T-cell oligoclonality in benign prostatic hyperplasia

About This Grant

PROJECT SUMMARY/ABSTRACT Based on clinical, epidemiological, histopathological and molecular data, the immune system appears to be an important driver of benign prostatic hyperplasia (BPH), though the details remain poorly understood. The long- term goal is to find BPH prevention and treatment approaches that counter immune-driven BPH processes. The objective of this proposal is to determine how an expansion of clonal T cells contributes to BPH pathogenesis. The central hypothesis is that T cells responding to specific microbial or self-antigen(s) drive the proliferation and activation of prostatic fibroblasts that subsequently recruit glandular epithelium. The resultant BPH nodules lead to prostate enlargement, bladder outlet obstruction and lower urinary tract symptoms. This hypothesis will be testing through three specific aims: (1) Define the oligoclonal T-cell subsets and their functionality in BPH stromal-rich nodules; (2) Identify the inciting antigens recognized by BPH oligoclonal T cells; and (3) Determine the role of lymphocyte chemoattractant CXCL13 in BPH nodular growth. The premise is based on the novel finding of T-cell oligoclonality in BPH, and we will incorporate innovative techniques including TCR repertoire profiling, single-cell spatial transcriptomics, cell-based high-throughput antigen screening, and a BPH tissue explant model system. The results will have an important impact immediately by establishing an improved understanding of how the immune system propels BPH, and longer term because they lay the foundation to develop rational approaches for the prevention and treatment of BPH.