The microbiota and allograft rejection: novel investigations into the consequences of obesity

微生物群和同种异体移植排斥：对肥胖后果的新研究

• 批准号: 10204895
• 负责人: Maria-Luisa Alegre
• 金额: $ 40.38万
• 依托单位: BRIGHAM AND WOMEN'S HOSPITAL
• 依托单位国家: 美国
• 财政年份: 2017
• 资助国家: 美国
• 起止时间: 2017-07-01 至 2023-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10204895
• 关键词: Affect; Alloantigen; Antibiotics; Antigen-Presenting Cells; Bacteroidetes; Bile Acids; Biological; Blood; Clinical; Communities; Data; Diet; Environmental Risk Factor; Enzymes; Experimental Models; Feces; Firmicutes; GPBAR1 gene; Gastrectomy; Genetic; Germ-Free; Graft Rejection; Graft Survival; High Fat Diet; Hydrolase; Image; Immune system; Immunosuppressive Agents; In Vitro; Intestines; Investigation; Kinetics; Link; Mediating; Metabolic; Metagenomics; Modality; Modification; Mus; Obese Mice; Obesity; Organ; Outcome; Oxides; Phenotype; Reporting; Role; Secondary to; Serum; Shapes; Shotgun Sequencing; Solid; Supplementation; T-Lymphocyte; Testing; Therapeutic; Thinness; Transplantation; Valine; allograft rejection; bacterial metabolism; bariatric surgery; base; clinically relevant; diet-induced obesity; dysbiosis; gut microbes; gut microbiota; host microbiota; human study; improved; in vivo; isoimmunity; microbial; microbial community; microbial composition; microbiome research; microbiota; novel; obese patients; organ transplant rejection; receptor; response; restoration

The extent of genetic disparities between donor and recipients constitutes the main driver that determines the strength of alloimmunity and subsequent kinetics of graft rejection. In recent years, a role for environmental factors has emerged. Our preliminary results have identified 2 inter-related environmental factors that can modulate the strength of the alloimmune response. The first is the microbiota, represented by the communities of microbes that inhabit the body. Here, we reported that the elimination of microbiota through the use of germ- free (GF) mice, or a decrease of microbial diversity induced by broad-spectrum antibiotics (Abx) in both donor and recipient mice prior to transplantation resulted in a reduction of alloreactivity and prolonged graft survival. Mechanistically, antigen-presenting cells (APCs) from GF and Abx-pre-treated mice had a reduced capacity to prime donor-reactive T cells. The second environmental factor is high fat diet (HFD). We showed that obese mice mounted an augmented alloimmunity and rejected transplants faster than lean mice. Mechanistically, APCs from obese mice had a greater capacity to present alloantigen to T cells compared with APCs from lean mice, a mirror image of the phenotype observed in GF and Abx-treated mice. Based on established links between obesity and the gut microbiota, we propose that obesity-dependent dysbiosis super-activates APCs, which, in turn, induces a more potent priming of alloreactive T cells leading to accelerated kinetics of transplant rejection. Using metagenomic shotgun sequencing, we have identified increased proportions of Firmicutes and decreased proportions of Bacteroidetes and Verrucomicrobia in diet-induced obese (DIO) mice. Interestingly, these changes were reversed in mice treated with bariatric surgery (sleeve gastrectomies, SGx), and in mice treated with TDCA/valine, co-metabolites that we found to be reduced in the serum of obese mice and restored by SGx. Of clinical relevance, we detected high levels of B. vulgatus, a commensal species that can metabolize TDCA, in the stool of an obese patient. Based on these preliminary data, we propose that shaping of microbial communities by diet modulates alloimmunity. Specifically, we hypothesize that obesity, via its alteration of the microbiota and through changes of co-metabolites in host/microbiota, enhances DC poising that results in increased priming of alloreactive T cells and accelerated graft rejection; those effects are reverted by bariatric surgery or through the restoration of metabolite levels. This hypothesis will be tested in the context of the following Specific Aims. Specific Aim 1. To determine if the microbiota shaped by HFD before and after bariatric surgery differentially modulates alloimmunity and the kinetics of graft rejection. Specific Aim 2. To investigate the mechanisms by which the microbiota-dependent metabolites TDCA and valine that are decreased in obesity and restored by SGx, modulate alloimmunity and graft rejection. Specific Aim 3. To determine the effects of bariatric surgery on the microbiota, TDCA/valine serum levels, and APC tuning in a pilot human study.

捐赠者和接受者之间遗传差异的程度构成了决定捐赠者和接受者之间遗传差异的主要驱动力。 同种异体免疫的强度和随后的移植物排斥动力学。近年来，环境保护的作用 因素出现了。我们的初步结果已经确定了2个相互关联的环境因素， 调节同种免疫反应的强度。第一个是微生物群， 微生物的数量。在这里，我们报道了通过使用细菌- 自由（GF）小鼠，或减少微生物多样性诱导的广谱抗生素（Abx）在两个供体 和受体小鼠导致同种异体反应性降低和移植物存活延长。 从机制上讲，来自GF和Abx预处理的小鼠的抗原呈递细胞（APC）具有降低的能力， 致敏供者反应性T细胞第二个环境因素是高脂肪饮食（HFD）。我们发现肥胖 小鼠产生了增强的同种免疫，并且比瘦小鼠更快地排斥移植物。机械地说， 肥胖小鼠的APCs比瘦小鼠的APCs有更强的向T细胞呈递同种抗原的能力， 小鼠，在GF和Abx处理的小鼠中观察到的表型的镜像。基于已建立的联系 在肥胖和肠道菌群之间，我们提出肥胖依赖性生态失调超级激活APC， 这反过来又诱导同种异体反应性T细胞的更有效的致敏，导致移植动力学加速。 排斥反应使用宏基因组鸟枪测序，我们已经发现厚壁菌门的比例增加， 降低饮食诱导肥胖（DIO）小鼠中拟杆菌和疣微菌的比例。有趣的是， 这些变化在接受减肥手术（袖状胃切除术，SGx）的小鼠中逆转， 用TDCA/缬氨酸处理，我们发现肥胖小鼠血清中的共代谢物减少， 在SGX临床相关性，我们检测到高水平的B。vulgatus，一种可以代谢 TDCA，在肥胖患者的粪便中。基于这些初步数据，我们提出， 通过饮食调节同种免疫。具体地说，我们假设肥胖，通过改变 通过改变宿主/微生物群中的共代谢物，增强DC平衡，导致 增加同种异体反应性T细胞的启动和加速移植物排斥反应;这些作用通过减肥逆转 手术或通过恢复代谢物水平。这一假设将在以下背景下进行检验： 遵循具体目标。 具体目标1。确定减肥手术前后HFD形成的微生物群是否 差异调节同种免疫和移植排斥的动力学。具体目标2。探讨 在肥胖症中减少的微生物群依赖性代谢物TDCA和缬氨酸的机制 并通过SGx恢复，调节同种免疫和移植排斥反应。具体目标3。以确定影响 减肥手术对微生物群、TDCA/缬氨酸血清水平和APC调节的影响。

项目成果

Association of balanced abdominal organ transplant center volumes with patient outcomes.

平衡腹部器官移植中心体积与患者预后的关系。

• DOI: 10.1111/ctr.14217
• 发表时间: 2021
• 期刊: Clinical transplantation
• 影响因子: 2.1
• 作者: Adler,JoelT;Tsai,ThomasC;Jin,Ginger;Cron,DavidC;Ross-Driscoll,KatherineH;Malek,SayeedK;Tullius,StefanG;Weissman,JoelS
• 通讯作者: Weissman,JoelS

Global Impact of the COVID-19 Pandemic on Solid Organ Transplant.

• DOI: 10.1016/j.transproceed.2022.02.009
• 发表时间: 2022-07
• 期刊: Transplantation proceedings
• 影响因子: 0.9
• 作者: Kute VB;Tullius SG;Rane H;Chauhan S;Mishra V;Meshram HS
• 通讯作者: Meshram HS

Accelerated chronic skin changes without allograft vasculopathy: A 10-year outcome report after face transplantation.

无同种异体移植血管病变的加速慢性皮肤变化：面部移植后 10 年结果报告。

• DOI: 10.1016/j.surg.2020.01.010
• 发表时间: 2020
• 期刊: Surgery
• 影响因子: 3.8
• 作者: Kollar,Branislav;Rizzo,NatalieM;Borges,ThiagoJ;Haug,Valentin;Abdulrazzak,Obada;Kauke,Martin;Safi,Ali-Farid;Lian,ChristineG;Marty,FranciscoM;Rutherford,AnnaE;Mitchell,RichardN;Murphy,GeorgeF;Tullius,StefanG;Riella,Leonard
• 通讯作者: Riella,Leonard