The recognition that inflammation has important roles in the pathogenesis of pulmonary arterial hypertension (PAH) arises from evidence that autoimmune and infectious diseases are associated with the development of PAH; inflammation can generate experimental pulmonary hypertension (PH); and perivascular inflammation is present in the pathology of human PAH and animal models of PH. However, whether inflammation is causal, an amplifier of alternative triggering mechanisms, or an epiphenomenon remains unclear. Prior studies on the role of T cells in disease pathogenesis have generated data of unclear relevance to PAH: Th2 and Th17 cells are detrimental in Aspergillus-exposed and chronically hypoxic mice, respectively, while regulatory T cells (Tregs) are protective in rats treated with SU5416 or monocrotaline. The translational application of these data is hampered by limited inflammation in the chronic hypoxia model and unclear mechanisms linking inflammation to vascular remodeling. We propose to interrogate a model system with a relevant antigen that activates specific Type 2 immunity; a perivascular compartment in which there is antigen uptake and presentation, cell proliferation and recruitment; and molecular mechanisms involving TGF-?1 resulting in pulmonary artery remodeling. We employ a mouse model triggered by the parasite Schistosoma mansoni, which reproduces key phenotypes of likely the most common cause of PAH worldwide. Our proposal seeks to identify the precise role of antigen- specific CD4 T cells as the source of IL-4 and IL-13; how this population arises, expands, and is activated; and its impact on monocyte recruitment and TGF-? activation. We hypothesize that exposure to Schistosoma egg antigens results in clonogenic Th2 CD4 T cell activation and proliferation, leading to production of IL-4 and IL-13; this prototypic Th2 response recruits Ly6C+ monocytes causing TGF-?-driven PH. Our overall goals are to determine the molecular mechanisms underlying the pathogenesis of Schistosoma-PH; identify approaches to develop immunotherapies, such as vaccination, against this parasitic disease; and to more broadly identify novel therapeutic targets in the inflammatory cascade, which may also be applicable to other inflammation-driven PAH etiologies.
Specific Aim 1 is to determine that T cell IL-4 and IL-13-driven inflammation caused by Schistosoma leads to TGF-? activation and PH. In this Aim we will investigate the necessity and sufficiency of Th2-activated CD4 T cells in Schistosoma-PH using a systematic series of experiments with deficient mice and immune reconstitution, to precisely determine whether CD4-derived IL-4/IL- 13 is critical for Ly6C+ monocyte recruitment and the overproduction of active TGF-?1 which results in PH.
Specific Aim 2 is to determine the Schistosoma antigen(s) taken up by antigen presenting cells that activate pathogenic, clonogenic IL-4/IL-13 producing CD4 T cells in Schistosoma-PH. In this Aim we will identify specific pathogenic Schistosoma antigens; the cells taking up, processing and presenting Schistosoma antigens to activate CD4 T cells; and the CD4 T cell receptor (TCR) repertoire indicative of clonal selection.

Public Health Relevance

The body's immune system likely contributes to the development of pulmonary hypertension, a fatal lung blood vessel disease, by causing too much of certain kinds of inflammation. Our research studies Schistosoma mansoni, a parasite that causes the disease schistosomiasis, which infects over 250 million people worldwide and is a major cause of pulmonary hypertension. By studying how the body responds to the parasite, we hope to find new treatments to help people with the disease.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Research Project (R01)
Project #
5R01HL135872-03
Application #
9607610
Study Section
Respiratory Integrative Biology and Translational Research Study Section (RIBT)
Program Officer
Caler, Elisabet V
Project Start
2016-12-15
Project End
2021-11-30
Budget Start
2018-12-01
Budget End
2019-11-30
Support Year
3
Fiscal Year
2019
Total Cost
Indirect Cost
Name
University of Colorado Denver
Department
Internal Medicine/Medicine
Type
Schools of Medicine
DUNS #
041096314
City
Aurora
State
CO
Country
United States
Zip Code
80045
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Asosingh, Kewal; Wanner, Nicholas; Weiss, Kelly et al. (2017) Bone marrow transplantation prevents right ventricle disease in the caveolin-1-deficient mouse model of pulmonary hypertension. Blood Adv 1:526-534

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