Mesh induced fibrosis: The protective role of T regulatory cells.

ABSTRACT

Polypropylene mesh is widely used in urogynecologic surgery, but complications rates (pain and exposure) approach 10%. Emerging evidence implicates the adaptive immune system in regulating the foreign body response to mesh, particularly regulatory T cells (Tregs), which modify macrophage differentiation and down-regulate CD8+ effector T cells. We hypothesize that Tregs protect against a profibrotic response, a likely mechanism of pain complications. Here, thin sections of mesh-tissue complexes removed for the primary complaint of pain (N = 14) or exposure (N = 15) were labeled for CD8, CD4 (Th), and FoxP3 (Tregs) via immunofluorescence. The same sections were analyzed for localized collagen deposition via a customized semi-quantitative assessment (0.25 mm2 grid) after trichrome staining. TGF-ß1 concentrations were determined by enzyme-linked immunosorbent assay. Fewer Treg and CD4+ cells were found in fibrotic areas versus non-fibrotic areas (503 and 550/cm2 fewer, respectively, both P < 0.001). TGF-ß1 was higher in mesh samples compared to autologous control biopsies. TGF-ß 1 inversely correlated with age, r -0.636(p = 0.008). No differences were found in T cell subgroups or fibrotic indices between pain and exposure groups. A moderate inverse relationship was found between TGF-ß1 and Tregs (r -0.402, P = 0.009). Tregs were present up to 12 years after mesh implantation, challenging the assumption that the adaptive immune response to a foreign body is transient. In conclusion, the inverse relationship between fibrosis and Tregs, and TGF-ß1 and Tregs points to a protective role of these cells. Similar immunologic responses in patients with pain and exposure suggest these complications exist along a spectrum. STATEMENT OF SIGNIFICANCE: The use of polypropylene mesh has been associated with improved outcomes in urogynecologic surgery, but is associated with significant complications, including pain and exposure through the vaginal epithelium. The host immune response features a prolonged inflammatory reaction containing innate immune cells and T lymphocytes clustered in capsules around the mesh fibers. This study uncovers the inverse relationship between T regulatory cells and the extent of fibrosis around the mesh, suggesting an anti-fibrotic effect. In addition, concentrations of T regulatory and T effector cells and levels of fibrosis connect these two most common complications into one mechanistic pathway. These new insights into the immune response to implanted mesh are an important step in understanding the causes of these surgical complications.