Helper T-cells Mediate Host Response in Urogynecologic Mesh Complications

Objectives: Polypropylene mesh (PP), commonly used to surgically treat uterovaginal prolapse is limited by complications. Studies of excised mesh from women with complications have demonstrated marked deformations (collapsed pores and wrinkles) in mesh initially implanted flat. M1 macrophages and T-cells were prominent cell types responding to deformed mesh removed from women. As little is known of the role of the adaptive immune response to biomaterials inserted onto the vagina, we aimed to study the impact of increased mesh burden imposed by deformations (pore collapse with or without wrinkling) on T-cell mediated inflammatory responses in a controlled non-human primate prolapse repair model.

Methods: Rhesus macaques (N = 28) underwent hysterectomy followed by sacrocolpopexy. Lightweight polypropylene mesh in which collapsed pores and wrinkles were intentionally introduced was implanted. Comparisons were made between mesh implanted 1) flat (R0, N=9), 2) flat with collapsed pores (R45, N=10), and 3) wrinkled with collapsed pores (RD, N=9). Seven animals underwent Sham surgery. At 12 weeks, vaginal-mesh complexes were harvested. Tissue sections (7μm) were labeled for the pan T cell marker CD3, CD8(T-cytotoxic), CD4 (T-helper), FOXP3 (Treg) and DAPI (nuclei). QuPath was utilized to calculate number of positively labeled cells for each marker. Custom Luminex beads of inflammatory and wound healing markers were used to assess cell signaling. Comparisons were made using Kruskal-Wallis test followed by post hoc analysis.

Results: In contrast to flat mesh (R0), mesh exposures were present in the pore collapsed (R45) and pore collapsed and wrinkled (RD) groups with the greatest number in RD. Mesh burden increased with the introduction of each deformation (R0< R45< RD, P= 0.002). With increased mesh burden, CD3+ T-cells were increased in the adventitia with twice as many responding in RD compared to R0 and R45 (P=0.005) (Figure 1a). T-helper cells predominated the response in all groups compared to T-cytotoxic cells and was highest in R45 (P= 0.0035). Treg density was increased in R45 (5.543 cells/mm2) and R0 compared (3.597 cells/mm2) to RD (2.962 cells/mm2) (P= 0.01) (Figure 1b). Cytokines IL-17A and IL-10 were increased in R45 as compared to RD (p=0.047 and p=0.02) (Figure1c-d) suggesting a resolving inflammatory response in pore collapsed and flat meshes (R0, R45) as compared to ongoing inflammation in RD.

Conclusions: A large T cell response is mounted in deformed PP mesh as compared to flat mesh with the highest elicited by the pore collapsed and wrinkled group (RD). Cytotoxic T-cells largely do not contribute to this response indicating an absence of an inflammatory signal. Among T-helper cells, Treg populations and ensuing cytokine signaling predominate in flat and pore collapsed but not wrinkled mesh indicating immune resolution in these groups. Ongoing T-helper recruitment in RD indicates a robust overwhelming active pro-inflammatory response related to high mesh burden.