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Macrophage colony-stimulating factor expression and macrophage accumulation in renal allograft rejection
Yannick Le Meur1, Matthew D Jose, Wei Mu
1Department of Nephrology, Monash Medical Centre, Clayton, Victoria, Australia.
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.
Insights
Acute kidney transplant rejection involves macrophages, whose proliferation is driven by macrophage colony-stimulating factor (M-CSF). This study shows M-CSF is upregulated during rejection, suggesting a pathogenic role in transplant survival.
Area of Science:
- Nephrology
- Immunology
- Transplantation Biology
Background:
- Acute renal allograft rejection is characterized by significant macrophage infiltration, correlating with poor transplant survival.
- Macrophage colony-stimulating factor (M-CSF) is implicated in macrophage recruitment and proliferation in kidney diseases.
Purpose of the Study:
- To investigate the expression and role of M-CSF in a rat model of acute renal allograft rejection.
Main Methods:
- Lewis rats received Dark Agouti allografts or Lewis isografts, with or without cyclosporine.
- Immunohistochemistry, Northern blotting, and in situ hybridization were used to identify macrophages, T cells, and M-CSF expression.
Main Results:
- Allografts showed progressive rejection with increased macrophages and tubulointerstitial damage.
- M-CSF mRNA expression was significantly upregulated in allografts, particularly in damaged tubules and infiltrating macrophages.
- M-CSF production originated from T cells early in rejection and later from tubular cells and macrophages.
Conclusions:
- Renal M-CSF production increases during acute rejection, produced by both infiltrating immune cells and resident renal cells.
- M-CSF likely plays a pathogenic role by promoting macrophage infiltration and proliferation, contributing to acute rejection.
- T cells may initiate macrophage proliferation, which is then sustained by M-CSF from tubular and macrophage sources.