Fibrosis-specific protein fragments may open door to IPF vaccine: Study
Approach significantly reduced scarring in mouse models, human cells
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Vaccines based on protein fragments unique to the scar-forming cells that drive idiopathic pulmonary fibrosis (IPF) significantly reduced lung scarring in both mouse models and human cell experiments, according to a study.
While the vaccine approach showed promise in mice, advancing it to clinical trials will require patient selection based on matching genetics and rigorous safety monitoring to minimize the risk of unintended immune reactions.
“This study indicates that [protein fragment] profiling provides a robust platform for discovering translatable antifibrotic immunotherapies,” the authors wrote in the study “Immunopeptidome profiling in pulmonary fibrosis provides a platform for identifying therapeutic targets,” published in Nature Immunology.
Levels of immune cells in lung tissue and fluid elevated in IPF
IPF is a chronic, progressive lung disease marked by continuous scarring of the lungs due to an unknown cause. Inflammation and immune activation are known features of IPF, with previous research finding elevated levels of immune cells in lung tissue and fluid.
The immune system relies on a process in which cells continuously break down proteins into small fragments, called immunopeptides, and display these fragments on their surface.
T-cells, a type of immune cell, constantly patrol the body and inspect these displayed fragments. When a T-cell encounters a fragment from a healthy cell, it doesn’t respond. When it encounters a fragment from a foreign or abnormal source, such as a virus or a cancerous cell, it triggers an immune response to eliminate the threat.
A technique called immunopeptidomics allows researchers to analyze these immunopeptides in large numbers. It’s been used to identify tumor-specific immunopeptides in the development of vaccines that stimulate an immune response against cancer. Yet no detailed immunopeptide profile of fibrotic lung tissue in IPF has been reported to date.
Mice vaccinated with the three immunopeptides had less fibrosis
Researchers first analyzed immunopeptides from fibrotic lung tissue of eight men with IPF, ages 51-70 years, and from normal lung tissue of four non-IPF male donors of similar age.
Overall, 27,682 peptides derived from 2,733 proteins were found to be unique to IPF. The team noted that the genes encoding IPF-specific immunopeptides tended to be more active in immune macrophages and fibroblasts, cells that drive inflammation and scarring in IPF.
A similar analysis was conducted in a commonly used IPF mouse model in which lung scarring is induced by the chemical bleomycin (BLM). IPF-specific immunopeptides accounted for almost two-thirds (64%) of the total, and proteins about half (49%), suggesting that the BLM model captures some of the disease-associated immune selection seen in human IPF.
Using a computational tool called Fib-SCORE, which prioritizes immunopeptides with potential antifibrotic (anti-scarring) activity, the team identified three genes encoding the source proteins of the top-ranked immunopeptides: Tns3, Apbb2, and Maf. The activity of these genes was elevated in two cell populations that specifically proliferate in the lungs of BLM-treated mice with fibrosis. Importantly, these findings were confirmed using human data.
The researchers then assessed whether immunopeptides from these proteins (MAF116-124, APBB270-78, or TNS3119-127) could be used as a vaccine to elicit an immune response against IPF-driving cells.
Our study demonstrates that immunopeptidome analysis in fibrotic diseases represents a feasible approach for finding effective immunotherapeutic targets.
At day 28 after BLM, multiple measures of lung fibrosis, including various tissue-staining methods, all showed that mice vaccinated with the three immunopeptides, either alone or in combination, had markedly less fibrosis than unvaccinated BLM-treated mice. Further experiments confirmed that the vaccines were activating the immune system as intended.
A more detailed analysis of the MAF116-124 immunopeptide found that vaccination may reprogram the fibrotic microenvironment by reducing the growth of disease-driving cell populations while simultaneously strengthening the response of cytotoxic T-cells, the immune cells that identify and destroy infected, damaged, or cancerous cells.
To test whether MAF116-124 could elicit a human immune response, blood cells from healthy donors were used to generate MAF116-124-specific cytotoxic T-cells. These cells grew more vigorously and produced more of the immune signaling protein IFN-gamma upon reexposure to MAF116-124 than upon exposure to an unrelated control peptide. They also directly killed scar-forming myofibroblasts and macrophages isolated from the lungs of IPF patients.
“Our study demonstrates that immunopeptidome analysis in fibrotic diseases represents a feasible approach for finding effective immunotherapeutic targets,” the researchers concluded. “Future efforts to translate these [immunopeptide] interventions into human applications will necessitate stratifying individuals with IPF enrolled in clinical trials based on shared [genetics].”
