Cell Biology – Immunology – Pathology

Kidney International (2004) 65, 1280–1289; doi:10.1111/j.1523-1755.2004.00536.x

Suppression of experimental crescentic glomerulonephritis by interleukin-10 gene transfer

ADEL GA EL-SHEMI, HIDEHIKO FUJINAKA, ASAKO MATSUKI, JUNICHI KAMIIE, PAVEL KOVALENKO, ZHENYUN QU, VLADIMIR BILIM, GORO NISHIMOTO, EISHIN YAOITA, YUATKA YOSHIDA, IGNACIO ANEGON and TADASHI YAMAMOTO

Department of Structural Pathology, Institute of Nephrology, Graduate School of Medical and Dental Sciences, Niigata University, Niigata, Japan; and INSERM U437, Laboratoire de Therapie Genique, Nantes, France

Correspondence: Tadashi Yamamoto, M.D., Ph.D., Department of Structural Pathology, Institute of Nephrology, Niigata University Graduate School of Medical and Dental Sciences, 1–757, Asahimachi-dori, Niigata 951–8510, Japan. E-mail: tdsymmt@med.niigata-u.ac.jp

Received 2 July 2003; Revised 2 October 2003; Accepted 21 November 2003.

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Abstract

Suppression of experimental crescentic glomerulonephritis by interleukin-10 gene transfer.

Background

 

Investigated were effects of overexpression of interleukin-10 (IL-10) on the outcome and progression of crescentic glomerulonephritis in Wistar-Kyoto (WKY) rats.

Methods

 

Rats were singly or simultaneously injected with antiglomerular basement membrane (a-GBM) antibody and adenoviral vector encoding rat IL-10 (Ad-rIL-10) or LacZ (Ad-LacZ) (3 times 1010 pfu/rat) intravenously, and were sacrificed at day 7. Their kidneys and other organs were isolated and examined by histology and immunohistochemistry. The In vivo expression of IL-10 mRNA in the liver of Ad-rIL-10–injected rats was confirmed by both reverse transcription-polymerase chain reaction (RT-PCR) and ribonuclease protection assay analysis and its translated protein was measured in the serum by enzyme-linked immunosorbent assay (ELISA).

Results

 

The exogenous IL-10 mRNA was strongly expressed in the liver in a dose-dependent manner and was intense at days 4 and 7 but was less intense at day 14. Ad-rIL-10 treatment significantly reduced the incidence of glomerular crescent formation from 67%plusminus 1.9% in a-GBM antibody–treated group or 69.8%plusminus 1.9% in a-GBM antibody + Ad-LacZ–treated group to 21.6%plusminus 1.8% (P < 0.001), the glomerular infiltration of macrophages from 35.7 plusminus 6.3 cell s/gcs (a-GBM antibody) or 37.6 plusminus 8.6 cells/gcs (both a-GBM antibody + Ad-LacZ) to 17.9 plusminus 5.5 cells/gcs (P < 0.001), that of major histocompatibility complex (MHC) class II–positive cells from 14.4 plusminus 5.3 cells/gcs (a-GBM antibody) or 15 plusminus 4.6 cells/gcs (a-GBM antibody + Ad-LacZ) to 5.7 plusminus 2.3 cells/gcs (P < 0.0001) at day 7, the glomerular and immune tissue expression of IL-1beta mRNA, as well as the proteinuria from 159.0 plusminus 22.7 mg/24 hours (a-GBM antibody) or 166 plusminus 28 mg/24 hours (a-GBM antibody + Ad-LacZ) to 42.2 plusminus 35.2 mg/24 hours (P < 0.01) at day 7. The serum creatinine and blood urea nitrogen levels were also reduced from 2.8 plusminus 0.1 mg/dL (a-GBM antibody) or 2.8 plusminus 0.1 mg/dL (a-GBM antibody + Ad-LacZ) to 1.0 plusminus 0.1 mg/dL (P < 0.001) and from 63.2 plusminus 8.9 mg/dL (a-GBM antibody) or 61.3 plusminus 5.2 mg/dL (a-GBM antibody + Ad-LacZ) to 27.0 plusminus 4.5 mg/dL (P < 0.001), respectively. However, the glomerular accumulation of CD8+ T cells was unaffected: 5.4 plusminus 1.1 cells/gcs (a-GBM antibody + Ad-rIL-10), 5.9 plusminus 1.5 cells/gcs (a-GBM antibody), and 5.8 plusminus 1.1 cells/gcs (a-GBM antibody + Ad-LacZ) (P = NS).

Conclusion

 

IL-10 gene transfer significantly attenuated the glomerular lesions and injury in the anti-GBM crescentic glomerulonephritis of WKY rats.

Keywords:

inteleukin-10, gene transfer, a-GBM glomerulonephritis, macrophage, CD8+ T cells, interleukin-1beta

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