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术。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移植排斥反应，除非患者在余生中一直服用免疫抑制药物。抗移植免疫反应的强度，也被称为同种异体反应，由遗传和环境因素决定。在小鼠皮肤和心脏移植模型中，我们先前已经发现，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。这支持了微生物感染作为环境因素可以调节同种异体反应的作用，尽管这些不是经常出现的环境因素。相比之下，居住在我们体内的共生细菌群落，统称为微生物区系，与感染细菌有许多相同的微生物模式，并不断出现在皮肤和肠道等屏障表面。最近的证据表明，微生物区系的组成是由免疫系统决定的，而微生物区系反过来又驱动免疫系统的几个效应器功能。因此，我们提出的假设是，微生物区系是一个重要的和普遍存在的环境因素，可以增强同种异体反应和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区系的无菌小鼠和使用广谱抗生素治疗的常规小鼠，以减少微生物区系的多样性。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都延长了，这表明微生物区系确实增强了同种异体反应的强度，并加速了移植排斥反应。在这项应用中，我们建议研究微生物区系促进移植物排斥反应的机制，以及对免疫抑制和持续同种异体反应的微生物区系组成的影响。最后，我们将尝试为了治疗目的而操纵微生物区系，以限制同种异体反应的强度，延长移植物的存活时间。这项研究将指导对人类的后续研究，以确定微生物区系的影响 关于同种异体免疫和移植结果。由于微生物区系的组成可以通过抗菌素以及益生菌(饮食)、益生菌(有益细菌)和益生菌(细菌代谢产物)来操纵，这一系列研究具有重要的可能的临床益处。

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.