Mechanisms of T cell-induced glomerular injury in anti-glomeruler basement membrane (GBM) glomerulonephritis in rats

Abstract

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.

Lymphocytes are dispensable for glomerulonephritis but required for renal interstitial fibrosis in matrix defect-induced Alport renal disease

“…[5][6][7][8][9][11][12][13] In contrast, our study demonstrates that T-cell depletion in our mouse model of progressive glomerular nephropathy does not impact the emergence of glomerulonephritis. The cellular composition of glomerular crescents in the a3KO mouse model does not appear to contain CD3 þ and CD19 þ lymphocytes, but is rather composed of proliferating visceral and parietal glomerular epithelial cells, and possibly macrophages, although their identification in glomerular crescents is challenging.…”

“…In these models, the mechanisms for glomerulonephritis implicates a CD3 þ T cell-driven Th1-type responses with delayed-type hypersensitivity. [5][6][7][8][9][10][11][12][13] In contrast, Ophascharoensuk et al 14 report that in their model of murine nephritis, proliferating glomerular epithelial cells are the main cellular components of the crescent, with early crescents devoid of macrophages and T cells. Furthermore, a growing body of evidence has suggested that parietal epithelial cells are involved in crescent formation, with transdifferentiation of parietal epithelial cells and acquisition of new epitopes, shared by macrophages.…”

Hydrodynamics-based delivery of the viral interleukin-10 gene suppresses experimental crescentic glomerulonephritis in Wistar–Kyoto rats

“…Many investigators have performed various treatments to reduce these factors in experimental crescentic GN. 5,[37][38][39] The administration of micro-encapsulated clodronate (dichloromethylene bisphosphonate) for macrophage depletion, 37 monoclonal antibodies against CD4, 37 IFNg, 5 and MCP-1, 38 and the soluble TNF receptor p55, 39 prevent glomerular macrophage infiltration, crescent formation, and proteinuria. In the present study, continuous high-level vIL-10 delivery by hydrodynamicsbased transfection suppressed these factors simultaneously.…”

T Cells in Crescentic Glomerulonephritis

“…Experimental studies have focused extensively on the role of CD4 ϩ T cells (1)(2)(3)(4)(5)(6)(7)(8) and to a lesser extent on CD8 ϩ T cells (2,9 -11). More recently, the potential role of regulatory T cells (Treg) has been demonstrated (12-14) and the contributions of T cell subsets that express ␣/␤ T cell receptors (TCR) and ␥/␦ TCR (15-18) to the development of GN have been explored (Table 1).…”