Chronic Graft Destruction: Interplay of Allo- and Autoantibodies and Nonadherence

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DESCRIPTION (provided by applicant): Heart transplantation remains a palliative therapy with few recipients achieving survival beyond 20 years. Early results have improved secondary to reductions in perioperative mortality and early acute rejection rates have also fallen. However, ongoing graft loss occurs at a steady state of 2-3% per year after the first year with 'chronic rejection' being the commonest cause of late graft loss. Current medication regimens are effective at preventing acute rejection but appear to be largely ineffective at preventing graft vasculopathy. Our failure to make strides in this area reflects our ignorance of the mechanisms driving this serious complication. An emerging literature suggests that donor-specific HLA antibodies (DSA) are key drivers of chronic graft loss, and nonadherence may play an important role in their development. There is also a mounting body of literature to suggest that immunity to self-antigens plays an important role in the development of graft vasculopathy, though this has not been studied in children. We aim to address the complex interplay between alloimmunity, autoimmunity and nonadherence. We will address these themes through three interrelated studies. Project 1 is an observational cohort study to determine the long-term impact of DSA (preformed versus de novo) and antibodies to self-antigens (cardiac myosin, vimentin) on chronic graft function. We will also evaluate the impact of allo- and autoantibodies on the incidence of late (>1 year) serious adverse events including death, acute rejection, and acute graft dysfunction. Risk factors for outcomes will be defined, and the molecular pathology of late rejection episodes will be evaluated. The impact of antibodies on the development of altered microvascular pathophysiology will be assessed through evaluation of endothelial cell structure and signaling, interstitial capillary network and obliterative microvasculopathy (arteriolopathy). Innovative multiplex labeling, automated image analysis and endothelial cell culture models will be used to accomplish this endpoint. We hypothesize that de novo DSA will be the strongest predictors of adverse outcomes and development of microvasculopathy and that nonadherence will drive this complication. Project 2 will be a randomized, controlled trial of a novel mobile device application (Teen Pocket PATH) to improve adherence in children greater than 11 years of age after heart transplantation. We hypothesize that the intervention will improve adherence to medications and will reduce acute rejection events. We also hypothesize that this will lead to less de novo production of allo- and autoantibodies. Project 3 will be a phase II non-randomized, open label trial of a bortezomib-based regimen for desensitization of highly sensitized pediatric heart transplant candidates to assess the safety of the regimen in a pediatric population and to assess efficacy via evaluation of calculated PRA, antibody strength and complement fixing ability/IgG subclass and proportion of patients with negative cross-match against donor on pre- versus post-treatment sera. We hypothesize that a bortezomib-based regimen will be effective in reducing anti-HLA antibodies and reducing calculated PRA.