Inflammatory Cellular Mechanisms for Establishing and Maintaining Lung Allograft Tolerance

项目摘要/摘要 利用小鼠肺移植模型的研究有助于加深我们对 肺移植特异性免疫调节的研究。与其他固体器官不同，肺依赖于促肾上腺皮质激素。 用于建立和维持移植物接受性的炎性反馈环。我们有 描述了CD8+T细胞，长期以来被认为对实体器官移植存活有害，在 在肺移植耐受中的关键作用。在上一个资助期内，我们发现 肺部嗜酸性粒细胞，也被认为是对移植物健康有害的细胞群，形状 CD8+T细胞的命运阻止了它们的效应器分化。我们也描述了这样的一个 嗜酸性粒细胞-CD8+T细胞反馈环在体内维持移植物存活中起着至关重要的作用。我们 进一步证明了这一发现的翻译潜力，并改进了移植物 气管内给药改变嗜酸性粒细胞向肺内迁移的排异反应 趋化因子。这些数据提供了利用小鼠进行机制研究的原理证据 模型为开发肺特异性免疫抑制方案提供了可能性 和耐受性诱导。在项目2中，我们建议破译同种异体肺移植的多个方面- 耐受性诱导和维持中的特定促炎环路。在目标1中，我们计划 探讨干扰素-γ和白介素1-β在肺移植接受中的相互作用，在目标2中我们将重点关注 耐受诱导中的抗原特异性及其机制/S 不稳定。在目标3中，我们将重点介绍PD-L1在维持耐受中的作用。此外 我们将探索双特异性抗体通过以下途径诱导耐受的可能性 嗜酸性粒细胞与T细胞的强迫相互作用。这里提出的研究将奠定基础 用于大动物和人类在肺移植管理方面的翻译性工作，以努力改善 生死存亡。

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.