A Critical Role for OX40 in T Cell–mediated Immunopathology during Lung Viral Infection

Imperial College of Science, Technology and Medicine, Exhibition Road, London SW7 2AZ, United Kingdom.
Journal of Experimental Medicine (Impact Factor: 12.52). 10/2003; 198(8):1237-42. DOI: 10.1084/jem.20030351
Source: PubMed

ABSTRACT Respiratory infections are the third leading cause of death worldwide. Illness is caused by pathogen replication and disruption of airway homeostasis by excessive expansion of cell numbers. One strategy to prevent lung immune-mediated damage involves reducing the cellular burden. To date, antiinflammatory strategies have affected both antigen-specific and naive immune repertoires. Here we report a novel form of immune intervention that specifically targets recently activated T cells alone. OX40 (CD134) is absent on naive T cells but up-regulated 1-2 d after antigen activation. OX40-immunoglobulin fusion proteins block the interaction of OX40 with its ligand on antigen-presenting cells and eliminate weight loss and cachexia without preventing virus clearance. Reduced proliferation and enhanced apoptosis of lung cells accompanied the improved clinical phenotype. Manipulation of this late costimulatory pathway has clear therapeutic potential for the treatment of dysregulated lung immune responses.

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Available from: Gerhard Walzl, Sep 26, 2015
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    • "Even though the PCN treatment did alter pulmonary micro-architecture by inducing iBALT structures and was able to elicit an influx of leukocytes into the airways, these changes to the immune environment of the lung were of no apparent consequence to the well being of the mice. In fact, our results suggest that the PCN-treatment prior to infection is associated with an amelioration of the often excessive inflammatory responses that are seen during the resolution of pulmonary viral infections [16] as well as airway hyperresponsiveness and inflammation associated with asthma. Interestingly, the alterations to the immune environment of the lung in response to the PCN treatment had no effect upon the resolution of pulmonary bacterial infections. "
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    ABSTRACT: Destruction of the architectural and subsequently the functional integrity of the lung following pulmonary viral infections is attributable to both the extent of pathogen replication and to the host-generated inflammation associated with the recruitment of immune responses. The presence of antigenically disparate pulmonary viruses and the emergence of novel viruses assures the recurrence of lung damage with infection and resolution of each primary viral infection. Thus, there is a need to develop safe broad spectrum immunoprophylactic strategies capable of enhancing protective immune responses in the lung but which limits immune-mediated lung damage. The immunoprophylactic strategy described here utilizes a protein cage nanoparticle (PCN) to significantly accelerate clearance of diverse respiratory viruses after primary infection and also results in a host immune response that causes less lung damage. Mice pre-treated with PCN, independent of any specific viral antigens, were protected against both sub-lethal and lethal doses of two different influenza viruses, a mouse-adapted SARS-coronavirus, or mouse pneumovirus. Treatment with PCN significantly increased survival and was marked by enhanced viral clearance, accelerated induction of viral-specific antibody production, and significant decreases in morbidity and lung damage. The enhanced protection appears to be dependent upon the prior development of inducible bronchus-associated lymphoid tissue (iBALT) in the lung in response to the PCN treatment and to be mediated through CD4+ T cell and B cell dependent mechanisms. The immunoprophylactic strategy described utilizes an infection-independent induction of naturally occurring iBALT prior to infection by a pulmonary viral pathogen. This strategy non-specifically enhances primary immunity to respiratory viruses and is not restricted by the antigen specificities inherent in typical vaccination strategies. PCN treatment is asymptomatic in its application and importantly, ameliorates the damaging inflammation normally associated with the recruitment of immune responses into the lung.
    PLoS ONE 09/2009; 4(9):e7142. DOI:10.1371/journal.pone.0007142 · 3.23 Impact Factor
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    • "Thus, the action of OX40 most likely reflected a preferential increase of Th1 effector cell differentiation and/or accumulation of Th1 cells in the salivary glands independent of IL-10. This conclusion is consistent with data where OX40 was shown to promote Th1 cell accumulation at the site of infection with influenza (32, 33) and Cryptococcus neoformans (20). Moreover, OX40 signaling can directly induce IFN-γ secretion and promote Th1 differentiation in tissue culture (16, 17). "
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    ABSTRACT: The salivary glands represent a major site of cytomegalovirus replication and transmission to other hosts. Despite control of viral infection by strong T cell responses in visceral organs cytomegalovirus replication continues in the salivary glands of mice, suggesting that the virus exploits the mucosal microenvironment. Here, we show that T cell immunity in the salivary glands is limited by the induction of CD4 T cells expressing the regulatory cytokine interleukin (IL)-10. Blockade of IL-10 receptor (IL-10R) with an antagonist antibody dramatically reduced viral load in the salivary glands, but not in the spleen. The mucosa-specific protection afforded by IL-10R blockade was associated with an increased accumulation of CD4 T cells expressing interferon gamma, suggesting that IL-10R signaling limits effector T cell differentiation. Consistent with this, an agonist antibody targeting the tumor necrosis factor receptor superfamily member OX40 (TNFRSF4) enhanced effector T cell differentiation and increased the number of interferon gamma-producing T cells, thus limiting virus replication in the salivary glands. Collectively, the results indicate that modulating effector T cell differentiation can counteract pathogen exploitation of the mucosa, thus limiting persistent virus replication and transmission.
    Journal of Experimental Medicine 06/2007; 204(5):1217-25. DOI:10.1084/jem.20062424 · 12.52 Impact Factor
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    • "This study suggests that CD8 + T cells may cause tissue injury in lungs by producing proinflammatory mediators (Small et al., 2001). In a study of OX40 role in T-cell-mediated immunopathology in influenza-infected mice, the blocking of OX40/OX40L ameliorated influenza-driven T cell immunopathology in lungs by reduced inflammatory responses and enhanced apoptosis (Humphreys et al., 2003). On the basis of our findings in the pig model system, we hypothesize that the higher mortality rate caused by human H3N2 influenza viruses in elderly patients is due to the high induction of TNF-a in the respiratory tract. "
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    ABSTRACT: Influenza viruses are reported to infect mainly the respiratory tract epithelium of hosts. Our studies in a pig model show that influenza A viruses infect alveolar macrophages that constitutively reside in the respiratory tract, without causing apoptosis. Tumor necrosis factor alpha was the inflammatory cytokine most highly induced in these macrophages. In vivo, alveolar macrophages infected with human H3N2 influenza virus showed greater expression of tumor necrosis factor alpha than did alveolar macrophages infected with human H1N1 influenza virus. Induction of specific inflammatory cytokine such as TNF-alpha is a polygenic trait that involves the HA and NA genes. Markedly elevated expression of tumor necrosis factor alpha may be responsible for the high mortality rate caused by H3N2 influenza virus infection in elderly patients.
    Virology 12/2004; 329(2):270-9. DOI:10.1016/j.virol.2004.08.019 · 3.32 Impact Factor
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