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Abstract: PO2050

Prolonged IL-6 Secretion Activates Inflammation Amplifier Loop (IL-6+IL-17) in Fibroblast Derived from Chronic Antibody-Mediated Rejection in Renal Allograft Recipient

Session Information

Category: Transplantation

  • 1901 Transplantation: Basic

Authors

  • Singh, Mantabya K., Sanjay Gandhi Post Graduate Institute of Medical Sciences, Lucknow, Uttar Pradesh, India
  • Prasad, Narayan, Sanjay Gandhi Post Graduate Institute of Medical Sciences, Lucknow, Uttar Pradesh, India
  • Agarwal, Vikas, Sanjay Gandhi Post Graduate Institute of Medical Sciences, Lucknow, Uttar Pradesh, India
Background

Recently, non-immune cells like fibroblast have been postulated to mediate allograft rejection via activation of the IL-6 amplifier loop. We evaluated IL-6 amplifier loop activation by IL-6 and Il-17 in chronic antibody mediated rejection (CABMR).

Methods

Fibroblasts from grafted kidneys from CABMR patients (n=6) were cultured, stimulated with IL-6 (20ng/ µl), IL-17(50ng/ µl), IL-6 plus IL-17 for 24 hours. Levels of IL-6, MCP-1, and CCL20 were estimated in culture supernatants by ELISA as markers of IL-6 amplifier loop activation mRNA expression of IL-6, MCP1, CCL20, SOCS3 genes were measured in the stimulated fibroblasts. Additionally, IL-6, MCP1, and CCL20 levels were measured in Healthy control (n=10) CABMR (n=20) and non-CABMR (n=30) patients.

Results

IL-6 and IL-17 synergistically induced more IL-6, CCL-20 & MCP-1 production from fibroblasts. Fig1 Gene expression analysis of IL-6, MCP1, and CCL20 was significantly higher with synergistic activation of IL-6 and IL-17 as compared to either IL-6 or IL-17 alone, while SOCS3 gene expression was downregulated. Fig 3. Additionally, concentrations of IL-6, CCL-20 & MCP-1 in sera were significantly higher in CABMR patients compared to non-rejection patients (p<0.001). Fig 2. There was a significant reduction in IL-6 concentration in culture supernatant with IL-6 and IL-17 inhibitor together Fig 4 and mRNA expression of IL-6 and MCP-1 was significantly reduced. Fig 5.

Conclusion

CABMR is perpetuated by inflammation amplifier loop or synergistic induction of IL-6 and IL-17. Inhibition of IL-6 with Anti-IL-6 (Tocilizumab) and IL-17 with Anti-IL-17 together reduces the tissue injury marker IL-6, MCP1, CCL20 and allograft rejection.