Fibrosis is the common final pathway for a number of pulmonary disorders such as sarcoidosis, asbestosis, rheumatoid arthritis, scleroderma and idiopathic pulmonary fibrosis. Although pulmonary fibrosis appears to be the end result of chronic unremitting immune activation, often neither the inciting agents of the inflammatory process nor the precise factors driving the fibrotic response are known. In humans, pulmonary fibrosis is associated with lymphocyte infiltration in the parenchyma and alveolar space. However, the precise role of these cells in the disease process has yet to be established. That is, it is unclear if the lymphocytes participate in accelerating fibrosis, are part of an overwhelmed anti-fibrotic negative feed back loop, or both. In this proposal, using a unique mouse model of selective deletion of CD4+ T cell effector subsets, we will test the hypothesis that T helper cells play a critical role in the modulation of pulmonary fibrosis.
In Aim 1 we will determine the role and mechanism by which Thi, Th2, Th17 and regulatory T cells accelerate or prevent the development of fibrosis.
In Aim 2 we will determine the role of alternatively activated macrophages (AAMs). This relatively new subset of macrophages is induced by the Th2 cytokines IL-4/IL-13 and thus we propose that Th2 T cells promote fibrosis in part through the generation of AAM.
In Aim 3 we will employ agents to modulate the T effector response (the TLR agonist LPS and a live viral vaccine) to test the hypothesis that in vivo skewing of T helper responses can be employed as a novel therapeutic strategy to treat or prevent lung fibrosis.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Research Program Projects (P01)
Project #
2P01HL010342-43A1
Application #
8114345
Study Section
Heart, Lung, and Blood Initial Review Group (HLBP)
Project Start
Project End
Budget Start
2011-06-01
Budget End
2012-02-28
Support Year
43
Fiscal Year
2011
Total Cost
$387,912
Indirect Cost
Name
Johns Hopkins University
Department
Type
DUNS #
001910777
City
Baltimore
State
MD
Country
United States
Zip Code
21218
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Zhong, Qiong; Jenkins, John; Moldobaeva, Aigul et al. (2016) Effector T Cells and Ischemia-Induced Systemic Angiogenesis in the Lung. Am J Respir Cell Mol Biol 54:394-401
Vigeland, Christine L; Collins, Samuel L; Chan-Li, Yee et al. (2016) Deletion of mTORC1 Activity in CD4+ T Cells Is Associated with Lung Fibrosis and Increased ?? T Cells. PLoS One 11:e0163288
Eldridge, Lindsey; Moldobaeva, Aigul; Zhong, Qiong et al. (2016) Bronchial Artery Angiogenesis Drives Lung Tumor Growth. Cancer Res 76:5962-5969
Collins, Samuel L; Chan-Li, Yee; Oh, MinHee et al. (2016) Vaccinia vaccine-based immunotherapy arrests and reverses established pulmonary fibrosis. JCI Insight 1:e83116
Limjunyawong, Nathachit; Fallica, Jonathan; Ramakrishnan, Amritha et al. (2015) Phenotyping mouse pulmonary function in vivo with the lung diffusing capacity. J Vis Exp :e52216

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