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Interleukin‐18 Affects Local Cytokine Expression But Does Not Impact on the Development of Kidney Allograft Rejection
Author(s) -
Wyburn K.,
Wu H.,
Chen G.,
Yin J.,
Eris J.,
Chadban S.
Publication year - 2006
Publication title -
american journal of transplantation
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 2.89
H-Index - 188
eISSN - 1600-6143
pISSN - 1600-6135
DOI - 10.1111/j.1600-6143.2006.01536.x
Subject(s) - medicine , elispot , immunology , kidney , inflammation , cytokine , interleukin 18 , downregulation and upregulation , kidney transplantation , interleukin , interleukin 10 , t cell , immune system , biology , endocrinology , gene , biochemistry
Interleukin‐18 is predominantly a macrophage‐derived cytokine with a key role in inflammation and cell‐mediated immunity. Having previously demonstrated IL‐18 upregulation in a rat model of kidney rejection, here we examined IL‐18 in a fully MHC‐mismatched murine model of acute kidney rejection using IL‐18‐deficient recipients (IL‐18 −/− ) and animals administered neutralizing IL‐18 binding protein (IL‐18BP). Gene expression of IL‐18 and its receptor were significantly upregulated in allografts compared to isografts, as was the cellular infiltrate (T cells and macrophages) (p < 0.001). Allografts developed kidney dysfunction (p < 0.05) and tubulitis (p < 0.01) not observed in controls. There was a significant reduction in gene expression of IL‐18 downstream pro‐inflammatory molecules (iNOS, TNFα and IFNγ) in IL‐18 −/− recipients (p < 0.01), and IL‐18BP‐treated animals. The CD4 + infiltrate and IL‐4 mRNA expression was greater in the IL‐18 −/− recipients than wild‐type (WT) allografts and IL‐18BP‐treated animals (p < 0.05), suggesting a Th2‐bias which was supported by IFNγ and IL‐4 ELISPOT data and an increased eosinophil accumulation (p < 0.001). Neither IL‐18 deficiency nor neutralization prevented renal dysfunction or tubulitis. This study demonstrates increased production of IL‐18 in murine kidney allograft rejection and provides evidence that IL‐18‐induced pathways of inflammation are active. However, neither IL‐18 deficiency nor neutralization was protective against the development of allograft rejection.