Calcineurin inhibitors in bronchiolitis obliterans syndrome following stem cell transplantation

Bronchiolitis obliterans (BO) is a complication after allogeneic hematopoietic stem cell transplantation (HSCT). BO-management 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).Methods: Cells were isolated from surgical lung biopsies of 8 HSCT-patients with BOS. Proliferation was assessed by [3H]-thymidine-incorporation.Results: Biopsies revealed constrictive BO in 3 and lymphocytic bronchiolitis (LB) in 5 patients. CsA and FK506 significantly induced proliferation of myofibroblasts. mPRED and MMF caused a significant inhibition of proliferation, whereas everolimus had no effect. Co-stimulation with FK506, mPRED and MMF significantly inhibited proliferation. Serial pulmonary function tests over 12 months after lung biopsy and under the triple-therapy demonstrated that patients with LB had a significant improvement of their FEV1, whereas FEV1 of patients with BO was unchanged.Conclusion: Our data demonstrate a pro-poliferative effect of calcineurin inhibitors on primary human lung myofibroblasts obtained from patients with BOS after HSCT. In contrast, based on the observed anti-proliferative capacity of MMF in vitro, MMF-based calcineurin inhibitor-free treatment strategies should be further evaluated in patients with BO after HSCT