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Biomedical subjects

P Openshaw

Publications and source records attributed to P Openshaw.

At least 19 recordsLinked to original sources
PubMed2005

Immune tolerance to hepatitis C virus acquired during engraftment of bone marrow transplant.

The CD4+ T-cell response appears to be important for clearance of hepatitis C virus (HCV) in the majority of individuals. We have recently described a series of human leucocyte antigen (HLA)-DR11-restricted T-cell epitopes derived from HCV proteins which enables distinct populations of memory CD4+ T cells to be detected and counted in all nonviraemic HCV subjects. We examined the case of an HLA-DR11+ recipient of a haematopoietic stem-cell transplant who was concurrently infected with HCV from an HLA-DR11+ donor sibling. An acute HCV hepatitis developed and was treated with type I interferon. After successful viral clearance, the recipient demonstrated a selective lack of HCV epitope-specific CD4+ T cells and absence of serological responses compared with the treated donor. The recipient had no evidence of any nonspecific immunosuppression. The subsequent effects of concurrent infection during immune reconstitution are not known in adult humans, but data from murine models suggest this can lead to a skewing of the T-cell repertoire because of thymic selection. From the above observations, it is plausible that the introduction of foreign viral antigen into the thymus may lead to subsequent acquired central tolerance.

Adult↗
PubMed2001

An improved protocol for measuring cytotoxic T cell activity in anatomic compartments with low cell numbers.

The study of target cell lysis and cytokine production are valuable tools to characterize antigen-specific T and NK cell function during virus infections. After localized infections in compartments such as the lung or the brain, however, cell numbers isolated from these organs are too low to perform standard assays with individual mice. Here, we report a few simple modifications of the classical 51Cr release assay allowing reduction of the number of required effector cells by a factor of 10 without loosing sensitivity or specificity. Using not more than 4x10(5) effector cells, we were able to study ex vivo virus-specific CTL or NK activity from the lungs of individual mice after infection with respiratory syncytial virus (RSV) and from the brains of mice infected with Borna disease virus (BDV). Flow cytometric analysis of interferon-gamma production by virus-specific T cells including appropriate controls was achieved with as few as 10(5) effector cells.

Animals↗
PubMed2001

Mucosal delivery of a respiratory syncytial virus CTL peptide with enterotoxin-based adjuvants elicits protective, immunopathogenic, and immunoregulatory antiviral CD8+ T cell responses.

In an effort to develop a safe and effective vaccine against respiratory syncytial virus (RSV), we used Escherichia coli heat-labile toxin (LT), and LTK63 (an LT mutant devoid of ADP-ribosyltransferase activity) to elicit murine CD8(+) CTL responses to an intranasally codelivered CTL peptide from the second matrix protein (M2) of RSV. M2(82-90)-specific CD8(+) T cells were detected by IFN-gamma enzyme-linked immunospot and (51)Cr release assay in local and systemic lymph nodes, and their induction was dependent on the use of a mucosal adjuvant. CTL elicited by peptide immunization afforded protection against RSV challenge, but also enhanced weight loss. CTL-mediated viral clearance was not dependent on IFN-gamma since depletion using specific mAb during RSV challenge did not affect cellular recruitment or viral clearance. Depletion of IFN-gamma did, however, reduce the concentration of TNF detected in lung homogenates of challenged mice and largely prevented the weight loss associated with CTL-mediated viral clearance. Mice primed with the attachment glycoprotein (G) develop lung eosinophilia after intranasal RSV challenge. Mucosal peptide vaccination reduced pulmonary eosinophilia in mice subsequently immunized with G and challenged with RSV. These studies emphasize that protective and immunoregulatory CD8(+) CTL responses can be mucosally elicited using enterotoxin-based mucosal adjuvants but that resistance against viral infection may be accompanied by enhanced disease.

Adjuvants, Immunologic↗
PubMed2001

Characterization of novel HLA-DR11-restricted HCV epitopes reveals both qualitative and quantitative differences in HCV-specific CD4+ T cell responses in chronically infected and non-viremic patients.

The CD4+ T cell response is of critical importance in determining the fate of many viral infections. Clearance of HCV has a strong association with the MHC class II antigen HLA-DR11 suggesting a key role for CD4+ T cells. We used an epitope-prediction program to identify multiple novel HLA-DR11-restricted epitopes derived from several HCV proteins. These epitopes then allowed us to explore the qualitative and quantitative aspects of specific CD4+ T cell responses in HLA-DR11+ patients. Irrespective of the time since viral clearance, all the non-viremic patients recognized four epitopes with a high frequency of IFN-gamma-producing memory CD4+ T cells. There appeared to be two subpopulations of memory cells, immediate "effector" memory cells (Th1 phenotype) and resting "central" memory cells (Th1/0). Chronically infected patients revealed an almost complete absence of HCV epitope-specific IFN-gamma-producing T cells. However, three of these epitopes induced IL-10 production (down-regulatory) raising the question as to whether these cells play a role in viral persistence. The frequency and phenotype of memory cells is likely to reflect the magnitude of the initial immune response, and suggests that a high frequency of IFN-gamma-secreting CD4+ T cells to multiple epitopes are important in clearance of HCV.

Antigens, Viral↗
PubMed2001

Long-term persistence and reactivation of T cell memory in the lung of mice infected with respiratory syncytial virus.

In mice acutely infected with respiratory syncytial virus (RSV), more than 20% of pulmonary CD8(+) T cells, but only 2-3% of CD8(+) T cells in the draining lymph node secreted interferon-gamma in response to a single peptide. Surprisingly, the percentage of virus-specific T cells in the lung remained at these high levels long after the acute infection. Pulmonary memory T cells were further studied in a sensitive adoptive transfer system, which allows visualizing polyclonal CD4(+) and CD8(+) virus-specific memory T cell responses. Fifty days after infection, persisting RSV-specific pulmonary T cells remained CD69(hi) CD62L(lo), but had returned to a resting memory state according to functional criteria. In the absence of neutralizing antibodies reinfection first induced cell division among virus-specific memory T cells 3 days after infection predominantly in the local lymph node. However, divided cells then rapidly accumulated in the lung without significantly increasing in the lymph node. These results suggest rapid export of reactivated cells from the lymph node to the target organ. Thus, although memory T cells can be maintained in the infected organ after a localized virus infection, amplification of a recall response appears to be most effective in organized lymphoid tissue.

Adoptive Transfer↗
PubMed2000

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Journal Article↗
PubMed1999

Recent developments in the biology of respiratory syncytial virus: are vaccines and new treatments just round the corner?

Respiratory syncytial virus (RSV) is the major cause of infantile bronchiolitis, and is an important pathogen in the elderly and in the developing world. The production of full length cDNA clones now allows precise genetic engineering of RSV, while knowledge of the immunopathogenesis of augmented disease gives hope that effective vaccines will soon be developed.

Animals↗
PubMed1997

IL-12 treatment attenuates T helper cell type 2 and B cell responses but does not improve vaccine-enhanced lung illness.

In humans and mice, sensitization to respiratory syncytial virus (RSV) Ags can result in severe inflammatory lung disease during subsequent infection with RSV. Although specific antiviral T cells are thought to be responsible for this augmentation of disease, the precise roles of different functional subsets are unknown, and no protective nonpathogenic subset has been defined. BALB/c mice sensitized to the major surface glycoprotein of RSV (G) expressed by recombinant vaccinia virus develop Th2-driven lung eosinophilia after intranasal challenge with RSV. In an attempt to manipulate the outcome of vaccination, we treated mice with IL-12 at various times during vaccination and challenge. IL-12 treatment reduced the vaccine-induced lung eosinophilia during RSV challenge, but increased the total lymphoid cell infiltration into the alveolar space. Analysis of intracellular cytokines by flow cytometry showed that IFN-gamma production during challenge was increased, and IL-4 and IL-5 levels were reduced by IL-12 treatment. In control treated mice, 40 to 50% of the lung lymphoid cells were B cells. Treatment with IL-12 reduced this figure to approximately 1.5%. Although IL-12 treatment reduced lung eosinophilia, illness (as assessed by weight loss) was not eliminated and, in some experiments, was increased. The present study shows that reversing Th2-associated pathology with IL-12 does not necessarily benefit the host.

Animals↗
PubMed1996

Reversibility of T helper 1 and 2 populations is lost after long-term stimulation.

Commitment of T helper 1 (Th1) or Th2 populations developing during an immune response to a pathogen, or an inappropriate immune response to an allergen or autoantigen, may determine the difference between health and chronic disease. We show that strongly polarized Th1 and Th2 populations assessed by immunoassay are heterogeneous using flow cytometry to detect single cells producing interferon gamma (IFN-gamma) and interleukin 4 (IL-4). Th1 populations arising after 1 wk of stimulation in IL-12 plus anti-IL-4 antibodies could convert to Th2 cells when restimulated in IL-4. Th2 populations resulting from stimulation for 1 wk in IL-4 could give rise to Th1 cells upon restimulation in IL-12 plus anti-IL-4. In contrast, the cytokine profiles of long-term Th1 and Th2 populations arising originally from repeated stimulation in IL-12 or IL-4 appeared more homogeneous and were not reversible, although IL-4 dramatically reduced the number of IFN-gamma-producing Th1 cells. This may explain previous reports that Th1 cells can be converted to Th2 cells.

Allergens↗
PubMed1996

Mouse gamma delta TCR+NK1.1+ thymocytes specifically produce interleukin-4, are major histocompatibility complex class I independent, and are developmentally related to alpha beta TCR+NK1.1+ thymocytes.

Mouse T cells co-expressing an alpha beta T cell receptor (TCR) and the NK1.1 antigen have been shown to be major interleukin (IL)-4-producing cells and could therefore regulate cell-mediated immune responses. We have identified a related sub-set of thymocytes co-expressing a gamma delta TCR and NK1.1 which also produce IL-4. Unlike alpha beta +NK1.1+ thymocytes, the selection of gamma delta +NK1.1+ thymocytes is not dependent upon beta 2-microglobulin (beta 2m)-associated class I molecule expression because these cells are present in beta 2m-deficient mice. This suggests that gamma delta +NK1.1+ T cells may regulate immune responses to a different variety of antigens. However, the development of alpha beta +NK1.1+ and gamma delta +NK1.1+ thymocytes appears to be related. Analysis of different mutant mice lacking alpha beta +NK1.1+ thymocytes revealed a specific increase in gamma delta +NK1.1+ thymocyte production when the block in alpha beta +NK1.1+ thymocyte differentiation occurs after beta TCR rearrangement.

Animals↗
PubMed1995

Heterogeneity of intracellular cytokine synthesis at the single-cell level in polarized T helper 1 and T helper 2 populations.

CD4+ T helper (Th) cells can be classified into different types based on their cytokine profile. Cells with these polarized patterns of cytokine production have been termed Th1 and Th2, and can be distinguished functionally by the production of IFN-gamma and IL-4, respectively. These phenotypes are crucial in determining the type of immune response that develops after antigen priming. There are no surface markers that define them, and cytokine immunoassay or mRNA analysis both have limitations for characterization of single cells. Using immunofluorescent detection of intracellular IFN-gamma and IL-4, we have studied the emergence of Th1 and Th2 cells in response to antigen exposure and the patterns of cytokine synthesis in established T cell clones. IFN-gamma production by Th1 clones was detectable in almost all cells by 4 h, and it continued in most cells for > 24 h. IL-4 production in Th2 cells peaked at 4 h, but declined rapidly. In Th0 cells containing both cytokines, fewer cells produced IFN-gamma, which did not appear until IL-4 synthesis declined. Cocultivation of clones showed no such cross-regulation. Antigen stimulation of transgenic T cells expressing an ovalbumin-specific T cell receptor generated Th2 cells, probably as a result of endogenous IL-4 production. Addition of IL-12 and/or anti-IL-4 caused Th1 cells to develop, while some Th0 cells were seen when IL-12 alone was added. These results show that stimulation in the presence of polarizing stimuli results in cells producing either IFN-gamma or IL-4, but that coproduction can occur in rare cells under defined conditions.

Animals↗
PubMed1987

Sputum in asthma.

A detailed questionnaire concerning sputum production was completed by 130 patients with variable airflow limitation fulfilling conventional criteria for asthma. The mean age at onset was 17 years and 75% had positive prick skin tests. One hundred of 130 (79%) reported sputum production; 21% were non secretors. In 68% of those with sputum it was a constant feature from the onset. Increased volumes of sputum was associated with more severe asthma and disability and negative skin tests. An additional component of persisting airflow limitation was found more frequently in the group characterized by no sputum and large volumes. It was less common in those with small sputum volumes. Irrespective of volume, 43% of 130 fulfilled the conventional criteria for MRC chronic bronchitis but 57% of these were non-smokers. We conclude that asthma and chronic bronchitis are not mutually exclusive diagnoses; a history of regular sputum production may lead to the underdiagnosis of asthma and its consequent under-treatment.

Adolescent↗
PubMed1984

Changes in rib cage geometry during childhood.

Age related changes in rib cage geometry were found from measurements made on chest radiographs from 38 individuals aged from 1 month to 31 years and on computed tomography (CT) scans in another 28 individuals, aged from 3 months to 18 years. Chest radiographs were taken for minor respiratory symptoms or fever and only films showing no abnormality were used. CT scans were obtained in children undergoing staging for solid tumours in whom no intrathoracic deposits were found. In infants and very young children the ribs were found to be more horizontal and the sternal clavicular heads and diaphragmatic domes higher than in older children and young adults. Most of these changes were observed in the first two years of life, with something close to the adult pattern by the age of 2 years. Similarly cross sectional chest shape changed from the rounded infantile form to the more ovoid adult form by the same age. The configuration of the ribs observed in infancy and early childhood reduces the potential for thoracic expansion and may contribute to the frequency of respiratory problems found in the very young.

Adolescent↗
PubMed1982

The rate of rise of alveolar carbon dioxide pressure during expiration in man.

1. The purpose of the study was to see whether the rate of rise of alveolar PCO2 (PA, CO2) in expiration was directly proportional to the rate of pulmonary elimination of CO2 (VCO2) in man in the steady state. 2. Alveolar ventilation at rest and during exercise in man was calculated from the difference between total ventilation and dead space ventilation, and from the ratio of the rate of pulmonary CO2 elimination to the mean expired alveolar CO2 (total) fraction. The results were indistinguishable. In agreement with other workers' findings alveolar ventilation changed in direct proportion to the rate of carbon dioxide elimination, confirming the isocapnia of exercise ventilation in man. 3. The rate of rise of expiratory alveolar PCO2 in individual breaths has been obtained by two methods. In the first, a pattern of respiration with constant expiratory flow in each breath brought expiratory alveolar profiles to the outermost end of the airway. In the second method, the early part of the alveolar PCO2 during normal expiration was calculated from airway PCO2 and expired volume. 4. The data obtained with both methods show that, in the steady state, expiratory alveolar PCO2 rises at a rate which is directly proportional to the rate of CO2 production.

Carbon Dioxide↗
PubMed1980

Importance of airway closure in limiting maximal expiration in normal man.

To elucidate the importance of airway closure in limiting maximum expiration, two complementary plethysmographic techniques have been used to estimate the volume of and pressure within the trapped thoracic gas. Three young (19-23 yr) and three older (43-66 yr) subjects were studied. The first study defined the curve of possible pressure-volume relationships for the trapped gas; the second study attempted to estimate the volume of trapped gas. In the first study the subject in a Mead plethysmograph expired through a pneumotachograph and back into the box. A reduction in box volume greater than that caused by drying and cooling of expired gas implies gas compression due mainly to airway closure. In the second study a known volume of air was withdrawn from the mouth at full expiration and changes in box volume and mouth pressure were recorded. The apparent volume in pressure communication with the mouth (Vpc) was calculated using Boyle's law. In the young subjects we did not detect thoracic gas compression although there was evidence of trapped gas (RV-Vpc greater than 0). In the older subjects there was a larger volume of trapped gas that was compressed to pressures of more than 22 cmH2O. Airway closure appears to limit maximal expiration in older subjects.

Adult↗