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Role of CXCL9/CXCR3 Chemokine Biology during Pathogenesis of Acute Lung Allograft Rejection

John A. Belperio, Michael P. Keane, Marie D. Burdick, Joseph P. Lynch III, David A. Zisman, Ying Ying Xue, Kewang Li, Abbas Ardehali, David J. Ross and Robert M. Strieter
J Immunol November 1, 2003, 171 (9) 4844-4852; DOI: https://doi.org/10.4049/jimmunol.171.9.4844
John A. Belperio
* Medicine,
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Michael P. Keane
* Medicine,
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Marie D. Burdick
* Medicine,
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Joseph P. Lynch III
* Medicine,
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David A. Zisman
* Medicine,
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Ying Ying Xue
* Medicine,
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Kewang Li
* Medicine,
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Abbas Ardehali
‡Thoracic Surgery, Division of Pulmonary and Critical Care Medicine, University of California School of Medicine, Los Angeles, CA 90095
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David J. Ross
* Medicine,
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Robert M. Strieter
* Medicine,
†Pathology and Laboratory Medicine, and
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  • FIGURE 1.
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    FIGURE 1.

    Temporal increases in A, perivascular; B, peribronchiolar; C, alveolar inflammation; D, alveolar wall change; and E, cumulative total acute rejection score in lung allografts over a 6-day time course (n = 6 left transplanted lungs evaluated at each time point; ∗, p < 0.05).

  • FIGURE 2.
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    FIGURE 2.

    CXCL9 and CXCL10 expression is markedly elevated in lung allografts during acute rejection. I, Real-time quantitative PCR determination of CXCL9 and CXCL10 mRNA expression presented as a fold increase of chemokine expression from the allografts, as compared with syngeneic controls at days 1, 4, and 6. II, Whole lung homogenate protein levels measured by ELISA, of CXCL9 and CXCL10 from lung allografts and syngeneic controls at days 1, 4, and 6 (n = 6 lungs at each time point; ∗, p < 0.05).

  • FIGURE 3.
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    FIGURE 3.

    CXCR3 mRNA expression in the lung is elevated during acute allograft rejection. Real-time quantitative PCR determination of CXCR3 mRNA expression presented as a fold increase of CXCR3 expression from the allografts, as compared with syngeneic controls at days 1, 4, and 6. (n = 6 lungs at each time point; ∗, p < 0.05).

  • FIGURE 4.
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    FIGURE 4.

    I, Neutralization of CXCL9 reduces infiltrating lung allograft mononuclear cells and the expression of CXCR3. A, FACS analysis of percentage of leukocyte cell surface markers CD3, CD4, CD8, NK cells, B cells, and Mφ (mononuclear phagocytes) from allografts treated with anti-CXCL9 vs control Abs (n = 6 lungs at each time point; ∗, p < 0.05). B, Real-time quantitative PCR determination of CXCR3 mRNA expression presented as fold decrease of CXCR3 expression from lung allografts of animals treated with anti-CXCL9, as compared with control Ab (n = 6 lungs at each time point; ∗, p < 0.05). II, Neutralization of CXCL9 inhibits leukocyte infiltration in acute lung allograft rejection. Quantitative histopathologic scores from days 6–10 of allografts from animals treated with anti-CXCL9, as compared with control Abs. A, Perivascular; B, peribronchiolar; C, alveolar inflammation; D, alveolar wall change; and E, cumulative total acute rejection score in lung allografts (n = 6 lung allografts evaluated at each time point; ∗, p < 0.05). III, Representative photomicrographs with H&E (×400) of the histopathology of lung allograft rejection from animals treated with anti-CXCL9, as compared with control Ab at days 6, 8, and 10.

  • FIGURE 5.
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    FIGURE 5.

    CsA given at a dose of 1.85 mg/kg/day beginning at day 0 and daily until sacrifice on day 6 or 8 attenuates acute lung allograft rejection scores at day 6, but not day 8. Quantitative histopathologic scores of lung allografts treated with low dose (1.85 mg/kg/day) CsA, as compared with control (Cemorphor EL oil) at days 6 and 8. A, Perivascular; B, peribronchiolar; C, alveolar inflammation; D, alveolar wall change; and E, cumulative total acute rejection score in lung allografts (n = 6 lung allografts at each time point; ∗, p < 0.05).

  • FIGURE 6.
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    FIGURE 6.

    Treatment with the combination of anti-CXCL9 (given every other day beginning at day 0 and until sacrifice or at day 14) and CsA (given everyday beginning at day 0 and until sacrifice) is synergistic for reducing acute lung allograft rejection scores. Quantitative histopathologic scores of lung allografts from animals treated with combined anti-CXCL9 Abs and low dose CsA, as compared with control Abs and low dose CsA at days 14–20. A, Perivascular; B, peribronchiolar; C, alveolar inflammation; D, alveolar wall change; and E, cumulative total acute rejection score in lung allografts (n = 6 lung allografts evaluated at each time point; ∗, p < 0.05).

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The Journal of Immunology: 171 (9)
The Journal of Immunology
Vol. 171, Issue 9
1 Nov 2003
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Role of CXCL9/CXCR3 Chemokine Biology during Pathogenesis of Acute Lung Allograft Rejection
John A. Belperio, Michael P. Keane, Marie D. Burdick, Joseph P. Lynch, David A. Zisman, Ying Ying Xue, Kewang Li, Abbas Ardehali, David J. Ross, Robert M. Strieter
The Journal of Immunology November 1, 2003, 171 (9) 4844-4852; DOI: 10.4049/jimmunol.171.9.4844

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Role of CXCL9/CXCR3 Chemokine Biology during Pathogenesis of Acute Lung Allograft Rejection
John A. Belperio, Michael P. Keane, Marie D. Burdick, Joseph P. Lynch, David A. Zisman, Ying Ying Xue, Kewang Li, Abbas Ardehali, David J. Ross, Robert M. Strieter
The Journal of Immunology November 1, 2003, 171 (9) 4844-4852; DOI: 10.4049/jimmunol.171.9.4844
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