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

• 批准号: 10304904
• 负责人: Maria-Luisa Alegre
• 金额: $ 48.04万
• 依托单位: UNIVERSITY OF CHICAGO
• 依托单位国家: 美国
• 财政年份: 2014
• 资助国家: 美国
• 起止时间: 2014-11-03 至 2024-11-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10304904
• 关键词: Address; Affect; Allografting; Animals; Antibiotics; Bacteria; Bacteroides thetaiotaomicron; Cell physiology; Clinical; Collection; Data; Dendritic Cells; Distal; Etiology; Feces; Funding; Genetic; Germ-Free; Gnotobiotic; Graft Rejection; Graft Survival; Half-Life; Heart; Heart Transplantation; Immune; Immune response; Immune system; Immunosuppression; Immunosuppressive Agents; Individual; Individual Differences; Interferons; Intervention; Intestines; Kidney Transplantation; Kinetics; Location; Lung; Lung Transplantation; MHC Class II Genes; Microbe; Minor; Mus; Organ; Organ Donor; Organ Transplantation; Outcome; Pharmacology; Phase; Probiotics; Role; Site; Skin; Skin Transplantation; Skin colonization; Skin graft; Small Intestines; Staphylococcus aureus; Staphylococcus epidermidis; Sterility; Stomach; System; T-Lymphocyte; Therapeutic; Tissue Donors; Tissues; Transgenic Organisms; Transplantation; allograft rejection; clinically relevant; draining lymph node; experimental study; fecal microbiome; fecal microbiota; genetic signature; germ free condition; gut colonization; gut microbiota; heart allograft; host colonization; improved; insight; isoimmunity; microbial; microbial community; microbiota; migration; negative affect; novel; prebiotics; reconstitution; response; side effect; skin allograft

PROJECT SUMMARY The strength of an immune response against a transplanted organ, termed the alloresponse, depends on the extent of genetic differences between the donor and the recipient and their recognition by the recipient’s immune system. Our studies from the previous funding cycle have shown that the microbiota, the collection of microbes that colonize the body and differ between individuals, is an additional novel factor that can causally modulate the intensity and kinetics of the alloresponse to a transplanted organ. Unlike donor and host genetics, the microbiota can be manipulated therapeutically, thus providing possible new interventions to protect the graft and help reduce the need for immunosuppressive drugs that can cause significant side effects. We initially considered the body’s microbiota as a whole and demonstrated that a reduction in microbial diversity induced by broad-spectrum antibiotic (Abx) pre-treatment, or an absence of microbiota using germ-free (GF) mice, both improved minor mismatched skin graft survival. Fecal microbiome transfer (FMT) from control, but not Abx-pre-treated mice, into GF mice was sufficient to accelerate skin graft rejection. This demonstrated both the causality of the microbiota on affecting graft outcome, and the divergent effects of distinct fecal microbial communities. Abx pre-treatment also delayed rejection of fully mismatched skin grafts, minor mismatched lung grafts, and MHC class II-mismatched heart grafts, indicating that whole-body microbiota affects the outcome of both colonized and sterile organs. We further showed that that some microbial communities could be dominantly protective of rejection. This protection was associated with fecal presence of bacteria of the genus Alistipes. In addition, the half-life of small bowel, lung and skin transplants is much shorter than that of heart and kidney grafts, supporting the hypothesis that the commensals in the graft may also be able to influence alloimmunity. Our recent preliminary experiments demonstrate that colonization of donor skin with the single commensal Staphylococcus epidermidis (S. epi), in the absence of intestinal colonization of the host, can be sufficient to accelerate skin graft rejection. This result clearly demonstrates that microbiota within the allograft also impacts graft outcome. Notably, the mechanism by which skin S. epi accelerates skin graft rejection appears different from how whole-body microbiota in SPF mice or FMT into GF mice accelerates skin graft rejection. We hypothesize a novel paradigm that the recipient gut microbiota affects immune responses in the whole animal by systemically modulating DCs up or down, whereas the microbiota in the donor graft locally affects the effector phase of the alloresponse upon migration of recipient alloreative T cells into the graft. Using a combination of TCR transgenic T cells and p:MHC multimers to track anti-commensal and anti-donor immune responses in parallel, as well as select bacterial colonization of distinct tissues in gnotobiotic mice, we will: 1. Investigate the mechanisms by which gut-only microbes can impact skin graft rejection distally; 2. Define the mechanisms by which skin-only commensals locally accelerate skin graft rejection.

项目概要 针对移植器官的免疫反应的强度（称为同种异体反应）取决于 捐赠者和接受者之间的遗传差异程度以及接受者的认可程度 免疫系统。我们上一个资助周期的研究表明，微生物群、 定殖在体内且在个体之间存在差异的微生物是另一个新因素，可以因果关系 调节对移植器官的同种异体反应的强度和动力学。与供体和宿主遗传学不同， 可以通过治疗手段控制微生物群，从而提供可能的新干预措施来保护移植物 并有助于减少对可能引起严重副作用的免疫抑制药物的需求。 我们最初将人体的微生物群视为一个整体，并证明微生物群的减少 广谱抗生素 (Abx) 预处理诱导的多样性，或使用无菌技术消除微生物群的情况 (GF) 小鼠，均改善了轻微不匹配的皮肤移植存活率。来自对照的粪便微生物组转移（FMT）， 但不是 Abx 预处理的小鼠，进入 GF 小鼠足以加速皮肤移植排斥。这证明了 微生物群对移植结果的因果关系以及不同粪便微生物的不同影响 社区。 Abx 预处理还延迟了完全不匹配的皮肤移植、轻微不匹配的肺的排斥反应 移植物和 MHC II 类不匹配的心脏移植物，表明全身微生物群影响结果 定植器官和无菌器官。我们进一步表明，一些微生物群落可能占主导地位 保护拒绝。这种保护作用与粪便中存在的Alistipes细菌有关。 此外，小肠、肺和皮肤移植的半衰期比心脏和皮肤移植的半衰期短得多。 肾移植物，支持移植物中的共生体也可能影响的假设 同种免疫。我们最近的初步实验表明，单一的供体皮肤定植 共生表皮葡萄球菌 (S. epi) 在没有宿主肠道定植的情况下，可以 足以加速植皮排斥反应。该结果清楚地表明同种异体移植物内的微生物群 也影响移植结果。值得注意的是，皮肤葡萄球菌加速皮肤移植排斥的机制出现 与 SPF 小鼠的全身微生物群或 GF 小鼠的 FMT 加速皮肤移植排斥的方式不同。我们 假设一种新的范例，即受体肠道微生物群影响整个动物的免疫反应 通过系统性地向上或向下调节 DC，而供体移植物中的微生物群局部影响效应器 受体同种异体 T 细胞迁移到移植物后的同种异体反应阶段。使用组合 TCR 转基因 T 细胞和 p:MHC 多聚体可追踪抗共生和抗供体免疫反应 平行，以及选择无菌小鼠不同组织的细菌定植，我们将： 1. 调查 仅肠道微生物影响远端皮肤移植排斥的机制； 2. 定义 仅皮肤共生体局部加速皮肤移植排斥的机制。