Obliterative bronchiolitis (OB) is a frequent and often devastating complication of lung transplantation that is usually refractory to treatments. Although the pathogenesis of OB is clearly immune-mediated, details of these mechanisms remain uncertain. We have recently shown that CD4 T-cells of transplant recipients with OB seem to be invariably characterized by extreme oligclonal proliferations and CD28 downregulation, and these abormalities are largely absent amoung recipients without rejection. We believe these abnormal T- cells play a critical role in development of OB by either causing direct injuries to the allograft, or by orchestrating an inflammatory cascade with elaborations of chemotactic and activating mediators. The projects of this proposal will conduct serial assays of a lung transplant recipient cohort, to establish whether findings of CD4 clonal expansions and CD28 downregulation are useful for diagnosis or prediction of OB. Other studies will characterize these unusual cells and establish their antigen specificities, and delineate their proliferative and cytolytic functions. We have also developed a novel human-murine chimeric model using xenografts of human airways in immunodeficient mice that will enable in vivo assays of immune effects and functions after adoptive transfer of allogeneic (to the airway) human T-cells. We anticipate the focus of these studies on the early events of the immune responses to allografts will result in important new findings that provide insights into the immunopathogenesis of OB. Furthermore, findings here may also open avenues for development of innovative, diagnostic and therapeutic modalities, including earlier and more efficacious interventions to prevent or treat OB.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Research Project (R01)
Project #
5R01HL073241-03
Application #
7350222
Study Section
Lung Cellular, Molecular, and Immunobiology Study Section (LCMI)
Program Officer
Reynolds, Herbert Y
Project Start
2006-02-01
Project End
2010-01-31
Budget Start
2008-02-01
Budget End
2009-01-31
Support Year
3
Fiscal Year
2008
Total Cost
$355,774
Indirect Cost
Name
University of Pittsburgh
Department
Internal Medicine/Medicine
Type
Schools of Medicine
DUNS #
004514360
City
Pittsburgh
State
PA
Country
United States
Zip Code
15213
Herazo-Maya, Jose D; Noth, Imre; Duncan, Steven R et al. (2013) Peripheral blood mononuclear cell gene expression profiles predict poor outcome in idiopathic pulmonary fibrosis. Sci Transl Med 5:205ra136
Dhillon, Gundeep S; Valentine, Vincent G; Levitt, Joseph et al. (2012) Clarithromycin for prevention of bronchiolitis obliterans syndrome in lung allograft recipients. Clin Transplant 26:105-10
Xue, Jianmin; Zhu, Xuehai; George, M Patricia et al. (2011) A human-mouse chimeric model of obliterative bronchiolitis after lung transplantation. Am J Pathol 179:745-53
Xue, Jianmin; Gochuico, Bernadette R; Alawad, Ahmad Samer et al. (2011) The HLA class II Allele DRB1*1501 is over-represented in patients with idiopathic pulmonary fibrosis. PLoS One 6:e14715
Chien, Jason W; Duncan, Steven; Williams, Kirsten M et al. (2010) Bronchiolitis obliterans syndrome after allogeneic hematopoietic stem cell transplantation-an increasingly recognized manifestation of chronic graft-versus-host disease. Biol Blood Marrow Transplant 16:S106-14
Gilani, Syed R; Vuga, Louis J; Lindell, Kathleen O et al. (2010) CD28 down-regulation on circulating CD4 T-cells is associated with poor prognoses of patients with idiopathic pulmonary fibrosis. PLoS One 5:e8959
Zhu, Xuehai; Gadgil, Aneal S; Givelber, Rachel et al. (2009) Peripheral T cell functions correlate with the severity of chronic obstructive pulmonary disease. J Immunol 182:3270-7
Studer, Sean M; George, M Patricia; Zhu, Xuehai et al. (2008) CD28 down-regulation on CD4 T cells is a marker for graft dysfunction in lung transplant recipients. Am J Respir Crit Care Med 178:765-73
Feghali-Bostwick, Carol A; Gadgil, Aneal S; Otterbein, Leo E et al. (2008) Autoantibodies in patients with chronic obstructive pulmonary disease. Am J Respir Crit Care Med 177:156-63
Feghali-Bostwick, Carol A; Tsai, Christopher G; Valentine, Vincent G et al. (2007) Cellular and humoral autoreactivity in idiopathic pulmonary fibrosis. J Immunol 179:2592-9