T regulatory cells: a key predictor of the host response in mesh - PowerPoint PPT Presentation

T regulatory cells: a key predictor of the host response in mesh complications Amanda Artsen, Rui Liang, Matthew Rytel, Leslie Meyn, Natalie Pace, Steve Abramowitch, Pamela Moalli University of Pittsburgh Medical Center, Magee-Womens Research Institute

Disclosures Funding: NIH HD083383 (Moalli) Tobacco Grant Settlement, State of PA I have no other relevant financial relationships to disclose

350,000 urogynecologic mesh surgeries annually foreign body response mesh implantation mesh fiber TGF b- 1 T reg T reg M1 healing M2 MMPs fibrosis M1 exposure pain M2 tissue degradation encapsulation ? Jonsson et al 2012, 2013 tissue integration Brown et al 2015 Nolfi et al 2013

350,000 urogynecologic mesh surgeries annually Immune Effector Function tolerance CD8 T reg TGF b- 1 T reg T reg M1 healing M2 MMPs fibrosis M1 exposure pain M2 tissue degradation encapsulation ? Jonsson et al 2012, 2013 tissue integration Brown et al 2015 Nolfi et al 2013

Hypothesis Proinflammatory environment suppresses T reg response and pathologic fibrosis leads to pain and suboptimal outcomes HIGHER baseline pain scores will be associated with: Effector Immune 2. Fibrosis Function tolerance CD8 1. T reg 3. TGF b -1 Patients with these these pro-fibrotic markers will be less likely to respond to removal

Study design Patients undergoing mesh excision for pain or exposure Questionnaires at baseline and 6 mo after removal: • PFD-20 questionnaires: yes/no pelvic pain, amount of bother • Visual analog scales (VAS) for pelvic pain VAS 0 100 Place a mark on the line to represent your pain +Response to removal if ≥13 mm improvement in VAS

Study design Trichrome Immunofluorescence CD4 15 14 (T h cells) Foxp3 (T reg cells) CD8 + exposure pain Fibrosis: >2.5 Enzyme-linked immunosorbent assay was performed to determine SD higher than TGF b -1 concentration vaginal control biopsies Statistical analysis Demographics: Chi2 and t tests Responders to non-responders: Mann-U Whitney and logistic regression

Results: Demographics Exposure (n=15) Pain (n=14) prolapse (n=4) sling (n=10) prolapse (n=8) sling (n=7) § Age 54.4±12.1y § BMI 28.8±4.0 kg/m 2 § Median Parity 3 (IQR 2-4) § Similar comorbidities § Mean duration implantation 51mo (IQR 22-66)

Results: Baseline Pain Median VAS: 45 (24-76) 0 100 P<0.002 VAS score associated “Do you have pelvic pain?” linearly with fibrosis, 78.6% “yes” p =0.013 Median Bother: 1. Not at all 2. Somewhat 3. Moderately 4. Quite a bit

Results: Responders vs Nonresponders Responders = 9 Nonresponders = 8 P>0.9 5 exposure 4 pain 4 exposure 4 pain Responders = 9 Nonresponders = 8 P>0.9 5 prolapse 4 sling 4 prolapse 4 sling

Results: Responders vs Nonresponders Responders (n=9) Nonresponders (n=8) P value Age (y) 57 (52.5-65.0) 55.5 (48.8-68.0) 0.82 BMI (kg/m 2 ) 28.2 (26.2-31.6) 29.6 (23.5-32.4) 0.96 Duration implantation 22.0 (10.5-61.3) 55.5(35.0-58.9) 0.17 (months) Fibrosis level (intensity) 54.6 (38.5-72.1) 66.2 (35.8-82.2) 0.89 No difference between responders and nonrensponders in age, BMI, or fibrosis level, but a trend toward lower duration of implantation

Results: Responders vs Nonresponders Responders (n=9) Nonresponders (n=8) P value T reg concentration (cells/mm 2 ) 7.8 (1.3-10.2) 0.3 (0.5-3.4) 0.036 CD8 (cells/sample) 562.0 (289.5-829.0) 291.0 (100.8-544.8) 0.17 T reg /CD8 + ratio (T reg /100 CD8 + ) 2.7 (1.1-7.3) 1.1 (0.1-1.8) 0.07 TGF- b 1 (pg/μg protein) 6.6 (5.7-10.2) 12.8 (10.0-13.3) 0.032 T reg concentration predicted responder status Patients were 1.6 times as likely to be a responder for every additional T reg /mm 2 , ( P =0.05)

Conclusions § Fibrosis is a plausible mechanism of pain complications § Responder rates not different by complication type or mesh type Lower TGF b 1 levels and higher concentrations of T regs are associated with § improvement of pain after removal regardless of fibrosis severity § Adaptive immune response may prevent complications and drive recovery Duration of implantation may matter § § Future studies: activated fibroblasts, therapeutic role of T cells

Acknowledgements Funding: NIH HD083383 (Moalli) Tobacco Grant Settlement, State of PA