Cell Biology – Immunology – Pathology
Kidney International (2001) 59, 975–984; doi:10.1046/j.1523-1755.2001.059003975.x
Depletion of CD4+ T cells aggravates glomerular and interstitial injury in murine adriamycin nephropathy
Yiping Wang, Yang Wang, Ximin Feng, Shisan Bao, Shounan Yi, Lukas Kairaitis, Yuet-Ching Tay, Gopala K Rangan and David C H Harris
Department of Renal Medicine, Department of Medicine, The University of Sydney at Westmead Hospital, Westmead, and Department of Veterinary Anatomy and Pathology, The University of Sydney, Sydney, New South Wales, Australia
Correspondence: Yiping Wang, Ph.D., Department of Renal Medicine, Westmead Hospital, Westmead NSW 2145, Australia. E-mail: yipingw@renal.wsahs.nsw.gov.au
Received 10 March 2000; Revised 13 September 2000; Accepted 27 September 2000.
Abstract
Depletion of CD4+ T cells aggravates glomerular and interstitial injury in murine adriamycin nephropathy.
Background
CD4+ T cells play an important role in various types of immunologic renal disease, including lupus nephritis, IgA nephropathy, and crescentic glomerulonephritis. CD4+ T cells are also major infiltrating lymphocytes in chronic tubulointerstitial inflammation associated with nonimmunological renal diseases. We suspected that CD4+ T cells might contribute to disease progression and loss of renal function in chronic proteinuric renal disease (CPRD). To investigate this possibility, the effect of monoclonal antibody against CD4+ lymphocytes (anti-CD4) was studied in a murine model (adriamycin nephropathy) of CPRD.
Methods
Adriamycin nephropathy was produced in male BALB/c mice by a single intravenous injection of adriamycin (11 mg/kg). Anti-CD4 was given by intraperitoneal injection following the development of proteinuria at days 5, 6, 7, 21, and 37 after adriamycin. After six weeks, renal function and histology were studied by histomorphometry, immunohistochemistry, and flow cytometry.
Results
Flow cytometric analysis showed a marked decrease in the number of CD4+ T cells in blood and spleen of the antibody-treated animals (N = 7, P < 0.01). Adriamycin plus CD4+ depletion mice had significantly greater mesangial expansion, glomerular sclerosis, and interstitial expansion than the mice on adriamycin alone. Interstitial infiltration with macrophages and CD8+ cells was significantly increased in adriamycin plus CD4+ depletion mice. Creatinine clearance (17.5 
0.54 vs. 29.2 0.89 
L/min, P < 0.001) was significantly worse in the adriamycin plus CD4+ depletion mice than in adriamycin alone mice and correlated with histologic change in glomeruli and interstitium.
Conclusions
Depletion of CD4+ T cells promotes glomerular and interstitial injury in mice with established adriamycin nephropathy. These findings suggest that CD4+ T cells have a protective role against the progression of adriamycin nephropathy.
Keywords:
progressive renal disease, chronic proteinuric renal disease, proteinuria, kidney dysfunction, tubulointerstitial injury, fibrosis, inflammatory interstitial nephritis
Abbreviations:
ADR, adriamycin; antiCD4, antibody against CD4+ lymphocytes; CCr, creatinine clearance; CPRD, chronic proteinuric renal disease; EDTA, ethylenediaminetetraacetic acid; FACS, fluorescence-activated cell sorter; GBM, glomerular basement membrane; ICAM, intracellular adhesion molecule; IFN-
, interferon-; IL, interleukin; MCP-1, monocyte chemoattractant protein-1; RT, room temperature; RT-PCR, reverse transcription-polymerase chain reaction; SCID, severe combined immunodeficient (mouse strain); VCAM, vascular cellular adhesion molecule
