Impact of Microbiota on Alloimmune Responses in Transplantation

描述（申请人提供）：实体器官移植是治疗终末期器官衰竭的救命手段。然而，在基因不同的个体之间进行器官移植会导致免疫系统的急性排斥反应，除非患者终生服用免疫抑制药物。抗移植免疫反应的强度，也称为同种异体反应，是由遗传和环境因素共同决定的。在小鼠皮肤和心脏移植模型中，我们之前发现，移植时的细菌感染可以增强同种异体反应，促进移植排斥反应。这支持微生物感染作为环境因素的作用，可以调节同种异体反应，尽管这些不是常见的环境因素。相比之下，居住在我们体内的共生细菌群落，统称为微生物群，与感染性细菌共享许多微生物模式，并且经常存在于皮肤和肠道等屏障表面。最近的证据表明，微生物群的组成是由免疫系统决定的，而微生物群反过来又驱动免疫系统的几种效应功能。因此，我们提出了微生物群是一个重要且无所不在的环境因素，可以增强同种异体反应并促进移植物排斥反应。为了解决这个问题，我们使用了缺乏微生物群的无菌小鼠和用广谱抗生素治疗的常规小鼠来减少微生物群的多样性。我们的初步结果显示，与对照动物相比，两组小鼠的皮肤移植存活时间更长，这表明微生物群确实增强了同种异体反应的强度，加速了移植排斥反应。在这项应用中，我们建议研究微生物群促进移植物排斥反应的机制，以及免疫抑制和正在进行的同种异体反应对微生物群组成的影响。最后，我们将尝试为治疗目的操纵微生物群，以限制同种异体反应的强度并延长移植物的存活时间。这项研究将指导后续的人类研究，以确定微生物群的影响

DESCRIPTION (provided by applicant): Solid organ transplantation is a life-saving procedure to treat end-stage organ failure. However, transplantation of organs between genetically distinct individuals results in acute graft rejection by the immune system unless patients take immunosuppressive drugs for the rest of their lives. The strength of the anti-transplant immune response, also called the alloresponse, is determined by both genetic and environmental factors. In mouse models of skin and heart transplantation, we have previously found that bacterial infections at the time of transplantation can enhance the alloresponse and promote transplant rejection. This supports the role of microbial infections as environmental factors that can modulate alloresponses, although these are not frequent environmental factors. In contrast, the communities of commensal bacteria that inhabit our body, collectively called the microbiota, share many microbial patterns with infectious bacteria, and are constantly present at barrier surfaces such as the skin and the intestine. Recent evidence indicates that the composition of the microbiota is determined by the immune system and that the microbiota, in turn, drives several effector functions of the immune system. Therefore, we have proposed the hypothesis that the microbiota is an important and omnipresent environmental factor that can enhance alloresponses and promote graft rejection. To address this question, we have used both sterile mice devoid of microbiota and conventional mice treated with broad spectrum antibiotics to reduce microbiota diversity. Our preliminary results show that both sets of mice display prolonged skin graft survival compared with control animals, demonstrating that the microbiota indeed enhances the strength of the alloresponse and accelerates graft rejection. In this application, we propose to investigate the mechanisms by which the microbiota promotes graft rejection, as well as the consequences on the composition of the microbiota of immunosuppression and ongoing alloresponses. Finally, we will attempt to manipulate the microbiota for therapeutic purposes to limit the strength of the alloresponse and prolong graft survival. This research will guide follow up studies in humans to identify the impact of microbiota on alloimmunity and graft outcome. As the composition of the microbiota can be manipulated via anti-microbials, as well as prebiotics (diet), probiotics (beneficial bacteria) and postbiotics (products of bacterial metabolism), this line of research has important possible clinical benefits.