Immunobiology of Lung Fibrosis

Emory University, Atlanta GA

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Abstract

DESCRIPTION (provided by applicant): Idiopathic pulmonary fibrosis (IPF) is a progressive, lethal form of interstitial lung disease. The pathogenesis of IPF is not well understood but a common paradigm postulates an initial alveolar injury, which triggers an inflammatory response and fibrosis. Certain subsets of T lymphocytes have been implicated in promoting lung fibrogenesis. Specifically, a predominantly T helper type 2 lymphocyte (Th2) response with the characteristic cytokine profile consisting of IL-4, IL-5, IL-10 and IL-13 production (as opposed to a Th1 response) predisposes towards a fibrotic response rather than repair. In addition, Th2 cytokines stimulate the production of TGF-beta, a critical fibrogenic factor. In this project, we propose to clarify the roles of T cell isotypes and their characteristic cytokines on lung fibrosis in animals. We will conduct parallel studies in the rodent bleomycin model and in a new murine gamma herpesvirus model that we believe relevant to the human disease. Therefore, we propose the following hypotheses: 1. Murine gamma herpesvirus (MHV68) infection of the lungs of susceptible mice will cause a predominantly Th2 lymphocyte response and will cause persistent and progressive pulmonary fibrosis. 2. Defective Th1 effector function and/or a predominance of Th2 responses predisposes to the development of lung fibrosis caused by either bleomycin or gamma herpesvirus infection. 3. The IL-4 receptor (IL-4Ralpha) signaling pathway in lung cells mediates increased TGF-beta production and lung fibrosis. To test these hypotheses, we propose the following specific aims: 1. In B cell deficient mice, to determine effects of bleomycin or infection of the lungs with MHV68 on lung function, histopathotogy, lung collagen content, Th1 and Th2 lymphocyte responses and cytokine ILL-4, IL-5, IL-13, IFNgamma, TGFbeta) production by whole lung and lung-derived T lymphocytes. 2. To determine effects of specific depletion of CD4+ and CD8+ T cell subsets on pulmonary responses to bleomycin or MHV68 infection. 3. Using adoptive transfer of in vitro polarized Th1 and Th2 cells and genetically engineered mice biased toward Th1 or Th2 responses, to clarify relationships between the T-lymphocyte responses and responses of the lungs to bleomycin or MHV68 infection. 4. Using IL-4 receptor deficient mice with and without adoptive transfer of normal Th2 cells, to determine whether IL-4 signaling in cells other than T lymphocytes is important to the lung fibrogenic response to MHV68 or bleomycin.