Selective CCR2-targeted macrophage depletion ameliorates experimental mesangioproliferative glomerulonephritis

L. M. McIntosh, J. L. Barnes, V. L. Barnes, J. R. McDonald

Research output: Contribution to journalArticle

17 Citations (Scopus)

Abstract

The CCL2/CCR2 chemokine/receptor axis directs the chemotaxis of infiltrating monocytes/macrophages and T cells and plays a pivotal role in tissue damage and fibrosis in kidney diseases. The eradication of the activated leucocytes should diminish the production of inflammatory mediators, limit tissue damage and ameliorate disease. A recombinant fusion protein (OPL-CCL2-LPM) comprised of the human CCL2 (monocyte chemoattractant protein-1) chemokine fused to a truncated form of the enzymatically active A1 domain of Shigella dysenteriae holotoxin (SA1) has been developed. The CCL2 portion binds specifically to CCR2-bearing leucocytes and the fusion protein enters the cells, where the SA1 moiety inhibits protein synthesis resulting in cell death. The compound was tested in a model of anti-thymocyte serum (ATS)-induced mesangioproliferative glomerulonephritis (ATS-GN). Male rats were injected with ATS on day 0 and treated intravenously with vehicle, 50 or 100 μg/kg of OPL-CCL2-LPM Q2D from days 2, 4, 6 and 8. Urine and blood were collected on days 0, 5 and 9. Animals were sacrificed on day 9. No treatment-related effects on body weight or signs of clinical toxicity were observed. Urine protein levels were decreased in treated animals. At the highest dose, histopathological analyses of kidney sections revealed maximum reductions of 36, 31, 30 and 24% for macrophage count, glomerular lesions, α-smooth muscle actin and fibronectin respectively. These results indicate a significant protective effect of OPL-CCL2-LPM in this model of nephritis.

Original languageEnglish (US)
Pages (from-to)295-303
Number of pages9
JournalClinical and Experimental Immunology
Volume155
Issue number2
DOIs
StatePublished - Feb 2009
Externally publishedYes

Fingerprint

Glomerulonephritis
Macrophages
Thymocytes
Leukocytes
CCR2 Receptors
Urine
Shigella dysenteriae
Recombinant Fusion Proteins
Proteins
Nephritis
Chemokine Receptors
Kidney Diseases
Chemotaxis
Serum
Fibronectins
Chemokines
Smooth Muscle
Actins
Monocytes
Fibrosis

Keywords

  • CCL2
  • CCR2
  • Chemokine
  • Glomerulonephritis
  • Macrophage depletion

ASJC Scopus subject areas

  • Immunology
  • Immunology and Allergy

Cite this

Selective CCR2-targeted macrophage depletion ameliorates experimental mesangioproliferative glomerulonephritis. / McIntosh, L. M.; Barnes, J. L.; Barnes, V. L.; McDonald, J. R.

In: Clinical and Experimental Immunology, Vol. 155, No. 2, 02.2009, p. 295-303.

Research output: Contribution to journalArticle

McIntosh, L. M. ; Barnes, J. L. ; Barnes, V. L. ; McDonald, J. R. / Selective CCR2-targeted macrophage depletion ameliorates experimental mesangioproliferative glomerulonephritis. In: Clinical and Experimental Immunology. 2009 ; Vol. 155, No. 2. pp. 295-303.
@article{a1672900d4a241a89e9b04c74a8a488f,
title = "Selective CCR2-targeted macrophage depletion ameliorates experimental mesangioproliferative glomerulonephritis",
abstract = "The CCL2/CCR2 chemokine/receptor axis directs the chemotaxis of infiltrating monocytes/macrophages and T cells and plays a pivotal role in tissue damage and fibrosis in kidney diseases. The eradication of the activated leucocytes should diminish the production of inflammatory mediators, limit tissue damage and ameliorate disease. A recombinant fusion protein (OPL-CCL2-LPM) comprised of the human CCL2 (monocyte chemoattractant protein-1) chemokine fused to a truncated form of the enzymatically active A1 domain of Shigella dysenteriae holotoxin (SA1) has been developed. The CCL2 portion binds specifically to CCR2-bearing leucocytes and the fusion protein enters the cells, where the SA1 moiety inhibits protein synthesis resulting in cell death. The compound was tested in a model of anti-thymocyte serum (ATS)-induced mesangioproliferative glomerulonephritis (ATS-GN). Male rats were injected with ATS on day 0 and treated intravenously with vehicle, 50 or 100 μg/kg of OPL-CCL2-LPM Q2D from days 2, 4, 6 and 8. Urine and blood were collected on days 0, 5 and 9. Animals were sacrificed on day 9. No treatment-related effects on body weight or signs of clinical toxicity were observed. Urine protein levels were decreased in treated animals. At the highest dose, histopathological analyses of kidney sections revealed maximum reductions of 36, 31, 30 and 24{\%} for macrophage count, glomerular lesions, α-smooth muscle actin and fibronectin respectively. These results indicate a significant protective effect of OPL-CCL2-LPM in this model of nephritis.",
keywords = "CCL2, CCR2, Chemokine, Glomerulonephritis, Macrophage depletion",
author = "McIntosh, {L. M.} and Barnes, {J. L.} and Barnes, {V. L.} and McDonald, {J. R.}",
year = "2009",
month = "2",
doi = "10.1111/j.1365-2249.2008.03819.x",
language = "English (US)",
volume = "155",
pages = "295--303",
journal = "Clinical and Experimental Immunology",
issn = "0009-9104",
publisher = "Wiley-Blackwell",
number = "2",

}

TY - JOUR

T1 - Selective CCR2-targeted macrophage depletion ameliorates experimental mesangioproliferative glomerulonephritis

AU - McIntosh, L. M.

AU - Barnes, J. L.

AU - Barnes, V. L.

AU - McDonald, J. R.

PY - 2009/2

Y1 - 2009/2

N2 - The CCL2/CCR2 chemokine/receptor axis directs the chemotaxis of infiltrating monocytes/macrophages and T cells and plays a pivotal role in tissue damage and fibrosis in kidney diseases. The eradication of the activated leucocytes should diminish the production of inflammatory mediators, limit tissue damage and ameliorate disease. A recombinant fusion protein (OPL-CCL2-LPM) comprised of the human CCL2 (monocyte chemoattractant protein-1) chemokine fused to a truncated form of the enzymatically active A1 domain of Shigella dysenteriae holotoxin (SA1) has been developed. The CCL2 portion binds specifically to CCR2-bearing leucocytes and the fusion protein enters the cells, where the SA1 moiety inhibits protein synthesis resulting in cell death. The compound was tested in a model of anti-thymocyte serum (ATS)-induced mesangioproliferative glomerulonephritis (ATS-GN). Male rats were injected with ATS on day 0 and treated intravenously with vehicle, 50 or 100 μg/kg of OPL-CCL2-LPM Q2D from days 2, 4, 6 and 8. Urine and blood were collected on days 0, 5 and 9. Animals were sacrificed on day 9. No treatment-related effects on body weight or signs of clinical toxicity were observed. Urine protein levels were decreased in treated animals. At the highest dose, histopathological analyses of kidney sections revealed maximum reductions of 36, 31, 30 and 24% for macrophage count, glomerular lesions, α-smooth muscle actin and fibronectin respectively. These results indicate a significant protective effect of OPL-CCL2-LPM in this model of nephritis.

AB - The CCL2/CCR2 chemokine/receptor axis directs the chemotaxis of infiltrating monocytes/macrophages and T cells and plays a pivotal role in tissue damage and fibrosis in kidney diseases. The eradication of the activated leucocytes should diminish the production of inflammatory mediators, limit tissue damage and ameliorate disease. A recombinant fusion protein (OPL-CCL2-LPM) comprised of the human CCL2 (monocyte chemoattractant protein-1) chemokine fused to a truncated form of the enzymatically active A1 domain of Shigella dysenteriae holotoxin (SA1) has been developed. The CCL2 portion binds specifically to CCR2-bearing leucocytes and the fusion protein enters the cells, where the SA1 moiety inhibits protein synthesis resulting in cell death. The compound was tested in a model of anti-thymocyte serum (ATS)-induced mesangioproliferative glomerulonephritis (ATS-GN). Male rats were injected with ATS on day 0 and treated intravenously with vehicle, 50 or 100 μg/kg of OPL-CCL2-LPM Q2D from days 2, 4, 6 and 8. Urine and blood were collected on days 0, 5 and 9. Animals were sacrificed on day 9. No treatment-related effects on body weight or signs of clinical toxicity were observed. Urine protein levels were decreased in treated animals. At the highest dose, histopathological analyses of kidney sections revealed maximum reductions of 36, 31, 30 and 24% for macrophage count, glomerular lesions, α-smooth muscle actin and fibronectin respectively. These results indicate a significant protective effect of OPL-CCL2-LPM in this model of nephritis.

KW - CCL2

KW - CCR2

KW - Chemokine

KW - Glomerulonephritis

KW - Macrophage depletion

UR - http://www.scopus.com/inward/record.url?scp=58149289793&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=58149289793&partnerID=8YFLogxK

U2 - 10.1111/j.1365-2249.2008.03819.x

DO - 10.1111/j.1365-2249.2008.03819.x

M3 - Article

VL - 155

SP - 295

EP - 303

JO - Clinical and Experimental Immunology

JF - Clinical and Experimental Immunology

SN - 0009-9104

IS - 2

ER -