Prospective Lung Transplant Database for Genetic Research
Condition: Lung Transplantation Rejection
Study type: Observational

Summary: 
      This study will create a database of clinical and biological research for use in future
      studies, with information obtained from lung transplant recipients. The database will consist
      of genetic material and clinical outcomes to be used in future genotyping studies, that is,
      studies regarding the genetic makeup of individuals. Lung transplantation has become an
      important option for patients with advanced lung disease. More than 10,000 patients have
      received them to date, and about 1,200 transplant operations are performed worldwide each
      year. Although short-term survival has continued to improve, the 5-year survival rate is less
      than 50 percent. Most post transplant deaths are directly or directly caused by chronic lung
      rejection, a condition of scarring that worsens lung function.

      Patients evaluated for lung transplants at Duke University Medical Center may be eligible for
      this study.

      For developing the database, a small amount of blood, about 3 tablespoons, will be collected
      from patients. Blood collection for the research will be done at the same time as blood is
      drawn for necessary tests. The blood cells and DNA (which contains genetic material) will be
      isolated for analysis. Patients' DNA samples collected will be identified by a code, and all
      other identifying information will be removed. Patients may be asked to donate additional
      blood samples after their lung transplant if researchers would like to reexamine their blood.

      This study will not have a direct benefit for participants. However, during the study, if it
      is found that any patients have an inherited risk for a disease likely to cause early death
      if the disease is not treated, then the researchers will attempt to notify those patients.
      Overall, it is hoped that information gained during this study will help medical
      professionals to learn more about immune activation and to see how the reactivity of lung
      transplant patients changes over time. If specific genetic risks could be identified, it
      might lead to individualized treatments that work on the immune system. Short-term and
      long-term survival of lung transplant recipients may thus be improved.
    

Detailed description: 
      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.
    

Keywords: Genetic Polymorphisms; Acute Rejection; Bronchiolitis Obliterans Syndrome; Transplant Rejection; Innate Immunity; Lung Transplantation Rejection