Macrophage colony-stimulating factor expression and macrophage accumulation in renal allograft rejection.
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.
Le Meur
Yannick
Y
Department of Nephrology, Monash Medical Centre, Clayton, Victoria, Australia.
Jose
Matthew D
MD
Mu
Wei
W
Atkins
Robert C
RC
Chadban
Steven J
SJ
D000818:Animals; D002455:Cell Division; D016572:Cyclosporine / Q000627:therapeutic use; D005786:Gene Expression Regulation / Q000502:physiology; D006084:Graft Rejection / Q000276:immunology / Q000473:pathology / Q000503:physiopathology*; D006085:Graft Survival / Q000502:physiology; D007166:Immunosuppressive Agents / Q000627:therapeutic use; D016030:Kidney Transplantation / Q000276:immunology / Q000473:pathology / Q000502:physiology*; D016173:Macrophage Colony-Stimulating Factor / Q000235:genetics*; D008264:Macrophages / Q000276:immunology / Q000473:pathology / Q000502:physiology*; D008297:Male; D009392:Nephrectomy; D051381:Rats; D011917:Rats, Inbred Lew; D011919:Rats, Inbred Strains; D013601:T-Lymphocytes / Q000276:immunology; D014158:Transcription, Genetic; D014184:Transplantation, Homologous; D014185:Transplantation, Isogeneic
D007166:Immunosuppressive Agents; D016173:Macrophage Colony-Stimulating Factor; D016572:Cyclosporine