SUMMARYThe effector mechanisms of T cell-dependent acute glomerular injury were studied in autologous phase anti-GBM glomerulonephritis (GN) in rats. Acute proliferative GN was induced in sensitized rats by a subnephritogenic dose of sheep anti-rat GBM antibody. Injury was manifested by proteinuria and glomerular leucocyte infiltration composed predominantly of macrophages but also CD4 þ and CD8 þ T cells. T cell depletion, using an anti-CD5 MoAb, demonstrated that glomerular leucocyte infiltration and proteinuria were T cell-dependent. Inhibition of T helper cell function using an anti-CD4 MoAb prevented proteinuria and glomerular macrophage and CD4 þ T cell influx, but not accumulation of CD8 þ T cells. Depletion of CD8 þ T cells also prevented proteinuria and the influx of macrophages and CD8 þ T cells, but not accumulation of CD4 þ T cells. Macrophage depletion, using micro-encapsulated clodronate, prevented proteinuria and glomerular macrophage infiltration, but not the accumulation of CD4 þ or CD8 þ T cells, indicating that macrophages are the common cellular effectors for both CD4 and CD8 T cell-dependent injury. Evidence for cytotoxic mechanisms of injury (increased numbers of apoptotic cells or accumulation of natural killer (NK) cells in glomeruli) could not be demonstrated. These data suggest that acute glomerular injury in anti-GBM GN is the result of macrophage recruitment, which is dependent on both CD4 and CD8 T cells, and that direct T cell-mediated injury (cellular cytotoxicity) is not involved.
SUMMARY: The role of T cells in directing macrophage recruitment and proliferation and giant cell formation was studied in crescentic glomerulonephritis (GN) in rats. Development of GN was associated with a significant glomerular influx of T cells and macrophages and crescent formation. Multi‐nucleated giant cells (MGCs) were also prominent in glomeruli and most frequently associated with crescents. Their phenotype suggested that they were derived from recently recruited blood monocytes. the majority of glomerular macrophages and MGCs showed evidence of recent proliferation. T cell depletion using anti‐CD5 or anti‐CD4 monoclonal antibodies significantly reduced T cells and macrophage accumulation, crescent formation (anti‐CD5 treated 12 ± 4.0%; anti‐CD4 treated 13 ± 3.0%; control 64 ± 10%; P<0.001) and MGC formation [anti‐CD5 treated 0.06 ± 0.01 cells per glomerular cross section (c/gcs); anti‐CD4 treated 0.06 ± 0.01 c/gcs; control treated 1.2 ± 0.1 c/gcs; P<0.001]. the proliferation index (fraction of cells expressing proliferating cell nuclear antigen) of macrophages and MGCs was not affected by T cell depletion (macrophage proliferation index: anti‐CD5 treated 0.88 ± 0.04; anti‐CD4 treated 0.83 ± 0.02; control 0.85 ± 0.02; MGC proliferation index: anti‐CD5 treated 0.84 ± 0.06; anti‐CD4 treated 0.86 ± 0.04; control 0.90 ± 0.05). These studies demonstrate that glomerular macrophage recruitment, MGC and crescent formation are dependent on T helper cells but proliferation of macrophages and MGCs is independent of T cells. This suggests that the major mechanism for T cell induced macrophage accumulation in crescentic GN is via directing their recruitment rather than their local proliferation. Giant cell formation, which is also predominantly T cell dependent, appears to be independent of their proliferative activity.
The ability of interleukin-10 (IL-10) to inhibit macrophage recruitment, activation, and proliferation in vivo was studied in a macrophage-mediated, but T cell-independent, passive anti-glomerular basement membrane antibody-induced model of glomerulonephritis (GN) in rats. Treatment with recombinant murine IL-10 resulted in dose-dependent reductions in proteinuria (high dose: 16 ± 1 mg/24 h; low dose: 30 ± 2 mg/24 h; control treatment: 69 ± 6 mg/24 h; normal: 7 ± 1 mg/24 h) and glomerular macrophage recruitment (high dose: 1.8 ± 0.1 macrophages per glomerular cross section [c/gcs]; low dose: 5.5 ± 0.2 c/gcs; control treatment: 12.1 ± 0.6 c/gcs). Macrophage and intrinsic glomerular cell proliferation were reduced at both doses of IL-10, as was glomerular expression of P-selectin and monocyte chemoattractant protein-1. IL-10 treatment also resulted in a dose-dependent reduction of macrophage activation as indicated by MHC class II and IL-1β expression. Glomerular nitrite production by isolated cultured glomeruli was reduced after IL-10 treatment in vivo (high dose: 2.3 ± 2.3 nmol/104 glomeruli per 72 h; low dose: 28 ± 5 nmol/104 glomeruli per 72 h; control treatment: 82 ± 11 nmol/104 glomeruli per 72 h). Tumor necrosis factor-α production was abolished by high-dose treatment and reduced by the lower dose (3.8 ± 3.8 pg/104 glomeruli per 72 h; control treatment: 249 ± 23 pg/104 glomeruli per 72 h). These studies demonstrate that IL-10 directly attenuates glomerular macrophage recruitment, activation, and proliferation in vivo and can significantly attenuate macrophage-mediated GN independent of any effects on T cells.
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