B-CELL TARGETED INDUCTION TO IMPROVE OUTCOMES IN PEDIATRIC LUNG TRANSPLANTATION

Washington University, Saint Louis MO

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Abstract

DESCRIPTION (provided by applicant): 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.