Kidney dendritic cell activation is required for progression of renal disease in a mouse model of glomerular injury
Felix Heymann, … , Hermann-Josef Gröne, Christian Kurts
Felix Heymann, … , Hermann-Josef Gröne, Christian Kurts
Published April 20, 2009
Citation Information: J Clin Invest. 2009;119(5):1286-1297. https://doi.org/10.1172/JCI38399.
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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 3

Histological analysis of periglomerular infiltrates in NOH mice.

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Histological analysis of periglomerular infiltrates in NOH mice. (A–C) P...
(A–C) PAS staining (A and B) or electron microscopy analysis (C) of kidney sections of NOH mice injected with 5 × 106 OT-I cells and 5 × 106 activated OT-II cells 7 days before analysis. Note in C multiple contacts of podocytes with parietal epithelia separated by a very thin membrane from the periglomerular infiltrate. C, capillary; E, erythrocyte; M, mesangium; MnC, mononuclear cell; P, podocyte; PE, parietal epithelium; pgs, periglomerular space; asterisk, capsule membrane. Original magnification, ×3,000. Scale bar: 10 μm. (D–I) Representative immunohistochemistry for expression of CD8 (D), CD4 (E), CD11c (F), CD11b (G), MHC II (I-Ab) (H), and CD86 (I). (J) The frequency of glomeruli surrounded by mononuclear infiltrates was determined in HE-stained kidney sections of NOH or non-Tg mice injected with OT-I and/or activated OT-II cells as indicated. Shown are data from a group of mice that repetitively received T cell injections on days 7, 14, and 21. That group was analyzed on day 28 (histology in Figure 8). (K) Affected glomeruli were scored for the severity of periglomerular infiltrates. Results are representative of 4 experiments in groups of 3–5 mice. (L) Quantitative analysis of 2 of these experiments, an example of which was given in Supplemental Figure 7. In J–L, symbols indicate results from individual mice and the bars their mean. *P < 0.05; **P < 0.01; ***P < 0.001.