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（由申请人提供）：在过去的二十年中，心脏移植第一年之后的死亡率并未显示出显着的改善。我们发现，未能改善长期结果可能与该领域对动物的依赖有关。排斥模型无法捕捉人类移植群体中先前存在或伴随的健康状况，可能影响移植结果的伴随状况的一个例子是高脂血症，这是一种在 95% 的患者中出现的合并症。 5年内，高脂血症主要由于血清胆固醇水平升高而导致动脉粥样硬化，但现在也很明显，高脂血症通过改变适应性和先天免疫来驱动人类和小鼠的全身炎症。为了验证这一假设，我们检查了高脂血症小鼠的心脏移植排斥反应，我们观察到高脂血症会促进同种异体心脏移植的排斥反应。对调节性 T 细胞 (Treg) 功能产生负面影响，并通过促进强 Th17 成分来改变参与排斥反应的 T 细胞亚群，而在正常脂质水平的小鼠中未观察到这些变化，这些变化共同导致对共刺激分子耐受诱导的抵抗。因此，我们的数据表明，高脂血症深刻影响排斥反应和使用临床相关策略诱导耐受的能力，因此研究排斥反应至关重要。 我们的中心目标是通过测试高脂血症通过改变参与排斥反应的 T 细胞亚群的性质来改变适应性同种免疫反应的假设，从而对高脂血症如何影响同种异体反应性和移植排斥产生机制性的理解。我们的具体目标是：1) 确定高脂血症改变 Treg 亚群和功能的机制；2) 确定 Th17 的作用；谱系细胞介导高脂血症小鼠的排斥反应以及形成其反应的机制；3）确定高脂血症如何促进对耐受诱导的抵抗力。高脂血症对排斥反应、其调节以及诱导耐受的能力的影响。