Edy Kim, MD

Edy Kim, MD

Institution: Brigham and Women’s Hospital

Project: Seeking Targeted Treatments for Unclassifiable Lung Fibrosis

Grant(s): Dalsemer Grant

Our project’s long-time goal is to develop new treatments for patients with earlier-stage pulmonary fibrosis. Our unique preliminary data examined lung tissue from patients in the earlier stages of disease–the best time to treat patients before irreversible lung scarring. We applied a powerful discovery technique, single-cell RNA-sequencing, to lung tissue from patients with earlier-stage pulmonary fibrosis, and we found a potential mechanism that drives disease in some patients. Our project uses in vitro (cells at the bench), in vivo (mouse models), and patient biospecimens to explore these findings that started in our human study. In this first year of our ALA-funded project, we have better defined how T cells drive inflammation by lung fibroblasts. We discovered that multiple cytokines (not only IFN-gamma) cooperate with granzyme K to drive this inflammation (Aim 1). Strikingly, the combination is synergistic–much more potent and each molecular mediator acting on its own. Over the past year, we have developed how this inflammation can drive disease by defining visually where in the lung the inflammatory mediators are located (Aim 3). We use “in situ hybridization” of slices of patient lung tissue to define how these inflammatory mediators cluster in the same place where T cell-fibroblasts gather, which supports our hypothesis that these cells may be a therapeutic target. We realize that blocking multiple molecular mediators (granzyme K, cytokines) would be challenging in patients. It would be more feasible if we could target a single molecular upstream that controls the disease process. To this end, our project examines how T cells, the productors of the inflammatory molecules, are recruited to come to the lung. In the past year, we have defined a new “positive feedback loop” (LIF and its receptor) in lung fibroblasts that amplifies the chemokines (recruiting molecules) that draw in T cells. We have targeted this potential “upstream, master regulator” of the T cell-fibroblast process in vitro (Aim 1) with plans to assess in vivo (mouse).

Update: Our project targets patients with “unclassifiable” interstitial lung disease (uILD) because they do not fit a well-established lung disease. Being “unclassifiable,” their treatment is empirical and broad spectrum. In uILD patient lung, we identified an inflammatory circuit in which lung fibroblasts recruit T cells into the lung, and, in turn, the T cells stimulate inflammatory fibroblasts. To date, we have defined autocrine loops in lung fibroblasts from uILD patients that drive chemokine production (attracting T cells) and the fibroblast gene programs driven by T cells. We have begun to define the spatial distribution of these findings in uILD lung tissue.

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