Chronic lung allograft dysfunction (CLAD) has emerged as the primary obstacle to long-term survival after lung transplantation. Although the pathogenesis of CLAD remains unclear, clinical risk factors including acute cellular rejection (ACR), lymphocytic bronchiolitis (LB), primary graft dysfunction (PGD), and the development of donor-specific antibodies (DSA) to mismatched human leukocyte antigens (HLA) have been consistently identified. Approximately 50% of lung transplant recipients develop DSA within the first year after transplantation. Clinical studies illustrate that DSA plays a central role in the development of CLAD and is associated with an increased risk of death. DSA increase the risk of high-grade and persistent ACR and LB. Furthermore, experimental studies suggest that antibodies to mismatched major histocompatibility complex (MHC) antigens have a direct pathogenic effect on the allograft resulting in airway lesions similar to human obliterative bronchiolitis. This project will use a pilot randomized controlled trial to assess the feasibility of conducting a large- scale randomized controlled trial that tests the hypothesis that Belatacept inhibits the development of DSA, decreases the risk of CLAD, and improves survival after lung transplantation. This pilot study's primary endpoint is a composite of DSA development, death, or re-transplantation, and key secondary endpoints are ACR, LB, antibody-mediated rejection (AMR), and CLAD. This project addresses an important problem in lung transplantation, and has the potential to change clinical practice and improve outcomes for lung transplant recipients.
Approximately 2,000 people undergo lung transplantation annually in the U.S. However, the median survival after lung transplantation is 5.5 years, and chronic rejection is the leading cause of death beyond the first year. The proposed study evaluates the efficacy of a novel maintenance immunosuppression protocol in preventing the development of chronic rejection. Findings from the study have the potential to change the routine care of lung transplant recipients and improve their survival.
