Bronchiolitis Obliterans Syndrome Complicating Lung or Heart-Lung Transplantation

Abstract

Lung transplantation is a therapeutic option for patients with end stage lung diseases, but long-term survival remains poor, primarily due to chronic allograft rejection. Bronchiolitis obliterans (BO), a fibrotic process resulting in progressive narrowing of bronchiolar lumens and airflow obstruction, is a manifestation of chronic allograft rejection. The term obliterative bronchiolitis ( OB) is synonymous. Once bronchiolitis obliterans syndrome (BOS) develops, progressive decline in pulmonary function is typical; most patients die of respiratory failure within 5 years of onset. The diagnosis of BOS is usually made by clinical, physiological, and radiographic parameters. The dominant risk factor for BOS is acute allograft rejection, but additional factors play contributory roles [e.g., infections; human leukocyte antigen (HLA) mismatching; and injury to the allograft or airways]. The pathogenesis of BOS is complex and involves myriad cell types (both immune and nonimmune) and release of diverse cytokines and chemokines. Unfortunately, current therapies for BOS are of unproven value. A greater understanding of the pathogenic mechanisms operative in BOS are critical to developing novel strategies to treat and prevent this devastating complication.

Differentiated transplant derived airway epithelial cell cytokine secretion is not regulated by cyclosporine

“…Despite improvement in peri-operative and early post-transplant outcomes, lung transplant recipients do not obtain the equivalent allograft longevity and resultant survival conferred upon other solid organ recipients [1]. Long-term outcomes in lung transplantation have been complicated by chronic rejection in the form of Bronchiolitis Obliterans Syndrome (BOS) with 50% of patients affected at five years [2,3].…”

Chemokines and Transplant Vasculopathy

“…Early allograft dysfunction in kidney and lung transplantation are known risk factors for chronic rejection (equivalent to TV) 6, 10. Acute cellular rejection in heart transplantation has also been shown to contribute to the development of chronic rejection 7–9. Despite this association, it is important to acknowledge that acute rejection and TV are likely caused by distinct processes.…”

CCR4 expression on host T cells is a driver for alloreactive responses and lung rejection

“…Unfortunately, our current immunosuppressive strategies have been ineffective for long-term lung allograft accommodation (7,9,11,47,48), underscoring the need for new insights into lung alloreactivity. Using stringent animal models of airway and lung allograft rejection, we demonstrate that the CCR4-ligand biological axis is central to the allopriming that leads to graft rejection and that CCR4 deficiency dramatically abolishes rejection by restricting nodal homing and subsequent intranodal activation of CD4 + and CD8 + Tn cells.…”