7 results on '"Doherty, T. Mark"'
Search Results
2. Effect of Non-tuberculous Mycobacteria on Host Biomarkers Potentially Relevant for Tuberculosis Management
- Author
-
Dhanasekaran, S., Jenum, Synne, Stavrum, Ruth, Wiker, Harald G., Kenneth, John, Vaz, Mario, Doherty, T. Mark, and Grewal, Harleen M. S.
- Subjects
Bacterial Diseases ,Male ,Immunology ,Down-Regulation ,India ,Microbiology ,Sensitivity and Specificity ,Cohort Studies ,Transforming Growth Factor beta1 ,Medicine and Health Sciences ,Tuberculosis ,Humans ,Prospective Studies ,Immune Response ,Interleukin-6 ,Tuberculin Test ,Infant, Newborn ,Biology and Life Sciences ,Infant ,Nontuberculous Mycobacteria ,Mycobacterium tuberculosis ,Tropical Diseases ,bacterial infections and mycoses ,Interleukin-10 ,Up-Regulation ,Infectious Diseases ,rab GTP-Binding Proteins ,Child, Preschool ,BCG Vaccine ,Interleukin-2 ,Female ,Biomarkers ,Research Article - Abstract
Background Non-tuberculous mycobacteria (NTM) are different from Mycobacterium tuberculosis (MTB) both in their ubiquitous environmental distribution and in their reduced capacity to cause disease. While often neglected in favour of other infectious diseases, NTM may interfere with important aspects of TB control and management, namely the efficacy of new anti-tuberculosis (TB) vaccines; the immuno-diagnostic Tuberculin skin test (TST) and QuantiFERON TB Gold In Tube assay (QFTGIT); and immune biomarkers explored for their diagnostic and/or predictive potential. Our objective was therefore to explore host immune biomarkers in children who had NTM isolated from respiratory and/or gastric specimens. Methodology and Principle Findings The present study was nested within a prospective cohort study of BCG-vaccinated neonates in Southern India. In this setting, immune biomarkers from peripheral blood were analyzed in 210 children aged, Author Summary Non-tuberculous mycobacteria (NTM) are a ubiquitous group of mycobacteria found in the environment. They are opportunistic pathogens causing human disease, especially in immunocompromised individuals. Differentiation between NTM infection and tuberculosis (TB) can be difficult. Data on incidence of NTM in TB endemic countries is limited due to resource intensive methods required for identification and a considerable workload due to other diseases. The present study was based on children investigated for TB and classified according to chest X-rays and mycobacterial culture reports. We explored host immune biomarkers which are potentially relevant to TB management, in children with confirmed NTM exposure. The findings from the present study suggest that NTM exposure modulates TB-relevant immune biomarkers in the host by eliciting some of the same immune responses as MTB infection. This is may be of importance when evaluating immunological correlates of protection in the setting of TB vaccine trials and potential TB diagnostic biomarkers.
- Published
- 2014
3. Combination of cytokine responses indicative of latent TB and active TB in Malawian adults
- Author
-
Kumar, Anil, Hur, Yun-Gyoung, Gorak-Stolinska, Patricia, Ben-Smith, Anne, Lalor, Maeve K., Chaguluka, Steven, Dacombe, Russell, Doherty, T. Mark, Ottenhoff, Tom H., Dockrell, Hazel M., and Crampin, Amelia C.
- Abstract
Background:\ud \ud An IFN-γ response to M. tuberculosis-specific antigens is an effective biomarker for M. tuberculosis infection but it cannot discriminate between latent TB infection and active TB disease. Combining a number of cytokine/chemokine responses to M. tuberculosis antigens may enable differentiation of latent TB from active disease.\ud Methods:\ud \ud Asymptomatic recently-exposed individuals (spouses of TB patients) were recruited and tuberculin skin tested, bled and followed-up for two years. Culture supernatants, from a six-day culture of diluted whole blood samples stimulated with M. tuberculosis-derived PPD or ESAT-6, were measured for IFN-γ, IL-10, IL-13, IL-17, TNF-α and CXCL10 using cytokine ELISAs. In addition, 15 patients with sputum smear-positive pulmonary TB were recruited and tested.\ud Results:\ud \ud Spouses with positive IFN-γ responses to M. tuberculosis ESAT-6 (>62.5 pg/mL) and TB patients showed high production of IL-17, CXCL10 and TNF-α. Higher production of IL-10 and IL-17 in response to ESAT-6 was observed in the spouses compared with TB patients while the ratios of IFN-γ/IL-10 and IFN-γ/IL-17 in response to M. tuberculosis-derived PPD were significantly higher in TB patients compared with the spouses. Tuberculin skin test results did not correlate with cytokine responses.\ud Conclusions:\ud \ud CXCL10 and TNF-α may be used as adjunct markers alongside an IFN-γ release assay to diagnose M. tuberculosis infection, and IL-17 and IL-10 production may differentiate individuals with LTBI from active TB.
- Published
- 2013
4. A T cell-inducing influenza vaccine for the elderly: safety and immunogenicity of MVA-NP+M1 in adults aged over 50 years
- Author
-
Doherty, T. Mark, Antrobus, Richard D., Lillie, Patrick J., Berthoud, Tamara K., Spencer, Alexandra J., McLaren, James E., Ladell, Kristin Ingrid, Lambe, Teresa, Milicic, Anita, Price, David, Hill, Adrian V. S., and Gilbert, Sarah C.
- Subjects
Male ,Viral Diseases ,T-Lymphocytes ,lcsh:Medicine ,medicine.disease_cause ,Influenza A virus ,Cytotoxic T cell ,lcsh:Science ,Immune Response ,Aged, 80 and over ,Multidisciplinary ,T Cells ,Genetically Modified Organisms ,Immunogenicity ,Vaccination ,hemic and immune systems ,Middle Aged ,Orthomyxoviridae ,Infectious Diseases ,medicine.anatomical_structure ,Medicine ,Female ,Safety ,Genetic Engineering ,Research Article ,Biotechnology ,Influenza vaccine ,Immune Cells ,T cell ,Molecular Sequence Data ,Vaccinia virus ,Biology ,complex mixtures ,Interferon-gamma ,Viral Proteins ,Vaccine Development ,medicine ,Humans ,Amino Acid Sequence ,Aged ,Influenza A Virus, H3N2 Subtype ,lcsh:R ,Immunity ,Viral Vaccines ,Virology ,Influenza ,Nucleoproteins ,Geriatrics ,Immunology ,Clinical Immunology ,lcsh:Q ,Memory T cell ,CD8 - Abstract
BACKGROUND: Current influenza vaccines have reduced immunogenicity and are of uncertain efficacy in older adults. We assessed the safety and immunogenicity of MVA-NP+M1, a viral-vectored influenza vaccine designed to boost memory T cell responses, in a group of older adults. METHODS: Thirty volunteers (aged 50-85) received a single intramuscular injection of MVA-NP+M1 at a dose of 1·5×10(8) plaque forming units (pfu). Safety and immunogenicity were assessed over a period of one year. The frequency of T cells specific for nucleoprotein (NP) and matrix protein 1 (M1) was determined by interferon-gamma (IFN-γ) ELISpot, and their phenotypic and functional properties were characterized by polychromatic flow cytometry. In a subset of M1-specific CD8(+) T cells, T cell receptor (TCR) gene expression was evaluated using an unbiased molecular approach. RESULTS: Vaccination with MVA-NP+M1 was well tolerated. ELISpot responses were boosted significantly above baseline following vaccination. Increases were detected in both CD4(+) and CD8(+) T cell subsets. Clonality studies indicated that MVA-NP+M1 expanded pre-existing memory CD8(+) T cells, which displayed a predominant CD27(+)CD45RO(+)CD57(-)CCR7(-) phenotype both before and after vaccination. CONCLUSIONS: MVA-NP+M1 is safe and immunogenic in older adults. Unlike seasonal influenza vaccination, the immune responses generated by MVA-NP+M1 are similar between younger and older individuals. A T cell-inducing vaccine such as MVA-NP+M1 may therefore provide a way to circumvent the immunosenescence that impairs routine influenza vaccination. TRIAL REGISTRATION: ClinicalTrials.gov NCT00942071.
- Published
- 2012
5. Modulation of Cell Death by M. tuberculosis as a Strategy for Pathogen Survival
- Author
-
Abebe, Markos, Kim, Louise, Rook, Graham, Aseffa, Abraham, Wassie, Liya, Zewdie, Martha, Zumla, Alimuddin, Engers, Howard, Andersen, Peter, and Doherty, T. Mark
- Subjects
Article Subject - Abstract
It has been clearly demonstrated that in vitro, virulent M. tuberculosis can favor necrosis over apoptosis in infected macrophages, and this has been suggested as a mechanism for evading the host immune response. We recently reported that an effect consistent with this hypothesis could be observed in cells from the blood of TB patients, and in this paper, we review what is known about evasion strategies employed by M. tuberculosis and in particular consider the possible interaction of the apoptosis-inhibiting effects of M. tuberculosis infection with another factor (IL-4) whose expression is thought to play a role in the failure to control M. tuberculosis infection. It has been noted that IL-4 may exacerbate TNF-α-induced pathology, though the mechanism remains unexplained. Since pathology in TB typically involves inflammatory aggregates around infected cells, where TNF-α plays an important role, we predicted that IL-4 would inhibit the ability of cells to remove M. tuberculosis by apoptosis of infected cells, through the extrinsic pathway, which is activated by TNF-α. Infection of human monocytic cells with mycobacteria in vitro, in the presence of IL-4, appears to promote necrosis over apoptosis in infected cells—a finding consistent with its suggested role as a factor in pathology during M. tuberculosis infection.
- Published
- 2011
- Full Text
- View/download PDF
6. Ex vivo cytokine mRNA levels correlate with changing clinical status of ethiopian TB patients and their contacts over time
- Author
-
Wassie, Liya, Demissie, Abebech, Aseffa, Abraham, Abebe, Markos, Yamuah, Lawrence, Tilahun, Hiwot, Petros, Beyene, Rook, Graham, Zumla, Alimuddin, Andersen, Peter, Doherty, T Mark, and VACSEL Study Group
- Subjects
Adult ,Male ,Tuberculosis ,Adolescent ,Science ,Disease ,Cohort Studies ,Infectious Diseases/Bacterial Infections ,Pathogenesis ,Immune system ,Immunology/Immunity to Infections ,Humans ,Medicine ,RNA, Messenger ,Multidisciplinary ,Reverse Transcriptase Polymerase Chain Reaction ,business.industry ,Infectious Diseases/Respiratory Infections ,Antagonist ,Middle Aged ,medicine.disease ,Cohort ,Immunology ,Cytokines ,Female ,Ethiopia ,business ,Ex vivo ,Research Article ,Cohort study - Abstract
There is an increasing body of evidence which suggests that IL-4 plays a role in the pathogenesis of TB, but a general consensus on its role remains elusive. We have previously published data from a cohort of Ethiopian TB patients, their contacts, and community controls suggesting that enhanced IL-4 production is associated with infection with M. tuberculosis, rather than overt disease and that long-term protection in infected community controls is associated with co-production of the IL-4 antagonist IL-4d2, alongside elevated IL-4. Here, for the first time, we compare data on expression of IFN-gamma, IL-4 and IL-4delta2 over time in TB patients and their household contacts. During the follow-up period, the TB patients completed therapy and ceased to display TB-like symptoms. This correlated with a decrease in the relative amount of IL-4 expressed. Over the same period, the clinical status of some of their contacts also changed, with a number developing TB-like symptoms or clinically apparent TB. IL-4 expression was disproportionately increased in this group. The findings support the hypothesis that elevated IL-4 production is generally associated with infection, but that TB disease is associated with a relatively increased expression of IL-4 compared to IFN-gamma and IL-4delta2. However, the data also suggest that there are no clear-cut differences between groups: the immune response over time appears to include changes in the expression of IFN-gamma, IL-4 and IL-4delta2, and it is the relative, not absolute levels of cytokine expression that are characteristic of clinical status.
- Published
- 2008
7. Development and Function of CD94-Deficient Natural Killer Cells
- Author
-
Lewis L. Lanier, Sigbjørn Fossum, Erik Dissen, Min Fang, Mark T. Orr, Thomas Egebjerg, Jun Wu, Joseph H. Phillips, Luis J. Sigal, Pieter Spee, and Doherty, T Mark
- Subjects
Receptor complex ,T-Lymphocytes ,Cell Culture Techniques ,Glycobiology ,Cytomegalovirus ,lcsh:Medicine ,NK cells ,Inbred C57BL ,Biochemistry ,Mice ,Interleukin 21 ,0302 clinical medicine ,Molecular Cell Biology ,Vaccinia ,Killer Cells ,2.1 Biological and endogenous factors ,Signaling in Cellular Processes ,Listeriosis ,Membrane Receptor Signaling ,Aetiology ,lcsh:Science ,Receptor ,Immunity, Cellular ,0303 health sciences ,Multidisciplinary ,Janus kinase 3 ,Immune cells ,3. Good health ,Cell biology ,Killer Cells, Natural ,Infectious Diseases ,Natural ,Interleukin 12 ,NK Cell Lectin-Like Receptor Subfamily C ,Immunologic Receptor Signaling ,Transmembrane Signaling ,Dimerization ,NK Cell Lectin-Like Receptor Subfamily D ,Research Article ,Signal Transduction ,General Science & Technology ,1.1 Normal biological development and functioning ,Immunology ,Biology ,Vaccine Related ,03 medical and health sciences ,Underpinning research ,Animals ,Humans ,Glycoproteins ,030304 developmental biology ,Lymphokine-activated killer cell ,Prevention ,lcsh:R ,Immunity ,Proteins ,Listeria monocytogenes ,Mice, Inbred C57BL ,Transmembrane Proteins ,Emerging Infectious Diseases ,Gene Expression Regulation ,lcsh:Q ,Cellular ,030215 immunology - Abstract
The CD94 transmembrane-anchored glycoprotein forms disulfide-bonded heterodimers with the NKG2A subunit to form an inhibitory receptor or with the NKG2C or NKG2E subunits to assemble a receptor complex with activating DAP12 signaling proteins. CD94 receptors expressed on human and mouse NK cells and T cells have been proposed to be important in NK cell tolerance to self, play an important role in NK cell development, and contribute to NK cell-mediated immunity to certain infections including human cytomegalovirus. We generated a gene-targeted CD94-deficient mouse to understand the role of CD94 receptors in NK cell biology. CD94-deficient NK cells develop normally and efficiently kill NK cell-susceptible targets. Lack of these CD94 receptors does not alter control of mouse cytomegalovirus, lymphocytic choriomeningitis virus, vaccinia virus, or Listeria monocytogenes. Thus, the expression of CD94 and its associated NKG2A, NKG2C, and NKG2E subunits is dispensable for NK cell development, education, and many NK cell functions.
- Published
- 2010
Catalog
Discovery Service for Jio Institute Digital Library
For full access to our library's resources, please sign in.