Modulation of innate immune cells to create transplant tolerance

项目摘要 这个项目解决了一个新的和新兴的领域-同种异体免疫细胞的同种异体特异性和记忆 特别关注巨噬细胞以及此类细胞如何影响移植结果。最近的报道说 在广泛的免疫抑制治疗下或在侵袭性T细胞耗尽后移植物丢失主要由 巨噬细胞，加上巨噬细胞可以区分自体和异体的有力证据 选定的移植模型，将巨噬细胞置于移植物损伤的聚光灯下。我们相信 诱导移植耐受需要综合的策略，既针对先天的也针对适应性的 免疫细胞，而这种方法需要详细了解先天免疫细胞如何对 同种异体抗原。 我们提供了巨噬细胞可能使用非常不同的机制来区分自身的第一个证据。 来自同种异体非我。我们发现巨噬细胞能有效地排斥抗原中的异体异体- 具体的方式。我们发现的一个突出特征是，这种同种异体特异性是诱导的，需要 同种异体抗原和CD40结合的刺激。我们产生了新的数据，即同种异体的配体 巨噬细胞是MHC I类分子的供体，巨噬细胞很可能使用配对的Ig样分子 受体(PIRS)对异体异体作出反应。在这个项目中，中心假设是 巨噬细胞使用成对的Ig样受体(PIR)来感知同种异体细胞，以及靶细胞的排斥反应 需要进一步获得细胞溶解M1功能。为了检验这一假设，我们提出了三个目标。目标1 阐述了PIR-A的同种异构体和信号通路及其与PIR-B的关系。目标 2研究了在巨噬细胞中诱导PIR和细胞溶解活性的分子途径， 调查这两个过程是否受到不同机制的调控。目标3决定 同种异体巨噬细胞是否可以通过调节其同种异体特异性或细胞溶解来重定向 有利于移植物在体内存活的途径。我们拥有研究PIR系统的所有工具，包括PIR-A/B 缺陷型小鼠和FCRγ缺陷型小鼠。这些模型和工具使我们在 解决本申请中提出的问题。这条调查路线将导致我们的重大进展 了解先天免疫细胞在移植耐受中的作用。

Project Summary This project addresses a new and emerging area- allospecificity and memory of innate immune cells with a specific focus on macrophages and how such cells impact transplant outcomes. The recent reports that graft loss under broad immunosuppression therapies or after aggressive T cell depletion is dominated by macrophages, plus the strong evidence that macrophages can discriminate self from allogeneic non-self in selected transplant models, place macrophages right under the limelight of graft damage. We believe that induction of transplant tolerance requires comprehensive strategies that target both the innate and adaptive immune cells, and this approach demands a detailed understanding of how innate immune cells respond to alloantigens. We provide the first evidence that macrophages may use a very different mechanism to discriminate self from allogeneic non-self. We showed that macrophages potently rejected allogeneic non-self in an antigen- specific manner. One outstanding feature of our findings is that this allospecificity is induced, and requires stimulation by alloantigens and CD40 engagement. We generated new data that the ligands for allospecific macrophages are donor MHC class I molecules, and macrophages most likely use the paired Ig-like receptors (PIRs) to respond to allogeneic non-self. In this project the central hypothesis is that macrophages use paired Ig-like receptors (PIR) to sense allogeneic cells, and that rejection of target cells requires further acquisition cytolytic M1 features. We put together 3 Aims ito test this hypothesis. Aim 1 addresses the allospecificity PIR-A isoforms and signaling apparatus, and its relationships with PIR-B. Aim 2 examines the molecular pathways leading to the induction of PIR and cytolytic activities in macrophages, investigating whether these two processes are regulated by different mechanisms. Aim 3 determines whether allospecific macrophages could be redirected by modulating either their allospecificity or cytolytic pathways to favor graft survival in vivo. We have all the tools to study the PIR system, including PIR-A/B deficient mice and FcR gamma deficient mice. These models and tools put us in a unique position in resolving the questions proposed in this application. This line of inquiry will lead to major advance in our understanding of innate immune cells in transplant tolerance.