Negative effects on organ transplant rejection and tolerance induced by diet

饮食对器官移植排斥和耐受的负面影响

• 批准号: 9030303
• 负责人: John J Iacomini
• 金额: $ 10.31万
• 依托单位: TUFTS UNIVERSITY BOSTON
• 依托单位国家: 美国
• 财政年份: 2015
• 资助国家: 美国
• 起止时间: 2015-12-01 至 2020-11-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9030303
• 关键词: Affect; Allogenic; Animal Model; Atherosclerosis; Cell Lineage; Cells; Cholesterol; Clinic; Comorbidity; Coronary Arteriosclerosis; Data; Development; Diet; Down-Regulation; Failure; Goals; Graft Rejection; Harvest; Health; Heart Diseases; Heart Transplantation; Human; Hyperlipidemia; Individual; Inflammation; Interleukin-17; Lead; Lipids; Mediating; Mus; Myocardial Ischemia; Natural Immunity; Nature; Organ Transplantation; Outcome; PPAR gamma; Patients; Phosphorylation; Population; Prevalence; Production; Recording of previous events; Regulation; Regulatory T-Lymphocyte; Resistance; Risk Factors; Role; Serum; Shapes; Staging; System; T-Lymphocyte; T-Lymphocyte Subsets; Testing; Therapeutic; Transplant Recipients; Transplantation; adaptive immunity; base; clinically relevant; improved; improved outcome; insight; mortality; novel; novel strategies; prevent; public health relevance; response

 DESCRIPTION (provided by applicant): The mortality rate beyond the first year of heart transplantation has not shown a significant improvement in the last two decades. We hypothesized that the failure to improve long-term outcomes may be related to the field's reliance on animal models of rejection that do not capture preexisting or concomitant health conditions present in the human transplant population. One example of a concomitant condition that could affect transplant outcome is hyperlipidemia, a comorbidity that develops in 95% of patients within 5 years. Hyperlipidemia leads to development of atherosclerosis primarily as a result of increased serum cholesterol levels, however it is also now apparent that hyperlipidemia drives systemic inflammation in humans and mice by altering adaptive and innate immunity. We hypothesized that alterations in adaptive immunity resulting from hyperlipidemia may affect transplant outcome. To test this hypothesis we examined heart transplant rejection in hyperlipidemic mice. We observed that hyperlipidemia promotes rejection of allogeneic hearts transplants. Our data indicate that hyperlipidemia has a negative effect on regulatory T cells (Treg) function and alters the T cell subsets involved in rejection by promoting a strong Th17 component that is not observed in mice with normal lipid levels. Together these changes lead to resistance to tolerance induction using costimulatory molecule blockade. Thus, our data show that hyperlipidemia profoundly affects rejection responses and the ability to induce tolerance using clinically relevant strategies. Therefore it is critical to study rejection in the context of hyperlipidemia in order to develop novel strategies to improve outcomes. Our central goal is to develop a mechanistic understanding of how hyperlipidemia affects alloreactivity and transplant rejection by testing the hypothesis that hyperlipidemia alters adaptive alloimmune responses by changing the nature of the T cell subsets involved in rejection and by altering Tregs. Our specific aims are to: 1) Determine the mechanisms by which hyperlipidemia alters Treg subsets and function; 2) Determine the role of Th17 lineage cells in mediating rejection in hyperlipidemic mice and mechanisms that shape their response; and 3) Determine how hyperlipidemia promotes resistance to tolerance induction. These studies provide novel insight that will fundamentally change how we view transplant rejection and tolerance by revealing a previously unappreciated effect of hyperlipidemia on rejection, its regulation, and the ability to induce tolerance.

 描述（由适用提供）：在过去二十年中，超过心脏移植第一年的死亡率尚未显着改善。我们假设未能改善长期结局的情况可能与该领域对拒绝动物模型的缓解有关，这些模型不会捕获人类移植人群中存在的先前存在或随之而来的健康状况。高脂血症是可能影响移植结果的伴随状况的一个例子，这种合并症在5年内在95％的患者中发展。高脂血症导致血清胆固醇水平升高导致动脉粥样硬化的主要发育，但是现在，高脂血症现在显然可以通过改变适应性和先天的免疫史来驱动人类和小鼠的全身性炎症。我们假设从高脂血症的适应性免疫培养可能会影响移植结果。为了检验这一假设，我们检查了高脂小鼠心脏移植的排斥反应。我们观察到高脂血症促进了同种异体心脏移植的排斥。我们的数据表明，高脂血症对调节性T细胞（TREG）功能具有负面影响，并通过促进在正常脂质水平的小鼠中未观察到的强Th17成分来改变与排斥的T细胞子集。这些变化共同导致使用共刺激分子阻断对耐受性诱导的抗性。这就是我们的数据表明，高脂血症深刻影响了拒绝反应以及使用临床相关策略诱导耐受性的能力。因此，在研究拒绝的背景下至关重要 高脂血症以制定新的策略来改善预后。我们的核心目标是通过测试高脂血症通过改变拒绝和改变Tregs的T细胞子集的性质来改变自适应同种异体反应的假说，对高脂血症如何影响异种反应性和移植排斥反应来发展机械理解。我们的具体目的是：1）确定高脂血症改变Treg子集和功能的机制； 2）确定Th17谱系细胞在介导排斥小鼠中的排斥和塑造其反应的机制中的作用； 3）确定高脂血症如何促进耐受性。这些研究提供了新的见解，从根本上讲，我们通过揭示了先前未经批准的高脂血症对排斥反应，其调节以及诱导耐受性的能力来改变我们如何看待移植排斥和宽容的方式。