Neoplasms/blood ; Neoplasms/genetics ; Prospective Studies ; Septins/blood ; Septins/genetics
Chemical Substances	Biomarkers, Tumor ; Cell-Free Nucleic Acids ; Homeodomain Proteins ; SHOX2 protein, human ; SEPTIN9 protein, human (EC 3.6.1.-) ; Septins (EC 3.6.1.-)
Language	English
Publishing date	2020-04-30
Publishing country	United States
Document type	Journal Article ; Observational Study ; Research Support, Non-U.S. Gov't
ZDB-ID	2000060-1
ISSN	1943-7811 ; 1525-1578
ISSN (online)	1943-7811
ISSN	1525-1578
DOI	10.1016/j.jmoldx.2020.04.205
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Article ; Online: Genetic disruption of CD8+ Treg activity enhances the immune response to viral infection.

Holderried, Tobias A W / Lang, Philipp A / Kim, Hye-Jung / Cantor, Harvey

Proceedings of the National Academy of Sciences of the United States of America

2013 Volume 110, Issue 52, Page(s) 21089–21094

Abstract: The immunological interactions that regulate the T-cell response to chronic viral infection are insufficiently understood. Here we study a cellular interaction that may enhance the antiviral immune response and constrain immunopathology. We analyze the ... ...

Abstract	The immunological interactions that regulate the T-cell response to chronic viral infection are insufficiently understood. Here we study a cellular interaction that may enhance the antiviral immune response and constrain immunopathology. We analyze the contribution of Qa-1-restricted CD8(+) regulatory T cells (Treg cells) to antiviral immunity after infection by lymphocytic choriomeningitis virus. These CD8(+) Treg cells recognize and eliminate target cells through an interaction with the murine class Ib MHC molecule Qa-1 (HLA-E in humans). Using Qa-1 mutant mice (B6.Qa-1-D227K [B6-DK]) that harbor a single mutation that abrogates binding of Qa-1 peptide to the CD8-TCR (T-cell receptor) complex, we show that disruption of immune suppression mediated by CD8(+) Treg cells results in robust antiviral immune responses in both acute and chronic viral infection. Enhanced antiviral responses of B6-DK mice were accompanied by increased control of virus, reduced tissue inflammation in the acute phase, and dramatic alleviation of disease in the chronic phase. In addition, CD8(+) effector T cells in B6-DK mice displayed a less exhausted phenotype characterized by decreased expression of programmed cell death 1 (PD-1), LAG3 (CD223), and 2B4 (CD244) and increased expression of NKG2D (CD314) and killer cell lectin-like receptor subfamily G member 1 (KLRG1). Enhanced antiviral immunity in B6-DK mice reflected, in part, reduced inhibition of CD8(+) effector cells by CD8(+) Treg cells. These findings indicate that direct inhibition of effector CD8(+) T cells by Qa-1-restricted CD8(+) Treg cells results in increased disease severity and delayed recovery. These data suggest that depletion or inactivation of CD8(+) Treg cells represents a potentially effective strategy to enhance protective immunity to chronic viral infection.
MeSH term(s)	Adoptive Transfer ; Animals ; CD8-Positive T-Lymphocytes/immunology ; DNA Virus Infections/immunology ; Flow Cytometry ; Histocompatibility Antigens Class I/genetics ; Histocompatibility Antigens Class I/immunology ; Immunity, Cellular/genetics ; Lymphocytic choriomeningitis virus ; Mice ; Mice, Inbred C57BL ; Mice, Transgenic ; Mutation/genetics ; Statistics, Nonparametric ; T-Lymphocytes, Regulatory/immunology
Chemical Substances	Histocompatibility Antigens Class I ; Q surface antigens
Language	English
Publishing date	2013-12-09
Publishing country	United States
Document type	Journal Article ; Research Support, N.I.H., Extramural ; Research Support, Non-U.S. Gov't
ZDB-ID	209104-5
ISSN	1091-6490 ; 0027-8424
ISSN (online)	1091-6490
ISSN	0027-8424
DOI	10.1073/pnas.1320999110
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