Graft-derived CCL2 increases graft injury during antibody-mediated rejection of cardiac allografts

T. Abe, C. A. Su, S. Iida, W. M. Baldwin, N. Nonomura, S. Takahara, R. L. Fairchild

Research output: Contribution to journalArticle

Abstract

The pathogenic role of macrophages in antibody-mediated rejection (AMR) remains unclear. Monocyte chemoattractant protein-1 (MCP-1/CCL2) is a potent chemotactic factor for monocytes and macrophages. The current studies used a murine model of AMR to investigate the role of graft-derived CCL2 in AMR and how macrophages may participate in antibody-mediated allograft injury. B6.CCR5 -/-/CD8-/- recipients rejected MHC-mismatched WT A/J allografts with high donor-reactive antibody titers and diffuse C4d deposition in the large vessels and myocardial capillaries, features consistent with AMR. In contrast, A/J.CCL2-/- allografts induced low donor-reactive antibody titers and C4d deposition at Day 7 posttransplant. Decreased donor-reactive CD4 T cells producing interferon gamma were induced in response to A/J.CCL2-/- versus WT allografts. Consequently, A/J.CCL2 -/- allograft survival was modestly but significantly longer than A/J allografts. Macrophages purified from WT allografts expressed high levels of IL-1β and IL-12p40 and this expression and the numbers of classically activated macrophages were markedly reduced in CCL2-deficient allografts on Day 7. The results indicate that allograft-derived CCL2 plays an important role in directing classically activated macrophages into allografts during AMR and that macrophages are important contributors to the inflammatory environment mediating graft tissue injury in this pathology, suggesting CCL2 as a therapeutic target for AMR. This study investigating the role of macrophage functions in antibody-mediated rejection of heart allografts in a mouse model indicates that the absence of allograft CCL2 expression markedly reduces antidonor antibodyinduced allograft inflammation including the infiltration of classically activated macrophages.

Original languageEnglish (US)
Pages (from-to)1753-1764
Number of pages12
JournalAmerican Journal of Transplantation
Volume14
Issue number8
DOIs
StatePublished - 2014
Externally publishedYes

Keywords

  • Alloantibody
  • animal models
  • chemokines/chemokine receptors
  • macrophage/monocyte

ASJC Scopus subject areas

  • Transplantation
  • Immunology and Allergy
  • Pharmacology (medical)

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  • Cite this

    Abe, T., Su, C. A., Iida, S., Baldwin, W. M., Nonomura, N., Takahara, S., & Fairchild, R. L. (2014). Graft-derived CCL2 increases graft injury during antibody-mediated rejection of cardiac allografts. American Journal of Transplantation, 14(8), 1753-1764. https://doi.org/10.1111/ajt.12780