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

T regulatory cells: a key predictor

• f 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

M2 M1 pain

fibrosis encapsulation

healing

MMPs tissue degradation

exposure M2 M1 tissue integration

?

mesh implantation

mesh fiber

foreign body response

350,000 urogynecologic mesh surgeries annually

Jonsson et al 2012, 2013 Brown et al 2015 Nolfi et al 2013

TGFb-1

Treg Treg

M2 M1 pain

fibrosis encapsulation

healing

MMPs tissue degradation

exposure M2 M1 tissue integration

?

350,000 urogynecologic mesh surgeries annually

Jonsson et al 2012, 2013 Brown et al 2015 Nolfi et al 2013

Immune

tolerance Effector Function

Treg CD8

TGFb-1

Treg Treg

Hypothesis

Proinflammatory environment suppresses Treg response and pathologic fibrosis leads to pain and suboptimal outcomes HIGHER baseline pain scores will be associated with: Immune

tolerance Effector Function

Treg

1. 2.

Fibrosis

3.

TGFb-1

Patients with these these pro-fibrotic markers will be less likely to respond to removal

CD8

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

100

Place a mark on the line to represent your pain VAS +Response to removal if ≥13 mm improvement in VAS

Study design

CD4 (Th cells) Foxp3 (Treg cells)

Immunofluorescence Trichrome

exposure pain

15 14

Enzyme-linked immunosorbent assay was performed to determine TGFb-1 concentration Statistical analysis Demographics: Chi2 and t tests Responders to non-responders: Mann-U Whitney and logistic regression

Fibrosis: >2.5 SD higher than vaginal control biopsies

CD8+

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/m2 § Median Parity 3 (IQR 2-4) § Similar comorbidities § Mean duration implantation 51mo (IQR 22-66)

Results: Baseline Pain 100

Median VAS: 45 (24-76) “Do you have pelvic pain?” 78.6% “yes” Median Bother:

• 1. Not at all
• 2. Somewhat
• 3. Moderately 4. Quite a bit

P<0.002

VAS score associated linearly with fibrosis, p =0.013

Results: Responders vs Nonresponders

Nonresponders = 8 Responders = 9 5 exposure 4 pain 4 exposure 4 pain P>0.9 Nonresponders = 8 Responders = 9 5 prolapse 4 sling 4 prolapse P>0.9 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/m2) 28.2 (26.2-31.6) 29.6 (23.5-32.4) 0.96 Duration implantation (months) 22.0 (10.5-61.3) 55.5(35.0-58.9) 0.17 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,

• r fibrosis level, but a trend toward lower duration of implantation

Results: Responders vs Nonresponders

Responders (n=9) Nonresponders (n=8) P value Treg concentration (cells/mm2) 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 Treg/CD8+ ratio (Treg /100 CD8+) 2.7 (1.1-7.3) 1.1 (0.1-1.8) 0.07 TGF-b1 (pg/μg protein) 6.6 (5.7-10.2) 12.8 (10.0-13.3) 0.032 Treg concentration predicted responder status Patients were 1.6 times as likely to be a responder for every additional Treg/mm2, (P=0.05)

Conclusions

§ Fibrosis is a plausible mechanism of pain complications § Responder rates not different by complication type or mesh type § Lower TGFb1 levels and higher concentrations of Tregs 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

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

Acknowledgements