Kidney dendritic cell activation is required for progression of renal disease in a mouse model of glomerular injury
Felix Heymann, Catherine Meyer-Schwesinger, Emma E. Hamilton-Williams, Linda Hammerich, Ulf Panzer, Sylvia Kaden, Susan E. Quaggin, Jürgen Floege, Hermann-Josef Gröne, Christian Kurts
Felix Heymann, Catherine Meyer-Schwesinger, Emma E. Hamilton-Williams, Linda Hammerich, Ulf Panzer, Sylvia Kaden, Susan E. Quaggin, Jürgen Floege, Hermann-Josef Gröne, Christian Kurts
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Research Article

Kidney dendritic cell activation is required for progression of renal disease in a mouse model of glomerular injury

Abstract

The progression of kidney disease to renal failure correlates with infiltration of mononuclear immune cells into the tubulointerstitium. These infiltrates contain macrophages, DCs, and T cells, but the role of each cell type in disease progression is unclear. To investigate the underlying immune mechanisms, we generated transgenic mice that selectively expressed the model antigens ovalbumin and hen egg lysozyme in glomerular podocytes (NOH mice). Coinjection of ovalbumin-specific transgenic CD8+ CTLs and CD4+ Th cells into NOH mice resulted in periglomerular mononuclear infiltrates and inflammation of parietal epithelial cells, similar to lesions frequently observed in human chronic glomerulonephritis. Repetitive T cell injections aggravated infiltration and caused progression to structural and functional kidney damage after 4 weeks. Mechanistic analysis revealed that DCs in renal lymph nodes constitutively cross-presented ovalbumin and activated CTLs. These CTLs released further ovalbumin for CTL activation in the lymph nodes and for simultaneous presentation to Th cells by distinct DC subsets residing in the kidney tubulointerstitium. Crosstalk between tubulointerstitial DCs and Th cells resulted in intrarenal cytokine and chemokine production and in recruitment of more CTLs, monocyte-derived DCs, and macrophages. The importance of DCs was established by the fact that DC depletion rapidly resolved established kidney immunopathology. These findings demonstrate that glomerular antigen–specific CTLs and Th cells can jointly induce renal immunopathology and identify kidney DCs as a mechanistic link between glomerular injury and the progression of kidney disease.

Authors

Felix Heymann, Catherine Meyer-Schwesinger, Emma E. Hamilton-Williams, Linda Hammerich, Ulf Panzer, Sylvia Kaden, Susan E. Quaggin, Jürgen Floege, Hermann-Josef Gröne, Christian Kurts

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Figure 8

Repetitive OT cell injection causes functional and structural kidney damage in NOH mice.

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Repetitive OT cell injection causes functional and structural kidney dam...
NOH mice were injected with 5 × 106 OT-I cells and with 5 × 106 activated OT-II cells on days 0, 7, 14, and 21. On day 7 (C and E) or day 28 (A, B, D, and F–I), kidneys were taken for PAS staining (A and B), type IV collagen staining for fibrotic areas (C and D), OVA staining (E and F; black arrows indicate OVA+ cells in Bowman capsule wall), and electron microscopy (G). White arrow, contact between podocytes and parietal cells; black arrow, podocyte foot processes. Original magnification, ×3,000. Scale bar: 10 μm. (H) Daily excretion of albumin (g/l) per creatinine (g/l) was determined in overnight urine of groups of NOH or non-Tg mice injected with nOT-I and/or activated OT-II cells. (I) 20 μl urine from mice in groups denoted by diamonds and open squares on day 7 were separated by gel electrophoresis and stained with Coomassie blue. Results are representative of 2 experiments.*P < 0.05; **P < 0.01; ***P < 0.001.