Researchers Discover New Targets to Inhibit Pulmonary Fibrosis

Researchers have uncovered an immunological mechanism that underlies fibrosis in different lung conditions, including sarcoidosis and idiopathic pulmonary fibrosis (IPF), a study reports.

In mouse models of pulmonary fibrosis (PF), the study also demonstrated that readily available medicines approved for other conditions may be repurposed to halt this immunological trigger and ease PF symptoms.

The study, “PD-1 up-regulation on CD4+ T cells promotes pulmonary fibrosis through STAT3-mediated IL-17A and TGF-β1 production,” was published in the journal Science Translational Medicine.

An international team, led by researchers at Vanderbilt University Medical Center in Nashville, Tennessee, examined cells from patients with sarcoidosis and IPF, and tackled the reason why a type of white blood cell called a CD4+ T-cell does not function properly in PF patients, compared with healthy controls. 

In these patients, CD4+ T-cells express higher levels of a receptor known as PD-1, or programmed cell death protein 1, which is an immune checkpoint that helps prevent the immune system from attacking the body’s own molecules.

CD4+ T-cells that overexpress PD-1 found in PF patients also belong to a specific cell group that produces a pro-inflammatory molecule known as interleukin (IL)-17.

When human lung fibroblasts — important structural cells intimately involved in the scarring process — were placed in lab cultures together with CD4+ T-cells from sarcoidosis and IPF patients, they began to overproduce type 1 collagen, a hallmark process in fibrosis development.

In contrast, CD4+ T-cells from healthy donors did not induce this collagen buildup.

However, if PD-1 was blocked by antibodies in the fibroblast-CD4+ T-cell co-cultures, collagen overproduction was corrected.

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Further molecular analysis then linked PD-1 overexpression in the CD4+ T-cells of PF patients to the increased expression of a gene transcription activator called STAT3, which leads to increased production of IL-17, resulting in fibrosis.

These results prompted researchers to test if anti-PD-L1 antibody therapy could halt PF progression in the bleomycin mouse model, a model in which PF-like symptoms are induced by administration of bleomycin, a cancer medication.

Results showed that anti-PD-L1 antibody therapy did in fact significantly reduce lung collagen levels and fibrosis marks, compared with untreated animals.

According to the team, this work identifies a critical, previously unrecognized role for PD-1-CD4+ T-cells in PF.

“Though they haven’t typically been considered important in pulmonary fibrosis, we’re showing a central role in a range of diseases for CD4+ T-cells with PD-1 upregulation,” Lindsay Celada, PhD, a research instructor of medicine at the Vanderbilt University School of Medicine, said in a press release.

The study also highlights three potential PF therapeutic targets for which medicines are readily available, namely by blocking PD-1, inhibiting STAT3, or targeting IL-17.

“I’m very excited by the implications of our study for drug repurposing and the important benefits that might accrue for a great many patients with lung disease,” said Wonder Drake, MD, a professor at the Vanderbilt University School of Medicine and senior author of the study.