Inflammatory Cellular Mechanisms for Establishing and Maintaining Lung Allograft Tolerance

项目总结/摘要 利用小鼠肺移植模型的研究有助于推进我们的理解 同种异体肺移植物特异性免疫调节。与其他实体器官不同，肺依赖于亲- 炎症反馈回路，用于建立和维持移植物接受性。我们有 描述了CD 8 + T细胞，长期以来被认为对实体器官移植物的存活有害， 在肺移植耐受中的关键作用。在上一次融资期间，我们发现， 肺内嗜酸性粒细胞也被认为是对移植物健康有害的细胞群， CD 8 + T细胞的命运，以防止其效应分化。我们还描述了这样的 嗜酸性粒细胞-CD 8 + T细胞反馈环在维持体内移植物存活中起关键作用。我们 进一步证明了这一发现的转化潜力， 通过气管内给药改变嗜酸性粒细胞向肺内迁移的排斥反应 趋化因子这样的数据提供了利用小鼠的机制研究 模型为肺特异性免疫抑制方案的开发提供了可能性 和耐受诱导。在项目#2中，我们建议破译肺移植的多个方面- 特异性促炎环在耐受诱导和维持中的作用。在目标#1中，我们计划 探讨IFN-γ和IL-1-β在肺移植物接受中的相互作用，在目标2中，我们将重点关注 免疫耐受诱导中的抗原特异性以及介导T细胞受体的机制 不稳定在目标3中，我们将重点关注PD-L1在维持耐受性方面的作用。此外 我们将探索双特异性抗体介导的耐受诱导的潜力， 嗜酸性粒细胞和T细胞的强制相互作用。这里提出的研究将奠定基础 在肺移植管理方面的大型动物和人类工作， 生存

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.