CD4+ T lymphocytes play a central role in regulating the magnitude and character of the immune response to infectious agents and environmental allergens. There is now a large body of evidence indicating that CD4+ T lymphocytes of the Th-2 subset mediate the development of the IgE antibody response and the pathologic changes, e.g. eosinophil infiltration, characteristic of asthma and atopic diseases of the respiratory tract Respiratory Syncytial Virus (RSV) is a major human pathogen and the primary cause of morbidity from respiratory infection in young children. RSV is unique among viral pathogens in that RSV infection of young children can result in pathologic changes similar to that observed in allergic lung disease with wheezing, eosinophil responses and IgE antibody production. We have examined the immune response to RSV in a murine model of pulmonary RSV infection and in a cohort of young children. Our results to date suggest that both CD8+ T lymphocyte and genetic factors may play an important role in regulating the differentiation of CD4+ T lymphocytes along the Th-1 or Th-2 differentiation pathway in response to RSV infection. The studies outlined in this proposal are designed to examine in a murine model and in the human the relationship between the development of a)8+ T lymphocyte responses to RSV proteins and the development of CD4+ lymphocyte responses of the Th-2 subtype. Studies will focus on 1.) the structural features of specific RSV proteins which influence CD4+ T lymphocyte differentiation, 2.) the role of RSV specific CD8+ T lymphocyte in regulating the development of CD4+ Th-1 and CD4+ Th-2 T lymphocyte responses, 3.) the affect of MHC linked and unlinked genes on the CD4+ T lymphocyte response to RSV. This analysis will include the characterization of the cytokine response of CD4+ T lymphocytes directed to the RSV-G and F glycoproteins and the CD8+ T lymphocyte response to RSV in children with a history of wheezing in response to RSV infection or with a history of asthma. The proposed studies should provide new information on the role of CD8+ T lymphocyte and genetic factors in the development of allergic pulmonary diseases.
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