title: Elevated CXCL10 (IP-10) in bronchoalveolar lavage fluid is associated with acute cellular rejection after human lung transplantation.
abstract: BACKGROUND
  CXCL10 (IP-10) is a potent chemoattractant for T cells that has been postulated to play a role in infection and acute cellular rejection (ACR) in animal models. We measured CXCL10 (IP-10) (and other cytokines previously implicated in the pathogenesis of ACR) in the bronchoalveolar lavage (BAL) of lung transplant recipients (LTRs) to determine the association between CXCL10 (IP-10) and ACR in LTRs.
  
  
  METHODS
  In a prospective study of 85 LTRs, expression of cytokines (tumor necrosis factor, interferon-γ, interleukin [IL]-6, IL-8, IL-15, IL-16, IL-17, CXCL10 [IP-10], and MCP-1 [CCL2]) in BAL samples (n=233) from patients with episodes of ACR (n=44), infection ("Infect"; n=25), concomitant "Infect+ACR" (n=10), and "No Infect and No ACR" (n=154) were analyzed.
  
  
  RESULTS
  The levels of both CXCL10 (IP-10) and IL-16 were significantly increased in histologically proven ACR compared with the "No Infect and No ACR" group (CXCL10 [IP-10]: 107.0 vs. 31.9 pg/mL [P=0.001] and IL-16: 472.1 vs. 283.01 pg/mL [P=0.01]). However, in a linear mixed-effects model, significant association was found only between CXCL10 (IP-10) and ACR. A one-log increase of CXCL10 (IP-10) was associated with a 40% higher risk of ACR (odds ratio, 1.4; 95% confidence interval, 1.12-1.84).
  
  
  CONCLUSIONS
  Higher values of CXCL10 (IP-10) in BAL fluid are associated with ACR in LTRs, suggesting a potential mechanistic role in the pathogenesis of ACR in LTRs. These results suggest that therapeutic strategies to inhibit CXCL10 (IP-10) and or its cognate receptor, CXCR3, warrant investigation to prevent and/or treat ACR in clinical lung transplantation.
authors.affiliation: 1 Division of Infectious Diseases, Department of Medicine, Multi-Organ Transplant Institute, University Health Network, University of Toronto, Toronto, Ontario, Canada. 2 Division of Infectious Diseases, Department of Medicine, Toronto General Research Institute, McLaughlin-Rotman Centre for Global Health, McLaughlin Centre for Molecular Medicine, University Health Network, University of Toronto, Toronto, Ontario, Canada. 3 The Toronto Lung Transplant Program, McEwen Centre for Regenerative Medicine, Toronto General Research Institute, University Health Network, University of Toronto, Toronto, Ontario, Canada. 4 Division of Pulmonary, Allergy, and Critical Care Medicine, Department of Medicine, University of Pittsburgh, Pittsburgh, PA. 5 Division of Respirology, Department of Medicine, The Toronto Lung Transplant Program, University Health Network, University of Toronto, Toronto, Ontario, Canada. 6 Department of Cardiothoracic Surgery, Cleveland Clinic, Cleveland, OH. 7 Departments of Pediatrics and Immunology, University of Pittsburgh, Pittsburgh, PA. 8 Department of Medicine, University of Washington, Seattle, WA. 9 Address correspondence to: Shahid Husain, M.D., M.S., Division of Infectious Diseases, Department of Medicine, Multi-Organ Transplant Institute, University Health Network, University of Toronto, Toronto, Ontario, Canada.
authors.forename: Shahid
authors.initials: S
authors.lastname: Husain
authors.forename: Mariangela R
authors.initials: MR
authors.lastname: Resende
authors.forename: Nimerta
authors.initials: N
authors.lastname: Rajwans
authors.forename: Ricardo
authors.initials: R
authors.lastname: Zamel
authors.forename: Joseph M
authors.initials: JM
authors.lastname: Pilewski
authors.forename: Maria M
authors.initials: MM
authors.lastname: Crespo
authors.forename: Lianne G
authors.initials: LG
authors.lastname: Singer
authors.forename: Kenneth R
authors.initials: KR
authors.lastname: McCurry
authors.forename: Jay K
authors.initials: JK
authors.lastname: Kolls
authors.forename: Shaf
authors.initials: S
authors.lastname: Keshavjee
authors.forename: W Conrad
authors.initials: WC
authors.lastname: Liles
mesh_terms: D000208:Acute Disease; D015415:Biomarkers / Q000032:analysis; D001992:Bronchoalveolar Lavage Fluid / Q000276:immunology*; D016022:Case-Control Studies; D054357:Chemokine CXCL10 / Q000032:analysis*; D005260:Female; D006084:Graft Rejection / Q000276:immunology*; D006801:Humans; D007111:Immunity, Cellular; D016014:Linear Models; D016040:Lung Transplantation / Q000009:adverse effects*; D008297:Male; D008875:Middle Aged; D016017:Odds Ratio; D009864:Ontario; D010414:Pennsylvania; D011446:Prospective Studies; D012307:Risk Factors; D015854:Up-Regulation
chemical_list: D015415:Biomarkers; C114753:CXCL10 protein, human; D054357:Chemokine CXCL10
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