CD4+ and CD8+ T cell dependent immune mechanisms of rhinovirus-mediated asthma ex

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DESCRIPTION (provided by applicant): The greatest morbidity associated with asthma is the occurrence of severe, potentially life- threatening exacerbations. Rhinovirus (RV) accounts for ~60-70% of childhood asthma exacerbations. Although an exacerbation would be predicted whenever a cytopathic inflammatory response is superimposed upon the asthmatic lung, this is not what is observed - and only RV infections are consistently associated with asthma exacerbations. RV-associated exacerbation are linked to the presence of an increased type 2 cytokine signature (IL-4, -5, and -13) and one explanation is that these cytokines are being produced by the RV-specific T cells themselves, either CD4+ helper (Th2-like) or CD8+ cytotoxic (Tc2-like) T lymphocytes. T lymphocytes responding to a viral infection produce inflammatory responses that can be harmful to the host. Exacerbations are also linked to the presence of diminished expression of the anti-inflammatory cytokine IL-10. IL-10 may to control the collateral damage associated with an exuberant T cell response. The source of this IL-10 during infection, we believe, is likely the effector T cells themselves. Objective/Hypothesis: We propose to focus on the production of type 2 cytokines and IL-10 by RV-specific effector/memory T-cells that predict the development of an asthma exacerbation following natural RV infection. We hypothesize that RV-specific memory T cells from children and adolescents who develop an exacerbation during RV infection release higher levels of type 2 cytokines and/or lower levels of IL-10. We will identify children with asthma who become infected with RV and validate our ability to identify circulating RV-specific CD4+ helper and CD8+ cytotoxic T effector lymphocytes. Specific aim #1 will enroll asthmatic children and adolescents who we will prospectively evaluate for RV infections and quantify the impact on their asthma. RV infection will be diagnosed by quantitative PCR of nasal secretions at regular clinic visits and when prompted by upper respiratory infections. Impact of RV infection will be evaluated primarily as change in methacholine sensitivity. Our preliminary studies demonstrate that during the fall RV pandemic >50% of children will demonstrate evidence for infection and ~half of those infections will be associated with an asthma exacerbation defined as a >2-fold increase in methacholine sensitivity. Specific aim #2 will examine the concept that RV-specific T cells orchestrate asthma exacerbations. We will assess the prevalence and cytokine profile of circulating RV-specific T memory cells after acute RV infections. We will identify RV-specific memory T cells and will define their production of type 1 (IFN-3) and type 2 cytokines (IL-4, -5, and -13). We will simultaneously define cellular production of IL-10. We propose that a high type 2/ low IL-10 cytokine profile within RV-specific helper (CD4+) and cytotoxic (CD8+) effector/memory T cells will predict asthma exacerbations. PUBLIC HEALTH RELEVANCE: The virus producing the "common cold" (rhinovirus) is responsible for most childhood and adolescent asthma exacerbations and, as such, most hospitalizations and deaths from asthma. The mechanism responsible for this unique feature of this virus is an enigma. Even though only a small subset of asthmatics is at risk for severe exacerbations, urgent care referral, hospitalization, or death, because of our inability to identify at risk individuals, current guidelines encourage aggressive daily treatment of all but the mildest asthmatics. Identifying the mechanism through which rhinovirus interacts with the immune system to produce an asthma exacerbation is central to identifying children who are at risk for asthma exacerbations and are most likely to benefit from specific interventions for prevention and treatment.