Human systemic sclerosis (SSc) is an autoimmune-like disease that results in excessive production of collagen in the skin as well as tissues such as kidney, heart, and lung. If this fibrosis is extensive it can prevent normal organ function. Fibrosis is a feature that is shared with other syndromes such as severe asthma and COPD, and therefore preventing the onset of fibrosis or blocking continued fibrosis is of great significance to a number of damaging diseases. Collagen deposition is thought mediated by deregulation of epithelial cells, macrophages, and fibroblasts, and inflammatory cells such as Th2 cells and eosinophils may play roles in promoting the activity of these cell types. Although cytokines such as TGF-?, IL-13, IL-4, and TNF are acknowledged to contribute to end-stage pathology, new and novel targets for therapy are warranted that may broadly suppress the activity of many of the inflammatory cell types that contribute to fibrotic disease. We recently reported in several models of severe asthma that LIGHT, a TNF superfamily protein, that can be expressed on a number of cell types including activated T cells, dendritic cells, and inflamed epithelial cells, was responsible for mediating collagen production, smooth muscle hyperplasia, and overall fibrotic symptoms. This activity was mediated through binding to two TNFR superfamily receptors, the herpes virus entry mediator (HVEM) and the lymphotoxin beta receptor (LT?R). We will test the novel hypothesis that LIGHT also controls fibrosis in multiple inflammatory situations and will be responsible for collagen deposition, skin thickening, and interstitial fibrosis of internal organs. We have evidence that HVEM and LT?R are expressed or induced on all of the cell types thought to mediate fibrotic activity, namely epithelial cells, macrophages, and fibroblasts. We also have found that patients with pulmonary fibrosis due to systemic sclerosis have T cells in the lungs that express LIGHT, which correlates with clinical reports of enhanced levels of soluble LIGHT in bronchoalveolar lavages from similar patients. This proposal will focus on three mouse models of systemic sclerosis that result in fibrosis in various organs and recapitulate many of the features exhibited by human patients. Using the tight- skin mouse that spontaneously develops skin fibrosis;a minor histocompatibility model of GVHD that also results in skin fibrosis as well as fibrosis of internal organs;and bleomycin injection that induces pulmonary fibrosis, we will test whether mice or cells lacking LIGHT, HVEM, or LT?R cannot succumb to sclerosis-like fibrotic disease. We will additionally test if therapeutic blockade of LIGHT interactions ameliorates inflammation and pathology associated with scleroderma and systemic sclerosis.

Public Health Relevance

Systemic sclerosis is a type of autoimmune disease present throughout the world and represented in all ethnic groups. It can either be localized and affect the hands, arms, and face, or can be systemic affecting both a large area of skin as well as internal organs such as the lungs, kidneys, and heart. The cause is unknown and treatment options involve non-specific immune suppression. This proposal will test the novel hypothesis that the extracellular protein LIGHT, and its receptors HVEM and LT?R, control fibrosis associated with sclerosis- like inflammatory diseases. By determining whether LIGHT and its receptors promote fibrosis in animal models, we will gain knowledge that might lead to ways to therapeutically target human fibrotic disease.

Agency
National Institute of Health (NIH)
Institute
National Institute of Allergy and Infectious Diseases (NIAID)
Type
Exploratory/Developmental Grants (R21)
Project #
5R21AI100905-02
Application #
8502626
Study Section
Hypersensitivity, Autoimmune, and Immune-mediated Diseases Study Section (HAI)
Program Officer
Rothermel, Annette L
Project Start
2012-07-02
Project End
2014-06-30
Budget Start
2013-07-01
Budget End
2014-06-30
Support Year
2
Fiscal Year
2013
Total Cost
$204,450
Indirect Cost
$86,950
Name
La Jolla Institute
Department
Type
DUNS #
603880287
City
La Jolla
State
CA
Country
United States
Zip Code
92037
Croft, Michael (2014) The TNF family in T cell differentiation and function--unanswered questions and future directions. Semin Immunol 26:183-90
Croft, Michael; Benedict, Chris A; Ware, Carl F (2013) Clinical targeting of the TNF and TNFR superfamilies. Nat Rev Drug Discov 12:147-68