title: A role for TNF receptor type II in leukocyte infiltration into the lung during experimental idiopathic pneumonia syndrome.
abstract: Idiopathic pneumonia syndrome (IPS) is a frequently fatal complication following allogeneic stem cell transplantation (allo-SCT). Experimental models have revealed that TNF-alpha contributes to pulmonary vascular endothelial cell (EC) apoptosis, and modulates the infiltration of donor leukocytes into the lung parenchyma. The inflammatory effects of TNF-alpha are mediated by signaling through the type I (TNFRI) or type II (TNFRII) TNF receptors. We investigated the relative contribution of TNFRI and TNFRII to leukocyte infiltration into the lung following allo-SCT by using established murine models. Wild-type (wt) B6 mice or B6 animals deficient in either TNFRI or TNFRII were lethally irradiated and received SCT from allogeneic (LP/J) or syngeneic (B6) donors. At week 5 following SCT, the severity of IPS was significantly reduced in TNFRII-/- recipients compared to wt controls, but no effect was observed in TNFRI-/- animals. Bronchoalveolar lavage fluid (BALF) levels of RANTES and pulmonary ICAM-1 expression in TNFRII-/- recipients were also reduced, and correlated with a reduction of CD8(+) cells in the lung. Pulmonary inflammation was also decreased in TNFRII-/- mice using an isolated MHC class I disparate model (bm1 --> B6), and in bm1 wt mice transplanted with B6 TNF-alpha-/- donor cells. Collectively, these data demonstrate a role for TNF-alpha signaling through TNFRII in leukocyte infiltration into the lung following allo-SCT, and suggest that disruption of the TNF-alpha:TNFRII pathway may be an effective tool to prevent or treat IPS.
authors.affiliation: Department of Pediatrics, Division of Hematology and Oncology, Blood and Marrow Transplantation Program, University of Michigan, Ann Arbor, Michigan, USA.
authors.forename: Gerhard C
authors.initials: GC
authors.lastname: Hildebrandt
authors.forename: Krystyna M
authors.initials: KM
authors.lastname: Olkiewicz
authors.forename: Leigh
authors.initials: L
authors.lastname: Corrion
authors.forename: Shawn G
authors.initials: SG
authors.lastname: Clouthier
authors.forename: Elizabeth M
authors.initials: EM
authors.lastname: Pierce
authors.forename: Chen
authors.initials: C
authors.lastname: Liu
authors.forename: Kenneth R
authors.initials: KR
authors.lastname: Cooke
mesh_terms: D000818:Animals; D001992:Bronchoalveolar Lavage Fluid; D005260:Female; D006085:Graft Survival; D006086:Graft vs Host Disease; D008168:Lung / Q000502:physiology*; D051379:Mice; D008810:Mice, Inbred C57BL; D008815:Mice, Inbred Strains; D011014:Pneumonia / Q000209:etiology / Q000503:physiopathology*; D047888:Receptors, Tumor Necrosis Factor, Type I / Q000172:deficiency / Q000235:genetics; D047889:Receptors, Tumor Necrosis Factor, Type II / Q000502:physiology*; D033581:Stem Cell Transplantation / Q000009:adverse effects; D013577:Syndrome; D014184:Transplantation, Homologous; D014409:Tumor Necrosis Factor-alpha / Q000502:physiology
chemical_list: D047888:Receptors, Tumor Necrosis Factor, Type I; D047889:Receptors, Tumor Necrosis Factor, Type II; D014409:Tumor Necrosis Factor-alpha