Blockade of CXCR3 receptor: Ligand interactions reduces leukocyte recruitment to the lung and the severity of experimental idiopathic pneumonia syndrome

Gerhard C. Hildebrandt, Leigh A. Corrion, Krystyna M. Olkiewicz, Bao Lu, Kathleen Lowler, Ulrich A. Duffner, Bethany B. Moore, William A. Kuziel, Chen Liu, Kenneth R. Cooke

Research output: Contribution to journalArticlepeer-review

Abstract

Idiopathic pneumonia syndrome (IPS) is a frequently fatal complication after allogeneic stem cell transplantation (allo-SCT) that responds poorly to standard immunosuppressive therapy. The pathophysiology of IPS involves the secretion of inflammatory cytokines including IFN-γ and TNF-α along with the recruitment of donor T cells to the lung. CXCR3 is a chemokine receptor that is expressed on activated Th1/Tc1 T cell subsets and the expression of its ligands CXCL9 (monokine induced by IFN-γ (Mig)) and CXCL10 (IFN-γ-inducible protein 10 (IP-10)) can be induced in a variety of cell types by IFN-γ alone or in combination with TNF-α. We used a lethally irradiated murine SCT model (B6 → bm1) to evaluate the role of CXCR3 receptor:ligand interactions in the development of IPS. We found that Mig and IP-10 protein levels were significantly elevated in the bronchoalveolar lavage fluid of allo-SCT recipients compared with syngeneic controls and correlated with the infiltration of IFN-γ-secreting CXCR3+ donor T cells into the lung. The in vivo neutralization of either Mig or IP-10 significantly reduced the severity of IPS compared with control-treated animals, and an additive effect was observed when both ligands were blocked simultaneously. Complementary experiments using CXCR3-/- mice as SCT donors also resulted in a significant decrease in IPS. These data demonstrate that interactions involving CXCR3 and its primary ligands Mig and IP-10 significantly contribute to donor T cell recruitment to the lung after allo-SCT. Therefore, approaches focusing on the abrogation of these interactions may prove successful in preventing or treating lung injury that occurs in this setting.

Original languageEnglish (US)
Pages (from-to)2050-2059
Number of pages10
JournalJournal of Immunology
Volume173
Issue number3
DOIs
StatePublished - Aug 1 2004
Externally publishedYes

ASJC Scopus subject areas

  • Immunology and Allergy
  • Immunology

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