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Abstract: FR-OR125

Protective Role of Kynurenine 3-Monooxygenase in Kidney Allograft Rejection

Session Information

Category: Transplantation

  • 1901 Transplantation: Basic

Authors

  • Wang, Youli, Augusta University, Augusta, Georgia, United States
  • Harner, Andrew, Augusta University, Augusta, Georgia, United States
  • Fang, Xuexiu, Augusta University, Augusta, Georgia, United States
  • Merchen, Todd D., Augusta University, Augusta, Georgia, United States
  • Ho, Chak-Sum, Gift of Hope Organ & Tissue Donor Network, Itasca, Illinois, United States
  • Kleven, Daniel T., Augusta University, Augusta, Georgia, United States
  • Thompson, Thomas Z., Augusta University, Augusta, Georgia, United States
  • Nahman, N. Stanley, Augusta University, Augusta, Georgia, United States

Group or Team Name

  • Augusta University, Augusta, GA
Background

Rejection of a transplanted kidney is a complex adaptive immune response and is the primary driver of graft loss. Kynurenine 3-monooxygenase (KMO) is an oxidoreductase involved in the kynurenine pathway of tryptophan metabolism and has been associated with inhibition of T cell proliferation. Our previous study demonstrated that indoleamine 2,3-dioxygenase (IDO) was upregulated in rejecting allografts, and was associated with reduced KMO expression. Herein, we investigated the role of KMO in preventing rejection in a pig model of kidney transplantation, and in protecting renal cortical epithelial cells (RCEC) following exposure to cytokines common to inflammation.

Methods

Outbred Yorkshire pigs underwent mismatched kidney transplants as we have described (Transplant Immunol 42:40). No immunosuppression was used and the tissue was studied 72 hours post-transplant. Immunohistochemistry (IHC) was performed to measure allograft expression of KMO. Cultured RCEC were utilized measure KMO, IDO, and the epithelial-mesenchymal transition markers E-cadherin and tight junction protein 1 (TJP1), following cytokine activation with and without treatment with the product of KMO, 3-hydroxykynurenine (3HK, 20mg/ml).

Results

RCEC-specific KMO staining was down-regulated by approximately 10-fold in rejecting allografts when compared to normal kidney. Following cytokine activation of RCEC, KMO was silenced, and the expression of E-cadherin and TJP1 was blunted. The addition of 3HK completely restored E-cadherin and TJP1 expression. In additional studies, we showed that high dose 3HK (100ug/ml) effectively inhibits human peripheral blood pan-T cell prolifereation.

Conclusion

KMO may be a key modulator of allograft immune responses as suggested by its downregulation in rejecting allografts. Moreover, KMO, through the generation of 3HK, may exert cytoprotective effects through preservation of normal renal parenchymal architecture, by retained expression of E-cadherin and TJP1 and inhibition of T cell proliferation. Inducing KMO, with the generation of 3HK in renal allografts, may provide an avenue for novel therapies in renal transplantation.

Funding

  • Private Foundation Support