Donor-derived TNF-α regulates pulmonary chemokine expression and the development of idiopathic pneumonia syndrome after allogeneic bone marrow transplantation

Gerhard C. Hildebrandt, Krystyna M. Olkiewicz, Leigh A. Corrion, Yayi Chang, Shawn G. Clouthier, Chen Liu, Kenneth R. Cooke

Research output: Contribution to journalArticlepeer-review

Abstract

Idiopathic pneumonia syndrome (IPS) is a significant cause of mortality after allogeneic bone marrow transplantation (allo-BMT), and tumor necrosis factor-α (TNF-α) is a significant effector molecule in this process. However, the relative contribution of donor- versus host-derived TNF-α to the development of IPS has not been elucidated. Using a lethally irradiated parent → F1 mouse IPS model, we showed that 5 weeks after transplantation allo-BMT recipients developed significant lung injury compared with syngeneic controls, which was associated with increased bronchoalveolar lavage (BAL) fluid levels of TNF-α, elevated numbers of donor-derived TNF-α-secreting T cells, and increased pulmonary macrophage production of TNF-α to lipopolysaccharide (LPS) stimulation. Allo-BMT with TNF-α-/- donor cells resulted in significantly reduced IPS severity, whereas utilization of TNF-α-deficient mice as BMT recipients had no effect on IPS. We next determined that TNF-α secretion from both donor accessory cells (monocytes/macrophages) and T cells significantly contributed to the development of IPS. Importantly, the absence of donor T-cell-derived TNF-α resulted in a significant decrease in inflammatory chemokine production in the lung and near complete abrogation of IPS. Collectively, these data demonstrate that donor TNF-α is critical to the development of IPS and reveal a heretofore unknown mechanism for T-cell-derived TNF-α in the evolution of this process.

Original languageEnglish (US)
Pages (from-to)586-593
Number of pages8
JournalBlood
Volume104
Issue number2
DOIs
StatePublished - Jul 15 2004
Externally publishedYes

ASJC Scopus subject areas

  • Biochemistry
  • Immunology
  • Hematology
  • Cell Biology

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