Exacerbations of asthma requiring unscheduled physician visits, emergency department care, or hospital admission are a major cause of the morbidity and cost of this disease, which affects up to 8% of the population. Extensive evidence suggests that a large proportion of these exacerbations during childhood (after three years of age) and among young adults are triggered by a viral infection, predominantly infections caused by rhinovirus (RV). In addition, a large body of evidence shows that patients who develop an exacerbation with RV are allergic to one or more common inhalant allergens. When patients presenting with acute asthma are studied in an emergency department, they have evidence of inflammation, which is usually interpreted as being part of the response to the virus. However, previous results using the RV challenge model suggest that inflammation, as judged by exhaled nitric oxide (FeNO) or eosinophilia, is as much a risk factor for a pulmonary response to the virus as it is a response that occurs during the viral infection. The mechanistic basis for this synergistic interaction between the viral infection and pre-existing allergy is not known. The clinical trial proposed here (AIM 1) is to treat subjects, who have allergic asthma, for two months with the monoclonal antibody omalizumab (anti-IgE) or placebo, prior to challenging them with the FDA-approved preparation of RV-39. This trial design has been approved by the FDA (FDA-BB-IND #10510) and the University of Virginia IRB. The primary outcome will be cumulative lower respiratory tract symptoms (CLTRS) during the first four days of infection. The patients will also be monitored for a wide range of markers relevant to inflammation of the respiratory tract, as well as for changes in cellular responses occurring during the viral infection. Thus, it will be possible to directly answer whether anti-IgE treatment is effective in reducing both lung symptoms and bronchial hyperreactivity because it decreases IgE and its receptor on relevant cells, or because it decreases inflammation prior to infection. The proposed cellular studies (AIM 2) will investigate whether anti-IgE treatment reduces the induction of allergen-specific or RV-specific CD4+ T cells with a Th2 cytokine signature. The capacity for anti-IgE to down-regulate Th2-promoting pathways in antigen presenting cells (DCs and possibly basophils) will be examined. In complementary T-cell studies, recent advances in the development of novel peptide/MHC II tetramers will be used to identify and enumerate circulating CD4+ T cells specific for allergen (grass and dust mite) and RV in parallel throughout the two-month treatment phase and subsequent RV challenge phase of the trial in order to monitor fluxes in these cells that correspond to migration to the inflamed respiratory tract. In conjunction, the capacity for RV infection to induce a Th2 profile and for anti-IgE treatment to ameliorate this effect will be assessed using in vitro cultures stimulated with allergen or RV. Taken together, these studies are designed to understand the importance of IgE antibodies and to better define the correct targets for the treatment of asthma that is designed to prevent exacerbations.

Public Health Relevance

The object of the proposed clinical trial is to provide information about the ways in which the common cold virus (or rhinovirus) can trigger exacerbations of asthma in patients who are allergic to one or more common allergens. The plan is to use injection of a monoclonal antibody to IgE (the antibodies that cause allergy) for two months before challenging them with a rhinovirus. The studies proposed will provide much clearer information about both the role that allergic inflammation plays in precipitating acute asthma and the mechanisms by which rhinovirus infection can cause acute or severe exacerbations of this extremely common condition.

Agency
National Institute of Health (NIH)
Institute
National Institute of Allergy and Infectious Diseases (NIAID)
Type
Research Project--Cooperative Agreements (U01)
Project #
5U01AI100799-04
Application #
8895252
Study Section
Special Emphasis Panel (ZAI1)
Program Officer
Davidson, Wendy F
Project Start
2012-08-03
Project End
2017-07-31
Budget Start
2015-08-01
Budget End
2017-07-31
Support Year
4
Fiscal Year
2015
Total Cost
Indirect Cost
Name
University of Virginia
Department
Internal Medicine/Medicine
Type
Schools of Medicine
DUNS #
065391526
City
Charlottesville
State
VA
Country
United States
Zip Code
22904
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Muehling, Lyndsey M; Turner, Ronald B; Brown, Kenneth B et al. (2018) Single-Cell Tracking Reveals a Role for Pre-Existing CCR5+ Memory Th1 Cells in the Control of Rhinovirus-A39 After Experimental Challenge in Humans. J Infect Dis 217:381-392
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Muehling, Lyndsey M; Mai, Duy T; Kwok, William W et al. (2016) Circulating Memory CD4+ T Cells Target Conserved Epitopes of Rhinovirus Capsid Proteins and Respond Rapidly to Experimental Infection in Humans. J Immunol 197:3214-3224
Kennedy, Joshua L; Steinke, John W; Liu, Lixia et al. (2016) Failure of itraconazole to prevent T-helper type 2 cell immune deviation: Implications for chronic rhinosinusitis. Am J Rhinol Allergy 30:379-384

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