Idiopathic pulmonary fibrosis (IPF) is a progressive interstitial pneumonia of unknown etiology with a mean survival rate of less than 3 years. It is hypothesised to be a result of aberrant remodelling and repair, which occurs after an unknown alveolar injury in genetically susceptible individuals. This process drives fibroblast proliferation, myofibroblast differentiation and excessive deposition of collagen and other extracellular matrix (ECM) components within the lung interstitium, which ultimately leads to destruction of the lung and respiratory failure.
Clinical trials in IPF remain extremely challenging due to the inability to identify patients at diagnosis at risk of developing rapidly progressive disease and in addition, due to the heterogeneity of IPF phenotypes. Currently, there is a significant and unmet clinical need to identify biomarkers which will facilitate disease stratification in IPF.
Recently, we identified a single nucleotide polymorphism in the human Toll-like receptor 3 (TLR3) gene, TLR3 Leu412Phe (L412F; rs3775291), in IPF patients which is associated with a significantly greater risk of mortality and an accelerated rate of decline in FVC in patients in two independent IPF cohorts (UK and INSPIRE trial cohort). Furthermore, we demonstrated that activation of TLR3 in 412F-homozygous primary human lung fibroblasts resulted in reduced fibroproliferation and IFN-β expression. Furthermore, using a bleomycin model of IPF in TLR3-KO mice, we demonstrated that TLR3-KO mice experience attenuated survival and increased pulmonary levels of TGF-β, IL-13, IL-4 and hydroxylproline. In this research project, we will characterise the effects of TLR3 L412F further in disease progression in IPF using in vitro (IPF primary human lung fibroblasts), ex vivo (IPF BAL fluid and associated cells) and in vivo (a novel, humanised TLR3 L412F knock-in mouse) pre-clinical models. In addition, we will also investigate the efficacy of recombinant IFN-β as a therapeutic agent in 412F-heterozygous and –homozygous IPF patients.
