Evidence for delayed-type hypersensitivity mechanisms in glomerular crescent formation

Abstract

The role of CD4-positive T cells in glomerular crescent formation was examined in WKY rats. Glomerulonephritis (GN) was induced by a subnephritogenic intravenous dose of sheep anti-rat GBM antibody in rats previously sensitized to sheep globulin. This resulted in a severe proliferative and crescentic GN, with marked proteinuria [143 ± 40 mg/24 hr (mean ± SD), normal 1.6 ± 0.7 mg/24 hr] and crescent formation involving 59 ± 8% of glomeruli at day 10 (normal 0%). Humoral immunity to sheep globulin was evident systemically by high titers of circulating anti-sheep globulin and locally by linear deposition of rat immunoglobulin in glomeruli and cell mediated immunity by cutaneous delayed-type hypersensitivity (DTH) to intradermal injection of sheep globulin. Glomerular accumulation of CD5 positive T cells [2.45 ± 0.21 cells per glomerular cross section (c/gcs), normal 0.18 ± 0.10 c/gcs], CD4 positive T cells, (1.87 ± 0.46 c/gcs, normal 0.14 ± 0.08 c/gcs), and macrophages (22.7 ± 5.9 c/gcs, normal 0.05 ± 0.05 c/gcs), together with the appearance of multinucleated giant cells (0.42 ± 0.15 c/gcs, normal 0 c/gcs) suggested a DTH-like reaction in glomeruli. Sensitized rats given anti-GBM globulin were treated with monoclonal anti-CD5 or anti-CD4 antibodies in a protocol which prevented cutaneous DTH to sheep globulin without altering the humoral immune response. Both treatments significantly reduced glomerular accumulation of CD5 and CD4 positive T cells at day 10. Crescent formation was significantly reduced (CD5 treated, 13 ± 4% of glomeruli affected; P < 0.001; CD4 treated 13 ± 3% of glomeruli affected, P < 0.001) compared to rats treated with an isotype-matched irrelevant monoclonal antibody. Glomerular macrophage accumulation, multinucleated giant cell formation and proteinuria were also significantly reduced by both treatments. These studies demonstrate a functional role for CD4 positive T cells as effector cells within glomeruli, separate from their role in humoral immunity, in the development of crescentic GN. The local participation of CD4 positive T cells, macrophages and multinucleated giant cells in crescent formation, and the attenuation of these features by functional T helper cell depletion suggest that local DTH-like mechanisms may contribute to glomerular crescent formation.