Abstract

Almost half of the pneumonias after allogeneic bone marrow transplant (BMT) are non infectious in origin, and are referred to as idiopathic pneumonia syndrome (IPS). During the first cycle of funding of this grant the authors have used well defined mouse models to investigate IPS pathophysiology after allogeneic BMT. Significant progress has been made in identifying two interrelated pathways of lung injury: (1) host antigen-non-specific inflammatory effectors, including endotoxin (LPS) and TNF which are linked through a gut-liver-lung axis; and (2) host antigen specific T cell effectors which home to the pulmonary interstitium and cause pneumonitis. In this first competing renewal of the grant, the investigators propose to investigate further the mechanisms of IPS lung injury using these well defined allogeneic BMT mouse models and to explore novel approaches to the prevention of such injury.
The Specific Aims are: 1) to analyze the contribution of inflammatory effectors to IPS lung injury after allogeneic BMT, 2) to analyze the contribution of T cell effectors to IPS by injury after allogeneic BMT, and 3) to analyze the mechanisms of chronic lung injury after allogeneic BMT.

  Funding Agency

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Research Project (R01)
Project #
2R01HL055162-06
Application #
6052783
Study Section
Surgery, Anesthesiology and Trauma Study Section (SAT)
Project Start
1995-09-15
Project End
2004-11-30
Budget Start
2000-02-14
Budget End
2000-11-30
Support Year
6
Fiscal Year
2000
Total Cost
$338,921
Indirect Cost

  Institution

Name
University of Michigan Ann Arbor
Department
Internal Medicine/Medicine
Type
Schools of Medicine
DUNS #
791277940
City
Ann Arbor
State
MI
Country
United States
Zip Code
48109

  Publications

Hildebrandt, Gerhard C; Olkiewicz, Krystyna M; Corrion, Leigh et al. (2008) A role for TNF receptor type II in leukocyte infiltration into the lung during experimental idiopathic pneumonia syndrome. Biol Blood Marrow Transplant 14:385-96
Hildebrandt, Gerhard C; Olkiewicz, Krystyna M; Choi, Sung et al. (2005) Donor T-cell production of RANTES significantly contributes to the development of idiopathic pneumonia syndrome after allogeneic stem cell transplantation. Blood 105:2249-57
Gerbitz, Armin; Ewing, Patricia; Olkiewicz, Krystyna et al. (2005) A role for CD54 (intercellular adhesion molecule-1) in leukocyte recruitment to the lung during the development of experimental idiopathic pneumonia syndrome. Transplantation 79:536-42
Gerbitz, Armin; Nickoloff, Brian J; Olkiewicz, Krystyna et al. (2004) A role for tumor necrosis factor-alpha-mediated endothelial apoptosis in the development of experimental idiopathic pneumonia syndrome. Transplantation 78:494-502
Hildebrandt, Gerhard C; Olkiewicz, Krystyna M; Corrion, Leigh A et al. (2004) Donor-derived TNF-alpha regulates pulmonary chemokine expression and the development of idiopathic pneumonia syndrome after allogeneic bone marrow transplantation. Blood 104:586-93
Hildebrandt, Gerhard C; Corrion, Leigh A; Olkiewicz, Krystyna M et al. (2004) Blockade of CXCR3 receptor:ligand interactions reduces leukocyte recruitment to the lung and the severity of experimental idiopathic pneumonia syndrome. J Immunol 173:2050-9
Cooke, Kenneth R; Olkiewicz, Krystyna; Erickson, Nicole et al. (2002) The role of endotoxin and the innate immune response in the pathophysiology of acute graft versus host disease. J Endotoxin Res 8:441-8
Teshima, T; Mach, N; Hill, G R et al. (2001) Tumor cell vaccine elicits potent antitumor immunity after allogeneic T-cell-depleted bone marrow transplantation. Cancer Res 61:162-71
Reddy, P; Teshima, T; Kukuruga, M et al. (2001) Interleukin-18 regulates acute graft-versus-host disease by enhancing Fas-mediated donor T cell apoptosis. J Exp Med 194:1433-40
Cooke, K R; Gerbitz, A; Crawford, J M et al. (2001) LPS antagonism reduces graft-versus-host disease and preserves graft-versus-leukemia activity after experimental bone marrow transplantation. J Clin Invest 107:1581-9

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