Prospective Lung Transplant Database for Genetic Research

Lung transplantation has emerged as a viable therapeutic option in the care of patients with advanced pulmonary parenchymal and pulmonary vascular disease. Currently, over 10,000 patients have received lung transplantation with approximately 1200 transplant operations performed worldwide each year. Short-term survival after lung transplantation has continued to improve since the widespread application of this procedure and one-year survival at most centers now approaches 80%. Unfortunately, long-term outcomes after lung transplantation are disappointing with five-year survival below 50%. Most posttransplant deaths are due directly or indirectly to the development of acute or chronic rejection. Acute rejection is defined by the presence of perivascular mononuclear inflammatory cells. Obliterative bronchiolitis (OB) describes fibrosis and obliteration of the small to medium size bronchioles, the histological manifestation of chronic lung rejection. Bronchiolitis obliterans syndrome (BOS) is thought to correlate with the development of histological OB when other causes of allograft dysfunction have been excluded. The diagnosis of OB is based primarily on a decline in spirometry with exclusion of alternative diagnoses with bronchoscopy and biopsy, i.e. development of clinical BOS. Since the introduction of BOS nomenclature, numerous studies have validated the clinical and prognostic importance of this syndrome and verified its correlation with histological OB.

Chronic rejection describes a histological pattern of fibrous obliteration of endothelial or epithelial structures in the allograft. A similar pattern of histological fibrosis is observed in all types of solid organ transplants (e.g., obliterative arteriopathy in heart transplant, BOS in lung transplant), and occurs despite the use of currently available, primarily T-cell based, immune suppression. The rates of chronic rejection vary considerably with the type of organ transplanted. By five years after transplantation histological fibrosis occurs in approximately 20% of kidney, 40% of heart and 60-80% of lung recipients. Thus, lung transplantation is characterized by an unusually high incidence of chronic graft rejection manifest as BOS.

Because of the high rate of acute and chronic lung transplant rejection, research designed to better correlate clinical outcomes with the genetic risks for rejection is critical to improving patient outcomes. We recently completed a study that demonstrated two single nucleotide polymorphisms (SNPs) Asp299Gly and Thr399Ile (polymorphisms of the human Toll 4 gene associated with endotoxin hyporesponsiveness) were associated with decreased acute rejection after lung transplantation.

We hypothesize that other SNPs associated with either increased or decreased innate or adaptive immune activation will be critical to determining the clinical outcome with regards to acute and chronic rejection after lung transplant. If specific genetic risks for rejection after transplant could be identified, this might lead to highly tailored immunosuppressive regimens and improved clinical outcomes.