title: Donor-derived TNF-alpha regulates pulmonary chemokine expression and the development of idiopathic pneumonia syndrome after allogeneic bone marrow transplantation.
abstract: Idiopathic pneumonia syndrome (IPS) is a significant cause of mortality after allogeneic bone marrow transplantation (allo-BMT), and tumor necrosis factor-alpha (TNF-alpha) is a significant effector molecule in this process. However, the relative contribution of donor-versus host-derived TNF-alpha 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-alpha, elevated numbers of donor-derived TNF-alpha-secreting T cells, and increased pulmonary macrophage production of TNF-alpha to lipopolysaccharide (LPS) stimulation. Allo-BMT with TNF-alpha(-/-) donor cells resulted in significantly reduced IPS severity, whereas utilization of TNF-alpha-deficient mice as BMT recipients had no effect on IPS. We next determined that TNF-alpha 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-alpha 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-alpha is critical to the development of IPS and reveal a heretofore unknown mechanism for T-cell-derived TNF-alpha in the evolution of this process.
authors.affiliation: University of Michigan Cancer Center, 1500 E Medical Center Dr, Ann Arbor, MI 48109, USA.
authors.forename: Gerhard C
authors.initials: GC
authors.lastname: Hildebrandt
authors.forename: Krystyna M
authors.initials: KM
authors.lastname: Olkiewicz
authors.forename: Leigh A
authors.initials: LA
authors.lastname: Corrion
authors.forename: Yayi
authors.initials: Y
authors.lastname: Chang
authors.forename: Shawn G
authors.initials: SG
authors.lastname: Clouthier
authors.forename: Chen
authors.initials: C
authors.lastname: Liu
authors.forename: Kenneth R
authors.initials: KR
authors.lastname: Cooke
mesh_terms: D000818:Animals; D016026:Bone Marrow Transplantation / Q000009:adverse effects / Q000276:immunology*; D002478:Cells, Cultured; D018925:Chemokines / Q000378:metabolism*; D005260:Female; D008168:Lung / Q000276:immunology*; D051379:Mice; D008810:Mice, Inbred C57BL; D008817:Mice, Mutant Strains; D011014:Pneumonia / Q000276:immunology*; D013601:T-Lymphocytes / Q000276:immunology; D014184:Transplantation, Homologous; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism*
chemical_list: D018925:Chemokines; D014409:Tumor Necrosis Factor-alpha