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Macrophage colony-stimulating factor expression and macrophage accumulation in renal allograft rejection

Citation

Le Meur, Y and Jose, MD and Mu, W and Atkins, RC and Chadban, SJ, Macrophage colony-stimulating factor expression and macrophage accumulation in renal allograft rejection, Transplantation, 73, (8) pp. 1318-1324. ISSN 0041-1337 (2002) [Refereed Article]

Copyright Statement

Copyright 2002 Lippincott Williams & Wilkins

DOI: doi:10.1097/00007890-200204270-00022

Abstract

BACKGROUND: Studies of infiltrating cells from acutely rejecting renal allografts show that a high proportion of these cells are macrophages, and early macrophage infiltration is a poor prognostic sign for transplant survival. Macrophage colony-stimulating factor (M-CSF), produced by tubular and mesangial cells, has been associated with macrophage infiltration and proliferation in experimental and human kidney diseases. We investigated the expression of M-CSF in a model of acute rejection.

METHODS: Lewis rats underwent bilateral nephrectomies and received an orthotopic Dark Agouti allograft or Lewis isograft. Animals received cyclosporine (10 mg/kg/day) from day 0 to day 3 and were killed at days 4, 8, or 14 after transplantation. Macrophages (ED1+) and T cells (W3-13+) were identified by immunohistochemistry, and M-CSF expression was identified by Northern blotting and in situ hybridization.

RESULTS: Isografts had normal renal function without histological evidence of rejection. Allografts exhibited a moderate infiltrate at day 4 but progressed to severe rejection at day 14, with elevated serum creatinine level and severe tubulointerstitial damage. Macrophages and T cells were present in equal proportion in the infiltrate at day 4. At day 14, the number of macrophages increased fivefold (2580/mm2), although T cells were unchanged (380/mm2). Proliferating macrophages (ED1+, BrdU+) increased from day 4 (4%) to day 14 (10%). M-CSF mRNA expression was strongly up-regulated in allografts compared with isografts and normal rat. In situ hybridization demonstrated M-CSF expression by resident and infiltrating cells. Renal tubular expression was minimally increased at day 4 but strongly up-regulated at day 14 (more than 50% of tubules positive), particularly in areas of tubular damage. Tubular M-CSF expression colocalized with areas of intense macrophage infiltration and proliferation. Serial sections with double labeling demonstrated that T cells were the dominant source of M-CSF at day 4, yet later in the rejection (day 14) the predominant sites of production were both renal tubular cells and interstitial macrophages.

CONCLUSIONS: Renal production of M-CSF by graft-infiltrating (macrophages and T lymphocytes) and resident (tubular) cells was up-regulated during acute rejection. M-CSF promotes macrophage recruitment and proliferation and may thereby play a pathogenic role in acute rejection. The kinetics of M-CSF production during acute rejection suggest that local macrophage proliferation may be initiated by T cells and perpetuated by both renal tubular and autocrine release.

Item Details

Item Type:Refereed Article
Keywords:allograft rejection
Research Division:Medical and Health Sciences
Research Group:Clinical Sciences
Research Field:Nephrology and Urology
Objective Division:Health
Objective Group:Clinical Health (Organs, Diseases and Abnormal Conditions)
Objective Field:Urogenital System and Disorders
Author:Jose, MD (Professor Matthew Jose)
ID Code:90569
Year Published:2002
Web of Science® Times Cited:33
Deposited By:Medicine (Discipline)
Deposited On:2014-04-10
Last Modified:2016-12-15
Downloads:0

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