title: Efficacy of inhaled cyclosporine in lung transplant recipients with refractory rejection: correlation of intragraft cytokine gene expression with pulmonary function and histologic characteristics.
abstract: BACKGROUND
  Refractory rejection is a major cause of morbidity and death among lung transplant recipients. Traditional rescue therapies have proved only modestly successful. We recently demonstrated the safety of inhaled cyclosporine for patients with end-stage chronic rejection; this trial was extended to patients with refractory acute rejection. The present study was to determine whether effective inhaled cyclosporine therapy was correlated with suppression of cytokine gene expression.
  
  
  METHODS
  Twelve lung transplant recipients were studied. Maintenance therapy, cyclosporine or FK 506, azathioprine, and prednisone, was continued, and inhaled cyclosporine at a dose of 300 mg/day was added. Pulmonary function testing and histologic characteristics from transbronchial biopsy specimens were used to assess efficacy of therapy. Bronchoalveolar lavage (BAL) and peripheral blood cells were analyzed for the presence of messenger RNA by using 32P-labeled primers of cytokines interleukin-2 (IL-2), IL-6, IL-10, and interferon-gamma (gamma) via reverse transcriptase-polymerase chain reaction.
  
  
  RESULTS
  Nine of 12 patients (five with acute rejection, four with chronic rejection) exhibited histologic resolution of rejection within 3 months of inhaled cyclosporine therapy. Pulmonary function (forced expiratory volume in 1 second) improved from pretherapy levels in the patients with acute rejection (p < 0.05). All of the nine histologic responders exhibited 4- to 150-fold decreases (p < 0.05) in IL-6 and interferon-gamma messenger RNA levels in the BAL, whereas the three patients who failed exhibited persistent or increased cytokine profiles. IL-2 and IL-10 in BAL and peripheral blood lymphocyte cytokines were not informative.
  
  
  CONCLUSIONS
  These results indicate that inhaled cyclosporine is effective therapy for refractory pulmonary rejection and that its mechanism of action is associated with suppression of proinflammatory cytokines IL-6 and interferon-gamma within the allograft.
authors.affiliation: Division of Cardiothoracic Surgery, University of Pittsburgh, Pa, USA.
authors.forename: R J
authors.initials: RJ
authors.lastname: Keenan
authors.forename: A
authors.initials: A
authors.lastname: Zeevi
authors.forename: A T
authors.initials: AT
authors.lastname: Iacono
authors.forename: K J
authors.initials: KJ
authors.lastname: Spichty
authors.forename: J Z
authors.initials: JZ
authors.lastname: Cai
authors.forename: S A
authors.initials: SA
authors.lastname: Yousem
authors.forename: N P
authors.initials: NP
authors.lastname: Ohori
authors.forename: I L
authors.initials: IL
authors.lastname: Paradis
authors.forename: A
authors.initials: A
authors.lastname: Kawai
authors.forename: B P
authors.initials: BP
authors.lastname: Griffith
mesh_terms: D000280:Administration, Inhalation; D000328:Adult; D001773:Blood Cells / Q000378:metabolism; D001992:Bronchoalveolar Lavage Fluid / Q000737:chemistry; D016572:Cyclosporine / Q000627:therapeutic use*; D016207:Cytokines / Q000235:genetics* / Q000378:metabolism; D005260:Female; D015870:Gene Expression; D006084:Graft Rejection / Q000188:drug therapy* / Q000473:pathology / Q000503:physiopathology; D006801:Humans; D008168:Lung / Q000473:pathology / Q000503:physiopathology*; D016040:Lung Transplantation; D008214:Lymphocytes / Q000378:metabolism; D008297:Male; D008875:Middle Aged
chemical_list: D016207:Cytokines; D016572:Cyclosporine