Impact of Microbiota on Alloimmune Responses in Transplantation

移植中微生物群对同种免疫反应的影响

基本信息

批准号：
9170958
负责人：
Maria-Luisa Alegre
金额：
$ 38.94万
依托单位：
UNIVERSITY OF CHICAGO
依托单位国家：
美国
项目类别：
财政年份：
2014
资助国家：
美国
起止时间：
2014-11-03 至 2019-10-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9170958
关键词：
Acute Address Affect Allografting Antibiotics Bacteria Bacterial Infections Body Surface Chronic Clinical Communities Complex Control Animal Cutaneous Dendritic Cells Dependence Diet Distal Environmental Risk Factor Follow-Up Studies Generations Genetic Germ-Free Graft Rejection Graft Survival Health Heart Heart Transplantation Human ITGAX gene Immune response Immune system Immunity Immunosuppression Immunosuppressive Agents Individual Infection Inflammation Intervention Intestines Ischemia Kidney Lead Life Lung Minor Modeling Molecular Mus Organ Organ Transplantation Outcome Patient-Focused Outcomes Patients Pattern Pharmaceutical Preparations Phase Phenotype Probiotics Procedures Prophylactic treatment Reperfusion Therapy Reporting Research Rest Role Savings Secondary to Signal Transduction Skin Skin Transplantation Skin graft Solid Sterility Surface T-Lymphocyte Testing Therapeutic Time Tissues Toll-like receptors Translating Transplant Recipients Transplantation allograft rejection antimicrobial bacterial metabolism commensal microbes end-stage organ failure experimental study gut microbiota immune system function improved isoimmunity lymph nodes microbial microbial community microbiota migration mouse model prebiotics prophylactic public health relevance response skin microbiota

项目摘要

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.

描述（由申请人提供）：固体器官移植是一种挽救生命的程序，用于治疗终阶段器官衰竭。但是，除非患者在余生中服用免疫抑制药物，否则在遗传上不同的个体之间的器官移植会导致免疫系统的急性移植排斥。抗移植免疫反应的强度（也称为同种异）由遗传和环境因素决定。在皮肤和心脏移植的小鼠模型中，我们先前发现，移植时的细菌感染可以增强同种异体响应并促进移植排斥。这支持微生物感染作为可以调节同种异常的环境因素的作用，尽管这些因素不是频繁的环境因素。相比之下，居住在我们体内的共生细菌群落（共同称为微生物群）与传染性细菌共享许多微生物模式，并且不断存在于皮肤和肠道等屏障表面。最近的证据表明，微生物群的组成由免疫系统确定，而微生物群反过来驱动了免疫系统的多种效应子功能。因此，我们提出了以下假设：微生物群是一个重要且无所不在的环境因素，可以增强同种异体调查并促进移植排斥。为了解决这个问题，我们已经使用了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。我们的初步结果表明，两组小鼠与对照动物相比表现出长时间的皮肤移植物存活率，这表明微生物群确实可以增强同种异腺响应的强度，并加速了移植物排斥。在此应用中，我们建议研究微生物群促进移植排斥反应的机制，以及对免疫抑制和持续同种反应的菌群组成的后果。最后，我们将尝试操纵微生物群以进行治疗目的，以限制同种异体响应的强度和延长移植物的生存。这项研究将指导人类的后续研究以确定菌群的影响关于同种免疫和移植结果。由于可以通过抗微生物剂以及益生元（饮食），益生菌（有益细菌）和生物后（细菌代谢产物）（细菌代谢产物）来操纵菌群的组成，因此这种研究系列具有重要的临床益处。