Mechanisms of microbiome-driven cardiac allograft outcomes

项目总结 虽然心脏移植的一年存活率已达90%-95%，但其死亡率超过了 在过去的二十年里，第一年没有改变。免疫介导的损伤仍然是导致 长期的移植物衰竭。我们和其他研究的发现为研究肠道提供了理论基础。 微生物组作为移植后结果的决定因素和诱导免疫的潜在工具 调节以改善移植的长期结果。这项研究的目标是通过以下方式确定其机制 肠道微生物群会影响同种异体移植的结果。我们推测，被扰乱的新陈代谢活动 肠道微生物群通过细胞类型特异性反应导致炎症反应和肠道损伤 肠道细胞网络，随后调节同种异体免疫，最终调节慢性心脏移植 结果。我们将利用我们的临床相关的慢性排斥反应小鼠心脏移植模型 具有良好特征的同种异体反应，由促炎或抗炎细菌诱导，以确定 AIM 1中微生物代谢活动的变化，然后确定局部肠道屏障的变化和 AIM 2中潜在的肠道细胞类型特异性反应，并最终表征全身同种异体反应 和移植物存活在目标3，以获得一个整体的确切机制的了解 微生物组驱动的慢性移植物结局。拟议的工作将确定基于微生物组的新的和关键的 诊断应用和治疗干预的目标，辨别复杂和双向 微生物群与同种异体免疫之间的对话促进移植免疫的静止期和长效 心脏移植物长期存活率。

PROJECT SUMMARY Though the one-year survival rate in cardiac transplantation has reached 90-95%, the mortality rate beyond the first year has not changed in the last two decades. Immune-mediated damage remains the primary cause of long-term graft failure. Findings from our and other studies provide the rationale for investigating the gut microbiome as a determinant of post-transplantation outcomes and as a potential tool to induce immune modulation to improve long-term graft outcomes. The goal of this study is to determine the mechanisms by which the gut microbiome impacts allograft outcome. We postulate that the disrupted metabolic activities of the gut microbiome lead to inflammatory responses and intestinal injury via cell-type specific responses in the intestinal cells network, which subsequently modulate alloimmunity and ultimately chronic cardiac graft outcomes. We will take advantage of our clinically-relevant cardiac transplant murine model of chronic rejection with well-characterized alloresponses, induced by pro- or anti-inflammatory bacteria, to determine the alterations in the microbial metabolic activities in Aim 1, then to identify local intestinal barrier changes and the underlying intestinal cell-type specific responses in Aim 2, and finally to characterize systemic alloresponses and graft survival in Aim 3, in order to obtain a holistic understanding of the precise mechanisms of microbiome-driven chronic graft outcomes. The proposed work will identify novel and critical microbiome-based targets for diagnostic application and therapeutic intervention, and discern the complex and bidirectional dialogue between the microbiome and alloimmunity to promote transplant immunologic quiescence and long- term cardiac graft survival.