Chronic rejection is the principal obstacle to long-term survival and function of heart allografts, both clinically and in our cynomolgus monkey non-human primate model. This application will test the hypothesis that pathogenic mechanisms driven by the CD28/B7, CD40/CD154, and ICOS costimulation pathways mediate CAV, and constitute the principal barrier to tolerance induction for a heart allograft. This hypothesis is strongly supported by our findings during the first term of this award mechanism. When combined with either a calcineurin inhibitor (CNI: cyclosporine A) or CD154 blockade, selective targeting of CD28 for three weeks after transplant significantly inhibited alloantibody elaboration and CAV at 90 days after transplant. Similarly, pre-emptive B-cell depletion with ?CD154 or CNI significantly inhibited pathogenic alloimmunity. This application will extend these observations and evaluate whether the ?CD28/B7- and ?CD40/CD40L-based costimulation pathway blocking regimens that appear most promising in our work to date will consistently induce tolerance to a cardiac allograft one year after cessation of treatment. Specifically, the durability and failure mode of our most promising regimens (anti-CD28 with additional CD40/CD154 blockade;?CD28 induction with delayed CNI withdrawal) will be established. In addition, selective ?CD28 with preemptive B-cell depletion and CD40 blockade or depletion to replace ?CD154 will be systematically evaluated for their tolerogenic potential. We predict that more effective control of pathogenic costimulation pathway activation will prevent alloantibody elaboration and CAV progression after treatment ends, and prevent loss of unresponsiveness to cardiac myosin, a heart-specific autoantigen. If so, we predict that graft acceptance and operational tolerance will also be observed in otherwise immunocompetent monkeys, as gauged by their responses to a panel of vaccine antigens. By measuring how alloimmunity and loss of tolerance to autoantigens are modulated by these candidate tolerance-inducing regimens, we will identify pathways resistant to costimulation-based tolerance induction and assess the biological and molecular correlates of graft injury or acceptance.
This Project will directly evaluate several promising costimulation blockade strategies to induce tolerance in cynomolgus monkey heart allograft recipients, and will improve our understanding of mechanisms of graft acceptance or injury that are associated with these regimens. Biomarkers predictive of acute or chronic rejection or associated with tolerance (graft acceptance after withdrawal of immunosuppression) will also be identified and their utility assessed.
|Zhang, Tianshu; Pierson 3rd, Richard N; Azimzadeh, Agnes M (2015) Update on CD40 and CD154 blockade in transplant models. Immunotherapy 7:899-911|
|Harris, Donald G; Quinn, Kevin J; French, Beth M et al. (2015) Meta-analysis of the independent and cumulative effects of multiple genetic modifications on pig lung xenograft performance during ex vivo perfusion with human blood. Xenotransplantation 22:102-11|
|Pierson 3rd, Richard N; Bromberg, Jonathan S (2015) Alloantibodies and Allograft Arteriosclerosis: Accelerated Adversity Ahead? Circ Res 117:398-400|
|Harris, Donald G; Quinn, Kevin J; Dahi, Siamak et al. (2014) Lung xenotransplantation: recent progress and current status. Xenotransplantation 21:496-506|
|Beazley, Kelly E; Zhang, Tianshu; Lima, Florence et al. (2012) Implication for transglutaminase 2-mediated activation of Ã½Ã½-catenin signaling in neointimal vascular smooth muscle cells in chronic cardiac allograft rejection. J Heart Lung Transplant 31:1009-17|
|Mohiuddin, M M; Corcoran, P C; Singh, A K et al. (2012) B-cell depletion extends the survival of GTKO.hCD46TgÃ½Ã½Ã½pig heart xenografts in baboons for up to 8 months. Am J Transplant 12:763-71|
|Zhang, T; Fresnay, S; Welty, E et al. (2011) Selective CD28 blockade attenuates acute and chronic rejection of murine cardiac allografts in a CTLA-4-dependent manner. Am J Transplant 11:1599-609|
|Kelishadi, Shahrooz S; Azimzadeh, Agnes M; Zhang, Tianshu et al. (2010) Preemptive CD20+ B cell depletion attenuates cardiac allograft vasculopathy in cyclosporine-treated monkeys. J Clin Invest 120:1275-84|
|Poirier, Nicolas; Azimzadeh, Agnes M; Zhang, Tianshu et al. (2010) Inducing CTLA-4-dependent immune regulation by selective CD28 blockade promotes regulatory T cells in organ transplantation. Sci Transl Med 2:17ra10|
|Pierson 3rd, Richard N (2009) Antibody-mediated xenograft injury: mechanisms and protective strategies. Transpl Immunol 21:65-9|
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