Abstract
Idiopathic pneumonia syndrome (IPS) is a frequently fatal complication following allogeneic stem cell transplantation (allo-SCT). Experimental models have revealed that TNF-α contributes to pulmonary vascular endothelial cell (EC) apoptosis, and modulates the infiltration of donor leukocytes into the lung parenchyma. The inflammatory effects of TNF-α 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-α-/- donor cells. Collectively, these data demonstrate a role for TNF-α signaling through TNFRII in leukocyte infiltration into the lung following allo-SCT, and suggest that disruption of the TNF-α:TNFRII pathway may be an effective tool to prevent or treat IPS.
Original language | English |
---|---|
Pages (from-to) | 385-396 |
Number of pages | 12 |
Journal | Biology of Blood and Marrow Transplantation |
Volume | 14 |
Issue number | 4 |
DOIs | |
State | Published - Apr 2008 |
Bibliographical note
Funding Information:This work was supported by grants 5R01 HL072258-03, R01 HL55162-05, and from the Walther Cancer Institute.
Funding
This work was supported by grants 5R01 HL072258-03, R01 HL55162-05, and from the Walther Cancer Institute.
Funders | Funder number |
---|---|
Walther Cancer Institute | |
National Heart, Lung, and Blood Institute (NHLBI) | R01HL072258 |
Keywords
- Cytokines
- Graft-versus-host disease
- Stem cell transplantation
- TNF-α
ASJC Scopus subject areas
- Hematology
- Transplantation