Macrophages act as effectors of tissue damage in acute renal allograft rejection

Matthew D. Jose, Yohei Ikezumi, Nico Van Rooijen, Robert C. Atkins, Steven J. Chadban

Research output: Contribution to journalArticle

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Abstract

Background. Macrophages constitute 38% to 60% of infiltrating cells during acute renal allograft rejection. Their contribution to tissue damage during acute rejection was examined by depleting macrophages in a rat model. Methods. Lewis rats underwent bilateral nephrectomy and then received a Dark Agouti renal allograft and liposomal-clodronate, control phosphate-buffered saline liposomes, or saline intravenously (n=7 per group) on days 1 and 3 postsurgery. Grafts were harvested on day 5. Results. Liposomal-clodronate treatment resulted in a 70% reduction in blood ED1+ monocytes and 60% reduction in intragraft ED1+ macrophages (both P < 0.01). Half of all remaining interstitial ED1+ cells were undergoing apoptosis (terminal deoxynucleotide transferase-mediated dUTP nick-end labeling +/ED1+), and thus functional depletion of more than 75% of macrophages was achieved. Histologic and functional parameters of acute rejection were attenuated: interstitial infiltrate, tubulitis, and glomerulitis (P < 0.01); tubular cell apoptosis (P < 0.001); tubular cell proliferation (P < 0.001); and serum creatinine (P < 0.01). Production of inducible nitric oxide synthase by infiltrating cells and urinary nitric oxide excretion was reduced by 90% (P < 0.001). In contrast, no reduction in the number of other leukocytes was seen (CD3+, CD4+, CD8 +, and natural killer cells). Activation of lymphocytes (CD25 +) and production of lymphocyte effector molecules (granzyme B) were unaltered. Conclusion. This study demonstrates that macrophages contribute to tissue damage during acute rejection.

Original languageEnglish
Pages (from-to)1015-1022
Number of pages8
JournalTransplantation
Volume76
Issue number7
DOIs
Publication statusPublished - 15-10-2003

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Allografts
Macrophages
Kidney
Clodronic Acid
Apoptosis
Granzymes
Nitric Oxide Synthase Type II
Lymphocyte Activation
Transferases
Nephrectomy
Leukocyte Count
Liposomes
Natural Killer Cells
Monocytes
Creatinine
Nitric Oxide
Phosphates
Cell Proliferation
Transplants
Serum

All Science Journal Classification (ASJC) codes

  • Transplantation

Cite this

Jose, Matthew D. ; Ikezumi, Yohei ; Van Rooijen, Nico ; Atkins, Robert C. ; Chadban, Steven J. / Macrophages act as effectors of tissue damage in acute renal allograft rejection. In: Transplantation. 2003 ; Vol. 76, No. 7. pp. 1015-1022.
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abstract = "Background. Macrophages constitute 38{\%} to 60{\%} of infiltrating cells during acute renal allograft rejection. Their contribution to tissue damage during acute rejection was examined by depleting macrophages in a rat model. Methods. Lewis rats underwent bilateral nephrectomy and then received a Dark Agouti renal allograft and liposomal-clodronate, control phosphate-buffered saline liposomes, or saline intravenously (n=7 per group) on days 1 and 3 postsurgery. Grafts were harvested on day 5. Results. Liposomal-clodronate treatment resulted in a 70{\%} reduction in blood ED1+ monocytes and 60{\%} reduction in intragraft ED1+ macrophages (both P < 0.01). Half of all remaining interstitial ED1+ cells were undergoing apoptosis (terminal deoxynucleotide transferase-mediated dUTP nick-end labeling +/ED1+), and thus functional depletion of more than 75{\%} of macrophages was achieved. Histologic and functional parameters of acute rejection were attenuated: interstitial infiltrate, tubulitis, and glomerulitis (P < 0.01); tubular cell apoptosis (P < 0.001); tubular cell proliferation (P < 0.001); and serum creatinine (P < 0.01). Production of inducible nitric oxide synthase by infiltrating cells and urinary nitric oxide excretion was reduced by 90{\%} (P < 0.001). In contrast, no reduction in the number of other leukocytes was seen (CD3+, CD4+, CD8 +, and natural killer cells). Activation of lymphocytes (CD25 +) and production of lymphocyte effector molecules (granzyme B) were unaltered. Conclusion. This study demonstrates that macrophages contribute to tissue damage during acute rejection.",
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Macrophages act as effectors of tissue damage in acute renal allograft rejection. / Jose, Matthew D.; Ikezumi, Yohei; Van Rooijen, Nico; Atkins, Robert C.; Chadban, Steven J.

In: Transplantation, Vol. 76, No. 7, 15.10.2003, p. 1015-1022.

Research output: Contribution to journalArticle

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T1 - Macrophages act as effectors of tissue damage in acute renal allograft rejection

AU - Jose, Matthew D.

AU - Ikezumi, Yohei

AU - Van Rooijen, Nico

AU - Atkins, Robert C.

AU - Chadban, Steven J.

PY - 2003/10/15

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N2 - Background. Macrophages constitute 38% to 60% of infiltrating cells during acute renal allograft rejection. Their contribution to tissue damage during acute rejection was examined by depleting macrophages in a rat model. Methods. Lewis rats underwent bilateral nephrectomy and then received a Dark Agouti renal allograft and liposomal-clodronate, control phosphate-buffered saline liposomes, or saline intravenously (n=7 per group) on days 1 and 3 postsurgery. Grafts were harvested on day 5. Results. Liposomal-clodronate treatment resulted in a 70% reduction in blood ED1+ monocytes and 60% reduction in intragraft ED1+ macrophages (both P < 0.01). Half of all remaining interstitial ED1+ cells were undergoing apoptosis (terminal deoxynucleotide transferase-mediated dUTP nick-end labeling +/ED1+), and thus functional depletion of more than 75% of macrophages was achieved. Histologic and functional parameters of acute rejection were attenuated: interstitial infiltrate, tubulitis, and glomerulitis (P < 0.01); tubular cell apoptosis (P < 0.001); tubular cell proliferation (P < 0.001); and serum creatinine (P < 0.01). Production of inducible nitric oxide synthase by infiltrating cells and urinary nitric oxide excretion was reduced by 90% (P < 0.001). In contrast, no reduction in the number of other leukocytes was seen (CD3+, CD4+, CD8 +, and natural killer cells). Activation of lymphocytes (CD25 +) and production of lymphocyte effector molecules (granzyme B) were unaltered. Conclusion. This study demonstrates that macrophages contribute to tissue damage during acute rejection.

AB - Background. Macrophages constitute 38% to 60% of infiltrating cells during acute renal allograft rejection. Their contribution to tissue damage during acute rejection was examined by depleting macrophages in a rat model. Methods. Lewis rats underwent bilateral nephrectomy and then received a Dark Agouti renal allograft and liposomal-clodronate, control phosphate-buffered saline liposomes, or saline intravenously (n=7 per group) on days 1 and 3 postsurgery. Grafts were harvested on day 5. Results. Liposomal-clodronate treatment resulted in a 70% reduction in blood ED1+ monocytes and 60% reduction in intragraft ED1+ macrophages (both P < 0.01). Half of all remaining interstitial ED1+ cells were undergoing apoptosis (terminal deoxynucleotide transferase-mediated dUTP nick-end labeling +/ED1+), and thus functional depletion of more than 75% of macrophages was achieved. Histologic and functional parameters of acute rejection were attenuated: interstitial infiltrate, tubulitis, and glomerulitis (P < 0.01); tubular cell apoptosis (P < 0.001); tubular cell proliferation (P < 0.001); and serum creatinine (P < 0.01). Production of inducible nitric oxide synthase by infiltrating cells and urinary nitric oxide excretion was reduced by 90% (P < 0.001). In contrast, no reduction in the number of other leukocytes was seen (CD3+, CD4+, CD8 +, and natural killer cells). Activation of lymphocytes (CD25 +) and production of lymphocyte effector molecules (granzyme B) were unaltered. Conclusion. This study demonstrates that macrophages contribute to tissue damage during acute rejection.

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