title: Calcineurin inhibitors in bronchiolitis obliterans syndrome following stem cell transplantation.
abstract: Bronchiolitis obliterans is a complication after allogeneic haematopoietic stem cell transplantation (HSCT). Management of bronchiolitis obliterans comprises intensive immunosuppression, but treatment response is poor. We investigated the effect of cyclosporine A (CsA), tacrolimus (FK506), methylprednisolone (mPRED), mycophenolate mofetil (MMF) and everolimus on the proliferation of primary lung myofibroblasts from HSCT patients with bronchiolitis obliterans syndrome (BOS). Cells were isolated from surgical lung biopsies of eight HSCT patients with BOS. Proliferation was assessed by [(3)H]-thymidine incorporation. Biopsies revealed constrictive bronchiolitis obliterans in three patients and lymphocytic bronchiolitis in five patients. CsA and FK506 significantly induced proliferation of myofibroblasts. mPRED and MMF caused a significant inhibition of proliferation, whereas everolimus had no effect. Costimulation with FK506, mPRED and MMF significantly inhibited proliferation. Serial pulmonary function tests over 12 months after lung biopsy and under triple therapy demonstrated that patients with lymphocytic bronchiolitis had a significant improvement in forced expiratory volume in 1 s (FEV1), whereas FEV1 of patients with bronchiolitis obliterans was unchanged. Our data demonstrate a pro-proliferative effect of calcineurin inhibitors on primary human lung myofibroblasts obtained from patients with BOS after HSCT. In contrast, based on the observed antiproliferative capacity of MMF in vitro, MMF-based calcineurin inhibitor-free treatment strategies should be further evaluated in patients with bronchiolitis obliterans after HSCT.
authors: University Hospital Basel, Basel.
authors: Katrin E
authors: KE
authors: Hostettler
authors: Jörg P
authors: JP
authors: Halter
authors: Sabine
authors: S
authors: Gerull
authors: Didier
authors: D
authors: Lardinois
authors: Spasenija
authors: S
authors: Savic
authors: Michael
authors: M
authors: Roth
authors: Michael
authors: M
authors: Tamm
mesh_terms: D000328:Adult; D001989:Bronchiolitis Obliterans / Q000188:drug therapy* / Q000209:etiology; D065095:Calcineurin Inhibitors; D049109:Cell Proliferation / Q000187:drug effects*; D002478:Cells, Cultured; D016572:Cyclosporine / Q000494:pharmacology / Q000627:therapeutic use; D004359:Drug Therapy, Combination; D000068338:Everolimus; D005260:Female; D005541:Forced Expiratory Volume; D018380:Hematopoietic Stem Cell Transplantation / Q000009:adverse effects*; D006801:Humans; D007166:Immunosuppressive Agents / Q000494:pharmacology* / Q000627:therapeutic use; D008168:Lung / Q000166:cytology*; D008297:Male; D008775:Methylprednisolone / Q000494:pharmacology / Q000627:therapeutic use; D009173:Mycophenolic Acid / Q000031:analogs & derivatives / Q000494:pharmacology / Q000627:therapeutic use; D058628:Myofibroblasts / Q000187:drug effects*; D020123:Sirolimus / Q000031:analogs & derivatives / Q000494:pharmacology / Q000627:therapeutic use; D016559:Tacrolimus / Q000494:pharmacology / Q000627:therapeutic use
chemical_list: D065095:Calcineurin Inhibitors; D007166:Immunosuppressive Agents; D016572:Cyclosporine; D000068338:Everolimus; D009173:Mycophenolic Acid; D020123:Sirolimus; D016559:Tacrolimus; D008775:Methylprednisolone