Endogenous Tim-1 (Kim-1) promotes T-cell responses and cell-mediated injury in experimental crescentic glomerulonephritis

Yuji Nozaki, David Nikolic-Paterson, Sarah Snelgrove, Hisaya Akiba, Hideo Yagita, Stephen Holdsworth, Arthur Kitching

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26 Citations (Scopus)

Abstract

The T-cell immunoglobulin mucin 1 (Tim-1) modulates CD4(+) T-cell responses and is also expressed by damaged proximal tubules in the kidney where it is known as kidney injury molecule-1 (Kim-1). We sought to define the role of endogenous Tim-1 in experimental T-cell-mediated glomerulonephritis induced by sheep anti-mouse glomerular basement membrane globulin acting as a planted foreign antigen. Tim-1 is expressed by infiltrating activated CD4(+) cells in this model, and we studied the effects of an inhibitory anti-Tim-1 antibody (RMT1-10) on immune responses and glomerular disease. Crescentic glomerulonephritis, proliferative injury, and leukocyte accumulation were attenuated following treatment with anti-Tim-1 antibodies, but interstitial foxp3(+) cell accumulation and interleukin-10 mRNA were increased. T-cell proliferation and apoptosis decreased in the immune system along with a selective reduction in Th1 and Th17 cellular responses both in the immune system and within the kidney. The urinary excretion and renal expression of Kim-1 was reduced by anti-Tim-1 antibodies reflecting diminished interstitial injury. The effects of anti-Tim-1 antibodies were not apparent in the early phase of renal injury, when the immune response to sheep globulin was developing. Thus, endogenous Tim-1 promotes Th1 and Th17 nephritogenic immune responses and its neutralization reduces renal injury while limiting inflammation in cell-mediated glomerulonephritis.Kidney International advance online publication, 28 December 2011; doi:10.1038/ki.2011.424.
Original languageEnglish
Pages (from-to)844 - 855
Number of pages12
JournalKidney International
Volume81
Issue number9
DOIs
Publication statusPublished - 2012

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