Although pediatric lung transplantation is an accepted therapy for end-stage lung and pulmonary vascular diseased of diverse etiologies in children with potential for normal extrapulmonary organ function and development, unlike other solid organ recipients, the over frequency of late complications has not improved significantly during the past decade. Several lines of evidence, including preliminary data from our Pediatric Lung Transplant Consortium, indicate that the development of antibodies directed against donor tissue antigens (DSA) and cryptic self-antigens (autoAb) correlate with poor long term survival. We propose to test the hypothesis that addition of an induction strategy designed to remove B-cells (rituximab) will improve pediatric lung transplant outcome by reducing the development of DSA and autoantibodies and by limiting T cell alloimmunity, without compromising patient safety. In our randomized, controlled phase II clinical trial, we will use a six center Pediatric Lung Transplant Consortium that includes core laboratories experienced in performance of time-dependent analyses of innate, cellular, and humoral immune responses necessary to define underlying mechanisms. Our clinical sites have sufficient volume to provide an adequate clinical cohort (N=50) to test whether rituximab induction will improve a composite clinical endpoint of bronchiolitis obliterans, death, and re-transplantation. In the accompanying mechanistic study, using state-of- the-art immune assays to assess mechanisms of graft injury in pediatric lung transplant recipients we will test the hypothesis that rituximab induction will reduce the development of donor specific alloantibodies and autoantibodies after transplantation and also limit B-cell antigen presentation that will reduce alloimmune and autoimmune cellular responses. We anticipate that these studies will lead to treatment strategies for improved outcomes in pediatric lung transplantation as well as identifying novel biomarkers predictive of lung allograft dysfunction.
The development of antibodies to both donor tissue and self antigens has been associated with poor outcomes in adult lung transplant recipients. Previous interventions to improve long-term outcomes (bronchiolitis obliterans, death or re-transplantation) in pediatric lung transplant recipients have not focused on prevention of antibody formation against donor specific antigens or self-antigens, and this may account for the lack of substantive improvement in outcomes in pediatric lung transplantation in the last decade. We will test the hypothesis that treatment to remove circulating B-cells, the precursors of antibody producing cells, will improve outcomes in pediatric lung transplant recipients. The associated mechanistic studies in this proposal will improve our understanding of the role that B-cells play in graft rejection and may identify biomarkers that will provide new strategies for early diagnosis and preventative treatment, leading to improved outcomes for pediatric lung transplant recipients.
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