Endogenous Tim-1 (Kim-1) promotes T-cell responses and cell-mediated injury in experimental crescentic glomerulonephritis.
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.
Centre for Inflammatory Diseases, Monash University Department of Medicine, Monash Medical Centre, Clayton, Victoria, Australia.
Yuji
Y
Nozaki
David J
DJ
Nikolic-Paterson
Sarah L
SL
Snelgrove
Hisaya
H
Akiba
Hideo
H
Yagita
Stephen R
SR
Holdsworth
A Richard
AR
Kitching
D000818:Animals; D000911:Antibodies, Monoclonal / Q000008:administration & dosage; D017209:Apoptosis; D001323:Autoantibodies; D015496:CD4-Positive T-Lymphocytes / Q000276:immunology / Q000378:metabolism* / Q000473:pathology; D049109:Cell Proliferation; D004195:Disease Models, Animal; D051858:Forkhead Transcription Factors / Q000378:metabolism; D005921:Glomerulonephritis / Q000235:genetics / Q000276:immunology / Q000378:metabolism* / Q000473:pathology / Q000517:prevention & control; D000072596:Hepatitis A Virus Cellular Receptor 1; D007111:Immunity, Cellular; D018836:Inflammation Mediators / Q000378:metabolism; D007275:Injections, Intravenous; D016753:Interleukin-10 / Q000235:genetics / Q000378:metabolism; D007668:Kidney / Q000276:immunology / Q000378:metabolism* / Q000473:pathology; D008213:Lymphocyte Activation; D008297:Male; D008565:Membrane Proteins / Q000037:antagonists & inhibitors / Q000235:genetics / Q000276:immunology / Q000378:metabolism* / Q000652:urine; D051379:Mice; D008810:Mice, Inbred C57BL; D012333:RNA, Messenger / Q000378:metabolism; D012756:Sheep; D015398:Signal Transduction; D018417:Th1 Cells / Q000276:immunology / Q000378:metabolism; D058504:Th17 Cells / Q000276:immunology / Q000378:metabolism; D018418:Th2 Cells / Q000276:immunology / Q000378:metabolism; D013997:Time Factors
D000911:Antibodies, Monoclonal; D001323:Autoantibodies; D051858:Forkhead Transcription Factors; C498833:Foxp3 protein, mouse; C442240:Havcr1 protein, mouse; D000072596:Hepatitis A Virus Cellular Receptor 1; D018836:Inflammation Mediators; D008565:Membrane Proteins; D012333:RNA, Messenger; C051951:antiglomerular basement membrane antibody; D016753:Interleukin-10