32 results on '"Katie Healy"'
Search Results
2. Persistence of salivary antibody responses after COVID-19 vaccination is associated with oral microbiome variation in both healthy and people living with HIV
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Mahin Ghorbani, Khaled Al-Manei, Sabrina Naud, Katie Healy, Giorgio Gabarrini, Michal Jacek Sobkowiak, Puran Chen, Shilpa Ray, Mira Akber, Sandra Muschiol, Gordana Bogdanovic, Peter Bergman, Per Ljungman, Marcus Buggert, Hans-Gustaf Ljunggren, Elisa Pin, Piotr Nowak, Soo Aleman, and Margaret Sällberg Chen
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Oral microbiome ,mRNA vaccination ,saliva ,SARS-CoV-2 ,campylobacter ,leptotrichia ,Immunologic diseases. Allergy ,RC581-607 - Abstract
Coevolution of microbiome and immunity at mucosal sites is essential for our health. Whether the oral microbiome, the second largest community after the gut, contributes to the immunogenicity of COVID-19 vaccines is not known. We investigated the baseline oral microbiome in individuals in the COVAXID clinical trial receiving the BNT162b2 mRNA vaccine. Participants (n=115) included healthy controls (HC; n=57) and people living with HIV (PLHIV; n=58) who met the study selection criteria. Vaccine-induced Spike antibodies in saliva and serum from 0 to 6 months were assessed and comparative analyses were performed against the individual salivary 16S ASV microbiome diversity. High- versus low vaccine responders were assessed on general, immunological, and oral microbiome features. Our analyses identified oral microbiome features enriched in high- vs. low-responders among healthy and PLHIV participants. In low-responders, an enrichment of Gram-negative, anaerobic species with proteolytic activity were found including Campylobacter, Butyrivibrio, Selenomonas, Lachnoanaerobaculum, Leptotrichia, Megasphaera, Prevotella and Stomatobaculum. In high-responders, enriched species were mainly Gram-positive and saccharolytic facultative anaerobes: Abiotrophia, Corynebacterium, Gemella, Granulicatella, Rothia, and Haemophilus. Combining identified microbial features in a classifier using the area under the receiver operating characteristic curve (ROC AUC) yielded scores of 0.879 (healthy controls) to 0.82 (PLHIV), supporting the oral microbiome contribution in the long-term vaccination outcome. The present study is the first to suggest that the oral microbiome has an impact on the durability of mucosal immunity after Covid-19 vaccination. Microbiome-targeted interventions to enhance long-term duration of mucosal vaccine immunity may be exploited.
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- 2023
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3. NK cell frequencies, function and correlates to vaccine outcome in BNT162b2 mRNA anti-SARS-CoV-2 vaccinated healthy and immunocompromised individuals
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Angelica Cuapio, Caroline Boulouis, Iva Filipovic, David Wullimann, Tobias Kammann, Tiphaine Parrot, Puran Chen, Mira Akber, Yu Gao, Quirin Hammer, Benedikt Strunz, André Pérez Potti, Olga Rivera Ballesteros, Joshua Lange, Jagadeeswara Rao Muvva, Peter Bergman, Ola Blennow, Lotta Hansson, Stephan Mielke, Piotr Nowak, Gunnar Söderdahl, Anders Österborg, C. I. Edvard Smith, Gordana Bogdanovic, Sandra Muschiol, Fredrika Hellgren, Karin Loré, Michal J. Sobkowiak, Giorgio Gabarrini, Katie Healy, Margaret Sällberg Chen, Evren Alici, Niklas K. Björkström, Marcus Buggert, Per Ljungman, Johan K. Sandberg, Soo Aleman, and Hans-Gustaf Ljunggren
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Anti-SARS-CoV-2 antibodies ,BNT162b2 mRNA vaccine ,Clinical trial ,COVID-19 ,NK cells ,Innate immunity ,Therapeutics. Pharmacology ,RM1-950 ,Biochemistry ,QD415-436 - Abstract
Abstract Adaptive immune responses have been studied extensively in the course of mRNA vaccination against COVID-19. Considerably fewer studies have assessed the effects on innate immune cells. Here, we characterized NK cells in healthy individuals and immunocompromised patients in the course of an anti-SARS-CoV-2 BNT162b2 mRNA prospective, open-label clinical vaccine trial. See trial registration description in notes. Results revealed preserved NK cell numbers, frequencies, subsets, phenotypes, and function as assessed through consecutive peripheral blood samplings at 0, 10, 21, and 35 days following vaccination. A positive correlation was observed between the frequency of NKG2C+ NK cells at baseline (Day 0) and anti-SARS-CoV-2 Ab titers following BNT162b2 mRNA vaccination at Day 35. The present results provide basic insights in regards to NK cells in the context of mRNA vaccination, and have relevance for future mRNA-based vaccinations against COVID-19, other viral infections, and cancer. Trial registration: The current study is based on clinical material from the COVAXID open-label, non-randomized prospective clinical trial registered at EudraCT and clinicaltrials.gov (no. 2021–000175-37). Description: https://clinicaltrials.gov/ct2/show/NCT04780659?term=2021-000175-37&draw=2&rank=1 .
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- 2022
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4. Process Development for Adoptive Cell Therapy in Academia: A Pipeline for Clinical-Scale Manufacturing of Multiple TCR-T Cell Products
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Daniela Nascimento Silva, Michael Chrobok, Giulia Rovesti, Katie Healy, Arnika Kathleen Wagner, Panagiota Maravelia, Francesca Gatto, Massimiliano Mazza, Lucia Mazzotti, Volker Lohmann, Margaret Sällberg Chen, Matti Sällberg, Marcus Buggert, and Anna Pasetto
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T cell modification ,process development ,pipeline ,TCR-T cells manufacturing ,clinical scale ,academia ,Immunologic diseases. Allergy ,RC581-607 - Abstract
Cellular immunotherapies based on T cell receptor (TCR) transfer are promising approaches for the treatment of cancer and chronic viral infections. The discovery of novel receptors is expanding considerably; however, the clinical development of TCR-T cell therapies still lags. Here we provide a pipeline for process development and clinical-scale manufacturing of TCR-T cells in academia. We utilized two TCRs specific for hepatitis C virus (HCV) as models because of their marked differences in avidity and functional profile in TCR-redirected cells. With our clinical-scale pipeline, we reproduced the functional profile associated with each TCR. Moreover, the two TCR-T cell products demonstrated similar yield, purity, transduction efficiency as well as phenotype. The TCR-T cell products had a highly reproducible yield of over 1.4 × 109 cells, with an average viability of 93%; 97.8–99% of cells were CD3+, of which 47.66 ± 2.02% were CD8+ T cells; the phenotype was markedly associated with central memory (CD62L+CD45RO+) for CD4+ (93.70 ± 5.23%) and CD8+ (94.26 ± 4.04%). The functional assessments in 2D and 3D cell culture assays showed that TCR-T cells mounted a polyfunctional response to the cognate HCV peptide target in tumor cell lines, including killing. Collectively, we report a solid strategy for the efficient large-scale manufacturing of TCR-T cells.
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- 2022
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5. Integrative proteo-transcriptomic and immunophenotyping signatures of HIV-1 elite control phenotype: A cross-talk between glycolysis and HIF signaling
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Sara Svensson Akusjärvi, Anoop T. Ambikan, Shuba Krishnan, Soham Gupta, Maike Sperk, Ákos Végvári, Flora Mikaeloff, Katie Healy, Jan Vesterbacka, Piotr Nowak, Anders Sönnerborg, and Ujjwal Neogi
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Glycobiology ,Molecular biology ,Immunology ,Virology ,Omics ,Science - Abstract
Summary: Natural control of HIV-1 is a characteristic of
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- 2022
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6. Human MAIT cells endowed with HBV specificity are cytotoxic and migrate towards HBV-HCC while retaining antimicrobial functions
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Katie Healy, Andrea Pavesi, Tiphaine Parrot, Michał J. Sobkowiak, Susanne E. Reinsbach, Haleh Davanian, Anthony T. Tan, Soo Aleman, Johan K. Sandberg, Antonio Bertoletti, and Margaret Sällberg Chen
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HCC ,HBV ,Adoptive cell transfer ,MAIT cells ,TCR-T cells ,Diseases of the digestive system. Gastroenterology ,RC799-869 - Abstract
Background & Aims: Virus-specific T cell dysfunction is a common feature of HBV-related hepatocellular carcinoma (HBV-HCC). Conventional T (ConT) cells can be redirected towards viral antigens in HBV-HCC when they express an HBV-specific receptor; however, their efficacy can be impaired by liver-specific physical and metabolic features. Mucosal-associated invariant T (MAIT) cells are the most abundant innate-like T cells in the liver and can elicit potent intrahepatic effector functions. Here, we engineered ConT and MAIT cells to kill HBV expressing hepatoma cells and compared their functional properties. Methods: Donor-matched ConT and MAIT cells were engineered to express an HBV-specific T cell receptor (TCR). Cytotoxicity and hepatocyte homing potential were investigated using flow cytometry, real-time killing assays, and confocal microscopy in 2D and 3D HBV-HCC cell models. Major histocompatibility complex (MHC) class I-related molecule (MR1)-dependent and MR1-independent activation was evaluated in an Escherichia coli THP-1 cell model and by IL-12/IL-18 stimulation, respectively. Results: HBV TCR-MAIT cells demonstrated polyfunctional properties (CD107a, interferon [IFN] γ, tumour necrosis factor [TNF], and IL-17A) with strong HBV target sensitivity and liver-homing chemokine receptor expression when compared with HBV TCR-ConT cells. TCR-mediated lysis of hepatoma cells was comparable between the cell types and augmented in the presence of inflammation. Coculturing with HBV+ target cells in a 3D microdevice mimicking aspects of the liver microenvironment demonstrated that TCR-MAIT cells migrate readily towards hepatoma targets. Expression of an ectopic TCR did not affect the ability of the MAIT cells to be activated via MR1-presented bacterial antigens or IL-12/IL-18 stimulation. Conclusions: HBV TCR-MAIT cells demonstrate anti-HBV functions without losing their endogenous antimicrobial mechanisms or hepatotropic features. Our results support future exploitations of MAIT cells for liver-directed immunotherapies. Lay summary: Chronic HBV infection is a leading cause of liver cancer. T cell receptor (TCR)-engineered T cells are patients’ immune cells that have been modified to recognise virus-infected and/or cancer cells. Herein, we evaluated whether mucosal-associated invariant T cells, a large population of unconventional T cells in the liver, could recognise and kill HBV infected hepatocytes when engineered with an HBV-specific TCR. We show that their effector functions may exceed those of conventional T cells currently used in the clinic, including antimicrobial properties and chemokine receptor profiles better suited for targeting liver tumours.
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- 2021
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7. Expansion of donor-unrestricted MAIT cells with enhanced cytolytic function suitable for TCR redirection
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Tiphaine Parrot, Katie Healy, Caroline Boulouis, Michał J. Sobkowiak, Edwin Leeansyah, Soo Aleman, Antonio Bertoletti, Margaret Sällberg Chen, and Johan K. Sandberg
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Immunology ,Medicine - Abstract
Progress in our understanding of MR1-restricted mucosa-associated invariant T (MAIT) cells has raised interest in harnessing these cells for immunotherapy. The innate-like response characteristics, abundance in the blood, donor-unrestricted nature, and tropism for tissues make MAIT cells suitable candidates for adoptive cell transfer therapies. However, reliable methods and tools to utilize MAIT cells in such approaches are lacking. Here, we established methodology for efficient expansion of human MAIT cells in culture with high purity and yield, while preserving their functional response toward their natural ligand and increasing their cytotoxic potential. The cultured MAIT cells retained their effector memory characteristics without signs of terminal differentiation and expressed a more diverse set of chemokine receptors, potentially widening their already broad tissue tropism. To investigate the potential of MAIT cells in a context outside their main role in controlling bacterial infection, we engineered cultured MAIT cells with a new TCR specificity to mediate effective antiviral HLA class I–restricted effector function. In summary, we developed robust and effective methodology for the expansion of human MAIT cells with enhanced cytolytic capacity and for their engineering with a new specificity. These findings form a basis for the development of MAIT cells as a platform for adoptive immunotherapy.
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- 2021
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8. Author Correction: Integrated targeted metabolomic and lipidomic analysis: A novel approach to classifying early cystic precursors to invasive pancreatic cancer
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Rogier Aäron Gaiser, Alberto Pessia, Zeeshan Ateeb, Haleh Davanian, Carlos Fernández Moro, Hassan Alkharaan, Katie Healy, Sam Ghazi, Urban Arnelo, Roberto Valente, Vidya Velagapudi, Margaret Sällberg Chen, and Marco Del Chiaro
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Medicine ,Science - Published
- 2022
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9. Chronic Viral Liver Diseases: Approaching the Liver Using T Cell Receptor-Mediated Gene Technologies
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Katie Healy, Anna Pasetto, Michał J. Sobkowiak, Chai Fen Soon, Markus Cornberg, Soo Aleman, and Margaret Sällberg Chen
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chronic infection ,viral hepatitis ,T-cell immunotherapy ,Cytology ,QH573-671 - Abstract
Chronic infection with viral hepatitis is a major risk factor for liver injury and hepatocellular carcinoma (HCC). One major contributing factor to the chronicity is the dysfunction of virus-specific T cell immunity. T cells engineered to express virus-specific T cell receptors (TCRs) may be a therapeutic option to improve host antiviral responses and have demonstrated clinical success against virus-associated tumours. This review aims to give an overview of TCRs identified from viral hepatitis research and discuss how translational lessons learned from cancer immunotherapy can be applied to the field. TCR isolation pipelines, liver homing signals, cell type options, as well as safety considerations will be discussed herein.
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- 2020
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10. Prevalence of Parvovirus B19 Viremia Among German Blood Donations and the Relationship to ABO and Rhesus Blood Group Antigens
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Katie, Healy, Linda B S, Aulin, Urban, Freij, Marie, Ellerstad, Lena, Brückle, Helen, Hillmering, Tor-Einar, Svae, Kristina, Broliden, and Rasmus, Gustafsson
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Infectious Diseases ,Immunology and Allergy - Abstract
Background Asymptomatic blood donors can transmit human parvovirus B19 (B19V). Methods We assessed the B19V prevalence among a large cohort of blood donations collected in Germany during 2015–2018. Results In total, 167 123 donations were screened for B19V deoxyribonucleic acid with 22 cases of viremia identified (0.013% positive). Infections peaked at a 4-year interval and the highest number of cases occurred in the summer months. All 22 infections were found in rhesus D-antigen-positive donations, suggesting a protective factor in donors who lack this antigen. Conclusions These findings contribute to our understanding of risk factors for B19V infection among central European blood and plasma donors.
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- 2022
11. Systemic and mucosal adaptive immunity to SARS-CoV-2 during the Omicron wave in patients with chronic lymphocytic leukemia
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Hanna Ingelman-Sundberg, Lisa Blixt, David Wullimann, Jinghua Wu, Yu Gao, Katie Healy, Sandra Muschiol, Gordana Bogdanovic, Mikael Åberg, Christian Kjellander, Alba Grifoni, Alessandro Sette, Soo Aleman, Puran Chen, Ola Blennow, Lotta Hansson, Hans-Gustaf Ljunggren, Margaret Sällberg Chen, Marcus Buggert, and Anders Österborg
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Patients with chronic lymphocytic leukemia (CLL) were at high risk early in the COVID-19 pandemic. The Omicron SARS-CoV-2 variant is considered less aggressive, but a significant fatality rate was recently reported from CLL register studies. Here we report on Omicron hybrid immunity in CLL after vaccinations against SARS-CoV-2 followed by disease. Post-infection systemic and mucosal immunity against SARS-CoV-2 were analyzed in patients with CLL (n = 38) during the Omicron BA.1/BA.2 time-period. Most patients (30/38, 79%) had received 3 to 4 vaccine doses, yet median anti-Spike antibody titers were 0 U/mL (range 0–6,528) at the onset of infection. Significantly elevated serum antibody levels were observed post-infection (p = 0.0027 vs baseline) to a median of 3,145 U/mL (range 0->25 000) which correlated with inhibition of Spike-ACE2 binding. Low convalescent IgA responses were noted in both saliva and serum in patients with ongoing BTKi/BCL-2i therapy compared with early-stage untreated patients (p = 0.010; p = 0.051). Post-Omicron CD4 + and CD8 + T cell responses were observed at levels similar to those of healthy donors. Forty-seven percent of the patients required hospitalization but there was only one possibly related death. Broad immunity was observed in patients with CLL following Omicron infection. Impaired mucosal immunity during BTKi therapy requires further studies.
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- 2023
12. Covid-19 in patients with chronic lymphocytic leukemia: clinical outcome and B- and T-cell immunity during 13 months in consecutive patients
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Lotta Hansson, Yu Gao, Lisa Blixt, Hemming Johansson, Olga Stromberg, Christian Kjellander, Sara Mravinacova, Sandra Muschiol, Marcus Buggert, Peter Nilsson, Gordana Bogdanovic, Marzia Palma, Sophia Hober, Anders Österborg, Margaret Chen, Elisa Pin, Rula Zain, C. I. Edvard Smith, and Katie Healy
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Adult ,Male ,Chronic lymphocytic leukaemia ,Cancer Research ,medicine.medical_specialty ,Saliva ,Multivariate analysis ,Coronavirus disease 2019 (COVID-19) ,T-Lymphocytes ,Chronic lymphocytic leukemia ,Antibodies, Viral ,Article ,Internal medicine ,Humans ,Medicine ,Seroconversion ,Stage (cooking) ,Aged ,Aged, 80 and over ,B-Lymphocytes ,biology ,SARS-CoV-2 ,business.industry ,ELISPOT ,COVID-19 ,Hematology ,Middle Aged ,Translational research ,Prognosis ,medicine.disease ,Antibodies, Neutralizing ,Combined Modality Therapy ,Leukemia, Lymphocytic, Chronic, B-Cell ,Oncology ,biology.protein ,Female ,Antibody ,business ,Follow-Up Studies - Abstract
We studied clinical and immunological outcome of Covid-19 in consecutive CLL patients from a well-defined area during month 1–13 of the pandemic. Sixty patients (median age 71 y, range 43–97) were identified. Median CIRS was eight (4–20). Patients had indolent CLL (n = 38), had completed (n = 12) or ongoing therapy (n = 10). Forty-six patients (77%) were hospitalized due to severe Covid-19 and 11 were admitted to ICU. Severe Covid-19 was equally distributed across subgroups irrespective of age, gender, BMI, CLL status except CIRS (p
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- 2021
13. Hybrid immunity in immunocompromised patients with CLL after SARS-CoV-2 infection followed by booster mRNA vaccination
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Lisa Blixt, Yu Gao, David Wullimann, Hanna Murén Ingelman-Sundberg, Sandra Muschiol, Katie Healy, Gordana Bogdanovic, Elisa Pin, Peter Nilsson, Christian Kjellander, Alba Grifoni, Alessandro Sette, Margaret Sällberg Chen, Hans-Gustaf Ljunggren, Marcus Buggert, Lotta Hansson, and Anders Österborg
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Immunocompromised Host ,SARS-CoV-2 ,Immunology ,Vaccination ,Humans ,COVID-19 ,Cell Biology ,Hematology ,RNA, Messenger ,Antibodies, Viral ,Biochemistry ,Leukemia, Lymphocytic, Chronic, B-Cell - Published
- 2022
14. OP01 High prevalence rates of unaddressed cardiometabolic risk and multi-morbidity in patients with non-alcoholic fatty liver disease
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Ashan Ginige, Sarah Allen-Griffiths, Katie Healy, Carol Matthews, Cyril Sieberhagen, Daniel Cuthbertson, and Theresa Hydes
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- 2022
15. Preserved Mucosal-Associated Invariant T Cells in the Cervical Mucosa of HIV-Infected Women with Dominant Expression of the TRAV1-2-TRAJ20 T Cell Receptor α-Chain
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Anna Gibbs, Katie Healy, Vilde Kaldhusdal, Christopher Sundling, Mathias Franzén-Boger, Gabriella Edfeldt, Marcus Buggert, Julie Lajoie, Keith R Fowke, Joshua Kimani, Douglas S Kwon, Sonia Andersson, Johan K Sandberg, Kristina Broliden, Haleh Davanian, Margaret Sällberg Chen, and Annelie Tjernlund
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Infectious Diseases ,Mucous Membrane ,Sex Workers ,Receptors, Antigen, T-Cell, alpha-beta ,Immunology and Allergy ,Humans ,Female ,HIV Infections ,Mucosal-Associated Invariant T Cells - Abstract
Background Mucosa-associated invariant T (MAIT) cells are innate-like T cells with specialized antimicrobial functions. Circulating MAIT cells are depleted in chronic human immunodeficiency virus (HIV) infection, but studies examining this effect in peripheral tissues, such as the female genital tract, are lacking. Methods Flow cytometry was used to investigate circulating MAIT cells in a cohort of HIV-seropositive (HIV+) and HIV-seronegative (HIV−) female sex workers (FSWs), and HIV− lower-risk women (LRW). In situ staining and quantitative polymerase chain reaction were performed to explore the phenotype of MAIT cells residing in paired cervicovaginal tissue. The cervicovaginal microbiome was assessed by means of 16S ribosomal RNA gene sequencing. Results MAIT cells in the HIV+ FSW group were low in frequency in the circulation but preserved in the ectocervix. MAIT cell T-cell receptor gene segment usage differed between the HIV+ and HIV− FSW groups. The TRAV1-2–TRAJ20 transcript was the most highly expressed MAIT TRAJ gene detected in the ectocervix in the HIV+ FSW group. MAIT TRAVJ usage was not associated with specific genera in the vaginal microbiome. Conclusions MAIT cells residing in the ectocervix are numerically preserved irrespective of HIV infection status and displayed dominant expression of TRAV1-2–TRAJ20. These findings have implications for understanding the role of cervical MAIT cells in health and disease.
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- 2022
16. Immunodeficiency syndromes differentially impact the functional profile of SARS-CoV-2-specific T cells elicited by mRNA vaccination
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Yu Gao, Curtis Cai, David Wullimann, Julia Niessl, Olga Rivera-Ballesteros, Puran Chen, Joshua Lange, Angelica Cuapio, Ola Blennow, Lotta Hansson, Stephan Mielke, Piotr Nowak, Jan Vesterbacka, Mira Akber, Andre Perez-Potti, Takuya Sekine, Thomas R. Müller, Caroline Boulouis, Tobias Kammann, Tiphaine Parrot, Jagadeeswara Rao Muvva, Michal Sobkowiak, Katie Healy, Gordana Bogdanovic, Sandra Muschiol, Gunnar Söderdahl, Anders Österborg, Fredrika Hellgren, Alba Grifoni, Daniela Weiskopf, Alessandro Sette, Karin Loré, Margaret Sällberg Chen, Per Ljungman, Johan K. Sandberg, C.I. Edvard Smith, Peter Bergman, Hans-Gustaf Ljunggren, Soo Aleman, and Marcus Buggert
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SARS-CoV-2 ,Vaccination ,Immunology ,T cells ,COVID-19 ,Immunology in the medical area ,Syndrome ,CD8-Positive T-Lymphocytes ,Antibodies, Viral ,Immunity, Humoral ,Infectious Diseases ,mRNA vaccine ,Viral Envelope Proteins ,Immunologi inom det medicinska området ,Humans ,Immunology and Allergy ,RNA, Messenger - Abstract
Many immunocompromised patients mount suboptimal humoral immunity after SARS-CoV-2 mRNA vaccination. Here, we assessed the single-cell profile of SARS-CoV-2-specific T cells post-mRNA vaccination in healthy individuals and patients with various forms of immunodeficiencies. Impaired vaccine-induced cell-mediated immunity was observed in many immunocompromised patients, particularly in solid-organ transplant and chronic lymphocytic leukemia patients. Notably, individuals with an inherited lack of mature B cells, i.e., X-linked agammaglobulinemia (XLA) displayed highly functional spike-specific T cell responses. Single-cell RNA-sequencing further revealed that mRNA vaccination induced a broad functional spectrum of spike-specific CD4+ and CD8+ T cells in healthy individuals and patients with XLA. These responses were founded on polyclonal repertoires of CD4+ T cells and robust expansions of oligoclonal effector-memory CD45RA+ CD8+ T cells with stem-like characteristics. Collectively, our data provide the functional continuum of SARS-CoV-2-specific T cell responses post-mRNA vaccination, highlighting that cell-mediated immunity is of variable functional quality across immunodeficiency syndromes.
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- 2022
17. Salivary IgG to SARS-CoV-2 indicates seroconversion and correlates to serum neutralization in mRNA-vaccinated immunocompromised individuals
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Katie Healy, Elisa Pin, Puran Chen, Gunnar Söderdahl, Piotr Nowak, Stephan Mielke, Lotta Hansson, Peter Bergman, C.I. Edvard Smith, Per Ljungman, Davide Valentini, Ola Blennow, Anders Österborg, Giorgio Gabarrini, Khaled Al-Manei, Hassan Alkharaan, Michał Jacek Sobkowiak, Jamil Yousef, Sara Mravinacova, Angelica Cuapio, Xinling Xu, Mira Akber, Karin Loré, Cecilia Hellström, Sandra Muschiol, Gordana Bogdanovic, Marcus Buggert, Hans-Gustaf Ljunggren, Sophia Hober, Peter Nilsson, Soo Aleman, and Margaret Sällberg Chen
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Infectious Medicine ,Translation to patients ,Infektionsmedicin ,Antibodies, Viral ,Immunocompromised Host ,antibody ,cancer ,Humans ,Prospective Studies ,RNA, Messenger ,BNT162 Vaccine ,saliva ,SARS-CoV-2 ,COVID-19 ,HIV ,General Medicine ,vaccination ,Leukemia, Lymphocytic, Chronic, B-Cell ,Seroconversion ,Immunoglobulin G ,Immunoglobulin A, Secretory ,Spike Glycoprotein, Coronavirus ,Clinical and Translational Article ,immunodeficiency ,serum ,transplantation - Abstract
Background Immunocompromised individuals are highly susceptible to severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection. Whether vaccine-induced immunity in these individuals involves oral cavity, a primary site of infection, is presently unknown. Methods Immunocompromised patients (n = 404) and healthy controls (n = 82) participated in a prospective clinical trial (NCT04780659) encompassing two doses of the mRNA BNT162b2 vaccine. Primary immunodeficiency (PID), secondary immunodeficiencies caused by human immunodeficiency virus (HIV) infection, allogeneic hematopoietic stem cell transplantation (HSCT)/chimeric antigen receptor T cell therapy (CAR-T), solid organ transplantation (SOT), and chronic lymphocytic leukemia (CLL) patients were included. Salivary and serum immunoglobulin G (IgG) reactivities to SARS-CoV-2 spike were measured by multiplex bead-based assays and Elecsys anti-SARS-CoV-2 S assay. Findings IgG responses to SARS-CoV-2 spike antigens in saliva in HIV and HSCT/CAR-T groups were comparable to those of healthy controls after vaccination. The PID, SOT, and CLL patients had weaker responses, influenced mainly by disease parameters or immunosuppressants. Salivary responses correlated remarkably well with specific IgG titers and the neutralizing capacity in serum. Receiver operating characteristic curve analysis for the predictive power of salivary IgG yielded area under the curve (AUC) = 0.95 and positive predictive value (PPV) = 90.7% for the entire cohort after vaccination. Conclusions Saliva conveys vaccine responses induced by mRNA BNT162b2. The predictive power of salivary spike IgG makes it highly suitable for screening vulnerable groups for revaccination. Funding Knut and Alice Wallenberg Foundation, Erling Perssons family foundation, Region Stockholm, Swedish Research Council, Karolinska Institutet, Swedish Blood Cancer Foundation, PID patient organization of Sweden, Nordstjernan AB, Center for Medical Innovation (CIMED), Swedish Medical Research Council, and Stockholm County Council (ALF)., Graphical abstract, Context and significance People with a weakened immune system may respond less well to vaccination and are more vulnerable to infections. This work investigates the predictive value of saliva antibodies in immunocompromised patients. We report that IgG to SARS-CoV-2 spike in saliva correlated remarkably well to that detected in blood after Pfizer mRNA vaccination. Among the immunosuppressive conditions studied, low spike-IgG responses were mainly associated with genetic immune disorders, organ transplantation, chronic lymphatic leukemia, and immunosuppressants, while people living with human immunodeficiency virus or stem cell transplant responded comparably to healthy participants. The clear correlation between anti-spike-IgG in saliva and blood extends to the neutralizing capacity in serum. In conclusion, saliva is suitable and efficient for monitoring vaccine immunity and revaccination., Healy et al. report a clear correlation between salivary and blood IgG to SARS-CoV-2 spike in immunocompromised patients after mRNA vaccination. The specific IgG also correlates to the serum-neutralizing capacity. Their findings indicate that saliva is highly suitable for monitoring vaccine immunity in these extremely vulnerable patients.
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- 2022
18. Appearance of IgG to SARS-CoV-2 in saliva effectively indicates seroconversion in mRNA vaccinated immunocompromised individuals
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Xinling Xu, Gordana Bogdanovic, Margaret Chen, Cecilia Hellström, Katie Healy, Lotta Hansson, Edvard Smith, Karin Loré, Marcus Buggert, Per Ljungman, Giorgio Gabarrini, Mira Akbar, Sandra Muschiol, Anders Österborg, Hans-Gustaf Ljunggren, Ola Blennow, Hassan Alkharaan, Stephan Mielke, Puran Chen, Elisa Pin, Michał J. Sobkowiak, Khaled Al-Manei, Gunnar Söderdahl, Peter Nilsson, Davide Valentini, Piotr Nowak, Peter Bergman, and Sophia Hober
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Saliva ,biology ,business.industry ,medicine.medical_treatment ,Chronic lymphocytic leukemia ,Hematopoietic stem cell transplantation ,medicine.disease ,Immunoglobulin G ,Vaccination ,Immunity ,Immunology ,medicine ,biology.protein ,Chimeric Antigen Receptor T-Cell Therapy ,Seroconversion ,business - Abstract
BackgroundImmunocompromised individuals are highly susceptible to severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) infection. Whether vaccine-induced immunity in these individuals involves the oral cavity, a primary site of infection, is presently unknown.MethodsImmunocompromised individuals (n=404) and healthy controls (n=82) participated in a prospective clinical trial encompassing two doses of the mRNA BNT162b2 vaccine. Immunocompromised individuals included primary immunodeficiencies (PID) and secondary immunodeficiencies caused by human immunodeficiency virus (HIV) infection, allogeneic hematopoietic stem cell transplantation (HSCT)/chimeric antigen receptor T cell therapy (CAR-T), solid organ transplantation (SOT), and chronic lymphocytic leukemia (CLL). Saliva and serum samples were collected at four time points from the first vaccine dose until 2 weeks after second dose. SARS-CoV-2 spike specific immunoglobulin G (IgG) responses were quantified by a multiplex bead-based assay in saliva and correlated to paired serum IgG titers determined by Elecsys® Anti-SARS-CoV-2 S assay.ResultsIgG responses to the SARS-CoV-2 spike full-length trimeric glycoprotein (Spike-f) and S1 subunit in saliva in the HIV and HSCT/CAR-T groups were comparable to healthy controls. In contrast, PID, SOT, and CLL patients all displayed weaker responses which were mainly influenced by disease parameters or immunosuppressants. Salivary IgG levels strongly correlated with serum IgG titers on days 21 and 35 (rho=0.8079 and 0.7768, p=ConclusionsSaliva conveys humoral responses induced by BNT162b2 vaccination. The predictive power makes it highly suitable for screening low responding/vulnerable groups for revaccination.Trial RegistrationClinicalTrials.govIdentifier:NCT04780659FundingKnut and Alice Wallenberg Foundation, Erling Perssons family foundation, Region Stockholm, Swedish Research Council, Karolinska Institutet, The Swedish Blood Cancer Foundation and the organization for PID patient group in Sweden, and Nordstjernan AB. Center for Medical Innovation (CIMED), the Swedish Medical Research Council and the Stockholm County Council (ALF).GRAPHIC ABSTRACT
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- 2021
19. Correction to: Persisting Salivary IgG Against SARS-CoV-2 at 9 Months After Mild COVID-19: A Complementary Approach to Population Surveys
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Hassan Alkharaan, Shaghayegh Bayati, Cecilia Hellström, Soo Aleman, Annika Olsson, Karin Lindahl, Gordana Bogdanovic, Katie Healy, Georgios Tsilingaridis, Patricia De Palma, Sophia Hober, Anna Månberg, Peter Nilsson, Elisa Pin, and Margaret Sällberg Chen
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Infectious Diseases ,Immunology and Allergy - Published
- 2022
20. Persisting Salivary IgG Against SARS-CoV-2 at 9 Months After Mild COVID-19: A Complementary Approach to Population Surveys
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Margaret Chen, Hassan Alkharaan, Patricia De Palma, Cecilia Hellström, Annika Olsson, Gordana Bogdanovic, Elisa Pin, Sophia Hober, Katie Healy, Georgios Tsilingaridis, Shaghayegh Bayati, Karin Lindahl, Soo Aleman, Anna Månberg, and Peter Nilsson
- Subjects
Adult ,Male ,0301 basic medicine ,Saliva ,Time Factors ,media_common.quotation_subject ,Population ,serology ,Enzyme-Linked Immunosorbent Assay ,Antibodies, Viral ,Serology ,Young Adult ,03 medical and health sciences ,0302 clinical medicine ,antibody ,Major Article ,medicine ,Humans ,Immunology and Allergy ,immunoassay ,education ,Aged ,media_common ,saliva ,education.field_of_study ,medicine.diagnostic_test ,biology ,SARS-CoV-2 ,business.industry ,Convalescence ,COVID-19 ,convalescence ,Middle Aged ,3. Good health ,AcademicSubjects/MED00290 ,030104 developmental biology ,Infectious Diseases ,Immunoglobulin G ,Immunoassay ,Humoral immunity ,Immunology ,Cohort ,biology.protein ,Female ,Antibody ,business ,030217 neurology & neurosurgery - Abstract
Background Declining humoral immunity in coronavirus disease 2019 (COVID-19) patients and possible reinfection have raised concern. Mucosal immunity, particularly salivary antibodies, may be short lived although long-term studies are lacking. Methods Using a multiplex bead-based array platform, we investigated antibodies specific to severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) proteins in 256 saliva samples from convalescent patients 1–9 months after symptomatic COVID-19 (n = 74, cohort 1), undiagnosed individuals with self-reported questionnaires (n = 147, cohort 2), and individuals sampled prepandemic (n = 35, cohort 3). Results Salivary IgG antibody responses in cohort 1 (mainly mild COVID-19) were detectable up to 9 months postrecovery, with high correlations between spike and nucleocapsid specificity. At 9 months, IgG remained in blood and saliva in most patients. Salivary IgA was rarely detected at this time point. In cohort 2, salivary IgG and IgA responses were significantly associated with recent history of COVID-19–like symptoms. Salivary IgG tolerated temperature and detergent pretreatments. Conclusions Unlike SARS-CoV-2 salivary IgA that appeared short lived, specific saliva IgG appeared stable even after mild COVID-19, as for blood serology. This noninvasive saliva-based SARS-CoV-2 antibody test with home self-collection may be a complementary alternative to conventional blood serology.
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- 2021
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21. Enrichment of oral microbiota in early cystic precursors to invasive pancreatic cancer
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Hassan Alkharaan, Marco Del Chiaro, Zeeshan Ateeb, Carlos Fernández Moro, Margaret Chen, Katie Healy, Asif Halimi, Haleh Davanian, Luisa W. Hugerth, Roberto Valente, Liyan Lu, and Rogier Aäron Gaiser
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Adult ,DNA, Bacterial ,Male ,0301 basic medicine ,medicine.medical_specialty ,Biopsy ,medicine.medical_treatment ,Gastroenterology ,03 medical and health sciences ,Pancreatectomy ,0302 clinical medicine ,Internal medicine ,Pancreatic cancer ,medicine ,Humans ,Neoplasm Invasiveness ,Cyst ,Aged ,Retrospective Studies ,Aged, 80 and over ,Mouth ,biology ,business.industry ,Microbiota ,Pancreatic Ducts ,Cancer ,Middle Aged ,medicine.disease ,biology.organism_classification ,Pancreatic Neoplasms ,030104 developmental biology ,Dysplasia ,Female ,030211 gastroenterology & hepatology ,Oral Microbiome ,Fusobacterium nucleatum ,Pancreatic cysts ,business ,Carcinoma, Pancreatic Ductal - Abstract
ObjectivesIntraductal papillary mucinous neoplasms (IPMNs) are pancreatic cysts that can progress to invasive pancreatic cancer. Associations between oncogenesis and oral microbiome alterations have been reported. This study aims to investigate a potential intracystic pancreatic microbiome in a pancreatic cystic neoplasm (PCN) surgery patient cohort.DesignPaired cyst fluid and plasma were collected at pancreatic surgery from patients with suspected PCN (n=105). Quantitative and qualitative assessment of bacterial DNA by qPCR, PacBio sequencing (n=35), and interleukin (IL)-1β quantification was performed. The data were correlated to diagnosis, lesion severity and clinical and laboratory profile, including proton-pump inhibitor (PPI) usage and history of invasive endoscopy procedures.ResultsIntracystic bacterial 16S DNA copy number and IL-1β protein quantity were significantly higher in IPMN with high-grade dysplasia and IPMN with cancer compared with non-IPMN PCNs. Despite high interpersonal variation of intracystic microbiota composition, bacterial network and linear discriminant analysis effect size analyses demonstrated co-occurrence and enrichment of oral bacterial taxa including Fusobacterium nucleatum and Granulicatella adiacens in cyst fluid from IPMN with high-grade dysplasia. The elevated intracystic bacterial DNA is associated with, but not limited to, prior exposure to invasive endoscopic procedures, and is independent from use of PPI and antibiotics.ConclusionsCollectively, these findings warrant further investigation into the role of oral bacteria in cystic precursors to pancreatic cancer and have added values on the aetiopathology as well as the management of pancreatic cysts.
- Published
- 2019
22. Expansion of donor-unrestricted MAIT cells with enhanced cytolytic function suitable for TCR redirection
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Soo Aleman, Edwin Leeansyah, Margaret Chen, Michał J. Sobkowiak, Antonio Bertoletti, Katie Healy, Caroline Boulouis, Tiphaine Parrot, and Johan K. Sandberg
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0301 basic medicine ,Adoptive cell transfer ,medicine.medical_treatment ,Immunology ,T cells ,Receptors, Antigen, T-Cell ,Context (language use) ,Human leukocyte antigen ,Biology ,Mucosal-Associated Invariant T Cells ,Minor Histocompatibility Antigens ,03 medical and health sciences ,0302 clinical medicine ,HLA Antigens ,medicine ,Cytotoxic T cell ,Humans ,Tropism ,Cells, Cultured ,T-cell receptor ,Histocompatibility Antigens Class I ,Cell Differentiation ,General Medicine ,Immunotherapy ,Cellular immune response ,Cell biology ,030104 developmental biology ,Technical Advance ,030220 oncology & carcinogenesis ,Tissue tropism ,Medicine ,Receptors, Chemokine - Abstract
Progress in our understanding of MR1-restricted mucosa-associated invariant T (MAIT) cells has raised interest in harnessing these cells for immunotherapy. The innate-like response characteristics, abundance in the blood, donor-unrestricted nature, and tropism for tissues make MAIT cells suitable candidates for adoptive cell transfer therapies. However, reliable methods and tools to utilize MAIT cells in such approaches are lacking. Here, we established methodology for efficient expansion of human MAIT cells in culture with high purity and yield, while preserving their functional response toward their natural ligand and increasing their cytotoxic potential. The cultured MAIT cells retained their effector memory characteristics without signs of terminal differentiation and expressed a more diverse set of chemokine receptors, potentially widening their already broad tissue tropism. To investigate the potential of MAIT cells in a context outside their main role in controlling bacterial infection, we engineered cultured MAIT cells with a new TCR specificity to mediate effective antiviral HLA class I–restricted effector function. In summary, we developed robust and effective methodology for the expansion of human MAIT cells with enhanced cytolytic capacity and for their engineering with a new specificity. These findings form a basis for the development of MAIT cells as a platform for adoptive immunotherapy.
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- 2021
23. Appearance of IgG to SARS-CoV-2 in Saliva Effectively Indicates Seroconversion in mRNA Vaccinated Immunocompromised Individuals
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Elisa Pin, Karin Loré, Marcus Buggert, Khaled Al-Manei, Giorgio Gabarrini, Lotta Hansson, Hassan Alkharaan, Edvard Smith, Davide Valentini, Sandra Muschiol, Katie Healy, Cecilia Hellström, Michał J. Sobkowiak, Margaret Chen, Per Ljungman, Mira Akber, Xinling Xu, Gordana Bogdanovic, Ola Blennow, Hans-Gustaf Ljunggren, Puran Chen, Gunnar Söderdahl, Sophia Hober, Stephan Mielke, Peter Nilsson, Soo Aleman, Piotr Nowak, Anders Österborg, and Peter Bergman
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History ,Saliva ,Polymers and Plastics ,biology ,business.industry ,medicine.medical_treatment ,Hematopoietic stem cell transplantation ,medicine.disease ,Industrial and Manufacturing Engineering ,Immunoglobulin G ,Transplantation ,Vaccination ,Immunology ,medicine ,biology.protein ,Business and International Management ,Antibody ,Seroconversion ,business ,Immunodeficiency - Abstract
Background: mmunocompromised individuals are highly susceptible to severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) infection. Whether vaccine-induced immunity in these individuals involves the oral cavity, a primary site of infection, is presently unknown. Methods: Immunocompromised individuals (n=404) and healthy controls (n=82) participated in a prospective clinical trial encompassing two doses of the mRNA BNT162b2 vaccine. Immunocompromised individuals included primary immunodeficiencies (PID) and secondary immunodeficiencies caused by human immunodeficiency virus (HIV) infection, allogeneic hematopoietic stem cell transplantation (HSCT)/chimeric antigen receptor T cell therapy (CAR-T), solid organ transplantation (SOT), and chronic lymphocytic leukemia (CLL). Saliva and serum samples were collected at four time points from the first vaccine dose until 2 weeks after second dose. SARS-CoV-2 spike specific immunoglobulin G (IgG) responses were quantified by a multiplex bead-based assay in saliva and correlated to paired serum IgG titers determined by Elecsys Anti-SARS-CoV-2 S assay. Results: IgG responses to the SARS-CoV-2 spike full-length trimeric glycoprotein (Spike-f) and S1 subunit in saliva in the HIV and HSCT/CAR-T groups were comparable to healthy controls. In contrast, PID, SOT, and CLL patients all displayed weaker responses which were mainly influenced by disease parameters or immunosuppressants. Salivary IgG levels strongly correlated with serum IgG titers on days 21 and 35 (rho=0.8079 and 0.7768, p=
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- 2021
24. Integrative proteo-transcriptomic and immunophenotyping signatures of HIV-1 elite control phenotype: A cross-talk between glycolysis and HIF signaling
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Anders Sönnerborg, Katie Healy, Maike Sperk, Ákos Végvári, Flora Mikaeloff, Jan Vesterbacka, Ujjwal Neogi, Sara Svensson-Akusjärvi, Soham Gupta, Shuba Krishnan, Piotr Nowak, and Anoop T. Ambikan
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Multidisciplinary ,biology ,Molecular biology ,Science ,Immunology ,Glycobiology ,Omics ,Phenotype ,Article ,Cell biology ,Transcriptome ,Immunophenotyping ,Downregulation and upregulation ,Virology ,biology.protein ,Glycolysis ,GLUT1 ,Signal transduction ,Flux (metabolism) - Abstract
Summary Natural control of HIV-1 is a characteristic of, Graphical abstract, Highlights • Proteo-transcriptomic integration identifying features of EC phenotype • Sex-specific differences in EC phenotypes • Enrichment of glycolysis and HIF signaling, a unique feature in the male EC • Enrichment of HIF signaling independent on HIF-1α protein levels in EC, Glycobiology; Molecular biology; Immunology; Virology; Omics
- Published
- 2022
25. Expansion of central memory and functionally active tcr-redirected t cells manufactured using the automated clinimacs prodigy platform
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Michael Chrobok, Matti Sällberg, Panagiota Maravelia, G. Rovesti, Katie Healy, Daniela Nascimento Silva, and Anna Pasetto
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Cancer Research ,Transplantation ,Oncology ,Computer science ,Immunology ,T-cell receptor ,Immunology and Allergy ,Cell Biology ,Genetics (clinical) ,Cell biology - Published
- 2021
26. Retrospective analysis of the Photo at Discharge scheme and readmission for surgical site infection following coronary artery bypass graft surgery
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Cheryl Lavack, Russel Lukban, Shahzad G. Raja, Reeshma Ramroop, Carlos Morais, Katie Healy, Kavita Bhugun, Nikki Fuller, Alexia Deakin, Melissa Rochon, Padma Rai, Sian Jenkinson, and Alison Soppa
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Advanced and Specialized Nursing ,medicine.medical_specialty ,business.industry ,Health Policy ,Public Health, Environmental and Occupational Health ,Surgery ,03 medical and health sciences ,0302 clinical medicine ,Infectious Diseases ,medicine.anatomical_structure ,030220 oncology & carcinogenesis ,Patient experience ,medicine ,Retrospective analysis ,030212 general & internal medicine ,Complication ,business ,Surgical site infection ,Artery - Abstract
Background: Surgical site infection (SSI) is a costly and devastating complication of surgery. Many cardiac SSIs develop after the patient leaves hospital, but evidence demonstrating the benefit of patient/carer involvement in the process of monitoring and promptly identifying SSI post-discharge is limited. This study estimates the probability of readmission for SSI for coronary artery bypass graft (CABG) patients receiving the Photo at Discharge (PaD). Methods: Trained personnel undertook continuous, prospective SSI surveillance using Public Health England protocol between January 2013 and December 2016. Baseline covariables were collected for 1747 CABG-only procedures. As a quasi-randomised design, we adjusted for non-random PaD assignment using retrospective propensity score (PS)-matching based on 12 variables of interest, assessed whether the model had been adequately specified and performed an outcomes analysis. Results: A total of 568 patients with PaD were PS-matched with 568 controls. The probabilities of SSI readmission were 0.352 (2/568) and 1.761 (10/568), respectively. The difference in risk of readmission for SSI was significant (relative risk = 0.2, 95% confidence interval = 0.04–0.91; P = 0.04). Conclusion: Findings from this single-centre observation study suggest the PaD is associated with a reduction in CABG readmission for SSI and a further study is warranted to verify the efficacy of this strategy.
- Published
- 2018
27. Human MAIT cells endowed with HBV specificity are cytotoxic and migrate towards HBV-HCC while retaining antimicrobial functions
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Haleh Davanian, Margaret Chen, Soo Aleman, Anthony T. Tan, Katie Healy, Antonio Bertoletti, Andrea Pavesi, Tiphaine Parrot, Johan K. Sandberg, Susanne E Reinsbach, and Michał J. Sobkowiak
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CAR, chimeric antigen receptor ,Adoptive cell transfer ,VLA-4, very late antigen-4 ,MAIT, mucosal-associated invariant T ,TNF, tumour necrosis function ,CCR, CC chemokine receptor ,RC799-869 ,VCAM-1, vascular cell adhesion molecule-1 ,TCR-T cells ,APC, allophycocyanin ,HBV ,Immunology and Allergy ,Cytotoxic T cell ,MFI, mean fluorescence intensity ,FMO, fluorescence minus one ,HCC ,CXCR, CXC chemokine receptor ,biology ,TCR, T cell receptor ,Gastroenterology ,5-OP-RU, 5-(2-oxopropylideneamino)-6-d-ribitylaminouracil ,Diseases of the digestive system. Gastroenterology ,PMA, phorbol myristate acetate ,MR1, MHC class I-related molecule ,RT, room temperature ,Research Article ,PBMC, peripheral blood mononuclear cell ,FSC, forward scatter ,MAIT cells ,Human leukocyte antigen ,Major histocompatibility complex ,DCI, dead cell index ,Immune system ,IR, irrelevant peptide ,UMAP, Uniform Manifold Approximation and Projection ,Internal Medicine ,MHC, major histocompatibility complex ,IFN, interferon ,CXCL, chemokine (CXC) ligand ,Hepatology ,HLA, human leukocyte antigen ,T-cell receptor ,ConT, conventional T ,PE, phycoerythrin ,digestive system diseases ,SSC, side scatter ,Cancer cell ,biology.protein ,Cancer research ,HCC, hepatocellular carcinoma ,CC chemokine receptors - Abstract
Background & Aims Virus-specific T cell dysfunction is a common feature of HBV-related hepatocellular carcinoma (HBV-HCC). Conventional T (ConT) cells can be redirected towards viral antigens in HBV-HCC when they express an HBV-specific receptor; however, their efficacy can be impaired by liver-specific physical and metabolic features. Mucosal-associated invariant T (MAIT) cells are the most abundant innate-like T cells in the liver and can elicit potent intrahepatic effector functions. Here, we engineered ConT and MAIT cells to kill HBV expressing hepatoma cells and compared their functional properties. Methods Donor-matched ConT and MAIT cells were engineered to express an HBV-specific T cell receptor (TCR). Cytotoxicity and hepatocyte homing potential were investigated using flow cytometry, real-time killing assays, and confocal microscopy in 2D and 3D HBV-HCC cell models. Major histocompatibility complex (MHC) class I-related molecule (MR1)-dependent and MR1-independent activation was evaluated in an Escherichia coli THP-1 cell model and by IL-12/IL-18 stimulation, respectively. Results HBV TCR-MAIT cells demonstrated polyfunctional properties (CD107a, interferon [IFN] γ, tumour necrosis factor [TNF], and IL-17A) with strong HBV target sensitivity and liver-homing chemokine receptor expression when compared with HBV TCR-ConT cells. TCR-mediated lysis of hepatoma cells was comparable between the cell types and augmented in the presence of inflammation. Coculturing with HBV+ target cells in a 3D microdevice mimicking aspects of the liver microenvironment demonstrated that TCR-MAIT cells migrate readily towards hepatoma targets. Expression of an ectopic TCR did not affect the ability of the MAIT cells to be activated via MR1-presented bacterial antigens or IL-12/IL-18 stimulation. Conclusions HBV TCR-MAIT cells demonstrate anti-HBV functions without losing their endogenous antimicrobial mechanisms or hepatotropic features. Our results support future exploitations of MAIT cells for liver-directed immunotherapies. Lay summary Chronic HBV infection is a leading cause of liver cancer. T cell receptor (TCR)-engineered T cells are patients’ immune cells that have been modified to recognise virus-infected and/or cancer cells. Herein, we evaluated whether mucosal-associated invariant T cells, a large population of unconventional T cells in the liver, could recognise and kill HBV infected hepatocytes when engineered with an HBV-specific TCR. We show that their effector functions may exceed those of conventional T cells currently used in the clinic, including antimicrobial properties and chemokine receptor profiles better suited for targeting liver tumours., Graphical abstract, Highlights • Mucosal-associated invariant T (MAIT) cells expanded in vitro can be engineered to kill HBV antigen-presenting hepatoma cells. • MAIT cells produce IL-17A upon encountering their HBV targets, a functional property not observed in conventional T cells currently used in immunotherapy. • HBV-specific MAIT cells migrate readily towards liver targets in a 3D microfluidics system. • Co-expression of an HBV-specific TCR does not affect the ability of MAIT cells to respond to their physiological stimuli.
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- 2021
28. Identification of targets for TCR-immunotherapy in hepatocellular carcinoma using a clinically relevant platform
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Panagiota Maravelia, Michael Chrobok, Takuya Sekine, D. Nascimento Silva, Marcus Buggert, Katie Healy, Matti Sällberg, A. Perez Potti, Anna Pasetto, and C. Jorns
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Cancer Research ,Transplantation ,business.industry ,medicine.medical_treatment ,Immunology ,T-cell receptor ,Cell Biology ,Immunotherapy ,medicine.disease ,Oncology ,Hepatocellular carcinoma ,Cancer research ,Immunology and Allergy ,Medicine ,Identification (biology) ,business ,Genetics (clinical) - Published
- 2021
29. T cell receptor-engineered mucosal-associated invariant T cells with antiviral cytotoxic potential against hepatitis virus replicating hepatoma cells
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Katie Healy, Andrea Pavesi, Tiphaine Parrot, Haleh Davanian, Anthony Tan, Johan K. Sandberg, Antonio Bertoletti, and Margaret Sällberg Chen
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Hepatology - Published
- 2020
30. Mucosal-associated invariant T cells and oral microbiome in persistent apical periodontitis
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Lars Engstrand, Luisa W. Hugerth, Jörgen Karlsson, Katie Healy, Liyan Lu, Leif Jansson, Johan K. Sandberg, Margaret Chen, Peggy Näsman, Rogier Aäron Gaiser, Mikael Silfverberg, Michał J. Sobkowiak, and Haleh Davanian
- Subjects
0301 basic medicine ,Adult ,Male ,Mucosal associated invariant T cell ,Biology ,Article ,Mucosal-Associated Invariant T Cells ,03 medical and health sciences ,0302 clinical medicine ,Immune system ,medicine ,Humans ,Microbiome ,General Dentistry ,Immunity, Mucosal ,Aged ,Periodontitis ,Microbiota ,Interleukin ,030206 dentistry ,Middle Aged ,medicine.disease ,lcsh:RK1-715 ,030104 developmental biology ,Mucosal immunology ,lcsh:Dentistry ,Immunology ,Natural Killer T-Cells ,Tumor necrosis factor alpha ,Female ,Oral Microbiome ,Periapical Periodontitis ,Cell signalling - Abstract
Opportunistic bacteria in apical periodontitis (AP) may pose a risk for systemic dissemination. Mucosal-associated invariant T (MAIT) cells are innate-like T cells with a broad and potent antimicrobial activity important for gut mucosal integrity. It was recently shown that MAIT cells are present in the oral mucosal tissue, but the involvement of MAIT cells in AP is unknown. Here, comparison of surgically resected AP and gingival tissues demonstrated that AP tissues express significantly higher levels of Vα7.2-Jα33, Vα7.2-Jα20, Vα7.2-Jα12, Cα and tumour necrosis factor (TNF), interferon (IFN)-γ and interleukin (IL)-17A transcripts, resembling a MAIT cell signature. Moreover, in AP tissues the MR1-restricted MAIT cells positive for MR1–5-OP-RU tetramer staining appeared to be of similar levels as in peripheral blood but consisted mainly of CD4+ subset. Unlike gingival tissues, the AP microbiome was quantitatively impacted by factors like fistula and high patient age and had a prominent riboflavin-expressing bacterial feature. When merged in an integrated view, the examined immune and microbiome data in the sparse partial least squares discriminant analysis could identify bacterial relative abundances that negatively correlated with Vα7.2-Jα33, Cα, and IL-17A transcript expressions in AP, implying that MAIT cells could play a role in the local defence at the oral tissue barrier. In conclusion, we describe the presence of MAIT cells at the oral site where translocation of oral microbiota could take place. These findings have implications for understanding the immune sensing of polymicrobial-related oral diseases.
- Published
- 2019
31. Integrated targeted metabolomic and lipidomic analysis: A novel approach to classifying early cystic precursors to invasive pancreatic cancer
- Author
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Marco Del Chiaro, Hassan Alkharaan, Alberto Pessia, Sam Ghazi, Margaret Chen, Urban Arnelo, Zeeshan Ateeb, Vidya Velagapudi, Roberto Valente, Katie Healy, Carlos Fernández Moro, Rogier Aäron Gaiser, Haleh Davanian, Institute for Molecular Medicine Finland, Helsinki Institute of Life Science HiLIFE, and University of Helsinki
- Subjects
0301 basic medicine ,Male ,Pathology ,endocrine system diseases ,Pancreatic Intraductal Neoplasms ,lcsh:Medicine ,Tumour biomarkers ,Cohort Studies ,0302 clinical medicine ,Cyst ,lcsh:Science ,Multidisciplinary ,Middle Aged ,Adenocarcinoma, Mucinous ,3. Good health ,Serous fluid ,medicine.anatomical_structure ,Serous cystic neoplasm ,Adenocarcinoma ,Female ,Pancreas ,Carcinoma, Pancreatic Ductal ,Adult ,medicine.medical_specialty ,3122 Cancers ,Intraductal papillary mucinous neoplasms ,Article ,03 medical and health sciences ,Pancreatectomy ,Pancreatic cancer ,medicine ,Carcinoma ,Biomarkers, Tumor ,Humans ,Metabolomics ,Aged ,business.industry ,lcsh:R ,Diagnostic markers ,medicine.disease ,Carcinoma, Papillary ,Cystic Neoplasm ,Pancreatic Neoplasms ,030104 developmental biology ,Dysplasia ,Lipidomics ,lcsh:Q ,Pancreatic Cyst ,business ,030217 neurology & neurosurgery - Abstract
Pancreatic cystic neoplasms (PCNs) are a highly prevalent disease of the pancreas. Among PCNs, Intraductal Papillary Mucinous Neoplasms (IPMNs) are common lesions that may progress from low-grade dysplasia (LGD) through high-grade dysplasia (HGD) to invasive cancer. Accurate discrimination of IPMN-associated neoplastic grade is an unmet clinical need. Targeted (semi)quantitative analysis of 100 metabolites and >1000 lipid species were performed on peri-operative pancreatic cyst fluid and pre-operative plasma from IPMN and serous cystic neoplasm (SCN) patients in a pancreas resection cohort (n = 35). Profiles were correlated against histological diagnosis and clinical parameters after correction for confounding factors. Integrated data modeling was used for group classification and selection of the best explanatory molecules. Over 1000 different compounds were identified in plasma and cyst fluid. IPMN profiles showed significant lipid pathway alterations compared to SCN. Integrated data modeling discriminated between IPMN and SCN with 100% accuracy and distinguished IPMN LGD or IPMN HGD and invasive cancer with up to 90.06% accuracy. Free fatty acids, ceramides, and triacylglycerol classes in plasma correlated with circulating levels of CA19-9, albumin and bilirubin. Integrated metabolomic and lipidomic analysis of plasma or cyst fluid can improve discrimination of IPMN from SCN and within PMNs predict the grade of dysplasia.
- Published
- 2018
32. 27P Methodology for identification of clinically relevant targets for TCR-immunotherapy in hepatocellular carcinoma
- Author
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Anna Pasetto, Marcus Buggert, Matti Sällberg, C. Jorns, Daniela Nascimento Silva, Takuya Sekine, Panagiota Maravelia, Katie Healy, A.P. Potti, and Michael Chrobok
- Subjects
Oncology ,business.industry ,medicine.medical_treatment ,Hepatocellular carcinoma ,T-cell receptor ,Cancer research ,Medicine ,Identification (biology) ,Hematology ,Immunotherapy ,business ,medicine.disease - Published
- 2020
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