Identifying the Inflammatory Process
Dr. Gelbard first encountered SGS during his residency, which ended in 2013. Over the course of his career, “it became clear that we knew little about the basic biology of airway stenosis. Beyond knowledge gaps in pathophysiology, we lacked a complete understanding of the natural history of the disorder,” he said.
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August 2020Building on well-phenotyped natural history data obtained from the recent prospective iSGS study, a number of researchers have been investigating iSGS scar tissue, including Alexander Hillel, MD, associate professor of otolaryngology–head and neck surgery at Johns Hopkins Medicine in Baltimore. “When you study the scar tissue, you find a lot of infiltrating immune cells within that scar,” he said. Subsequent work has demonstrated an increased adaptive immune response consisting of antigen-presenting dendritic cells as well as CD4 and CD8 T lymphocytes. It also appears that interleukin (IL)-17A is abundant in the mucosa of iSGS patients and “appears to drive fibroblast proliferation, but we don’t know if there’s a common mechanism in the immune cells and in the fibroblasts. What are the principal cell types that lead to unregulated fibrosis? If we could target the abnormal immune cells as well as the abnormal metabolism of the fibroblast, then we might be able to shut off the dysfunctional system,” Dr. Hillel said.
Powerful new techniques, including single-cell RNA sequencing (scRNA-seq), are proving essential to identifying the individual cell types within the scar tissue. “This technique is so useful because it provides a high-resolution atlas of the cellular constituents of airway scarring, as well as transcriptional data that can be used to understand the cells’ function,” reported Dr. Gelbard. “Additionally, scRNA-seq provides information on the T-cell receptor sequence of the infiltrating immune cells, which can be used to work backward to understand the target of the observed host immune response. Together, this knowledge is beginning to provide insight into what started this disease and offer new routes to treat it.”
Robert J Morrison, MD, assistant professor in the department of otolaryngology–head and neck surgery at Michigan Medicine in Ann Arbor, also studied fibroblast behavior in the scar tissue of patients with iSGS while working with Dr. Gelbard. “Experimental treatment of the scar tissue with IL-17A inhibitors seems to block the fibroblast proliferation and activation seen in the scar tissue,” he said. “There is research interested in looking at these IL-17 inhibition agents, including what’s the best way to deliver them—intravenously, through intralesional injection, or topically,” Dr. Morrison said. “Our hope is that in five to 10 years, iSGS will be a medically treated disease, rather than a surgical one.”