Inflammatory Cellular Mechanisms for Establishing and Maintaining Lung Allograft Tolerance

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PROJECT SUMMARY/ABSTRACT Studies utilizing the murine model of lung transplantation have helped advance our understanding of lung allograft-specific immunoregulation. Unlike other solid organs, the lung relies on pro-inflammatory feedback loops for establishing and maintaining graft acceptance. We have described that CD8+ T cells, long considered deleterious to solid organ allograft survival, play a critical role in lung allograft tolerance. During the last funding period we have uncovered that lung-resident eosinophils, also considered a detrimental cell population for graft health, shape CD8+ T cell fate to prevent their effector differentiation. We have also described that such eosinophil-CD8+ T cell feedback loops play a crucial role in maintaining graft survival in vivo. We have further demonstrated the translational potential of this discovery and ameliorated graft rejection by altering eosinophil migration into the lung through intra-tracheal administration of chemokines. Such data provides proof of principle that mechanistic studies utilizing murine models offer the possibility for the development of lung-specific protocols for immunosuppression and tolerance induction. In project #2 we propose to decipher multiple aspects of lung allograft-specific proinflammatory loops in tolerance induction and maintenance. In aim #1 we plan to explore the interactions of IFN-γ and IL1-β in lung allograft acceptance and in aim #2 we will focus on antigen specificity in tolerance induction as well as mechanism/s mediating T cell receptor instability. In aim #3 we will focus on the role of PD-L1 in maintenance of tolerance. In addition we will explore the potential for bi-specific antibody-mediated induction of tolerance through forced interaction of eosinophils and T cells. The studies proposed here would lay the foundation for translational large animal and human work in lung allograft management in an effort to improve survival.