Negative effects on organ transplant rejection and tolerance induced by diet

 描述（申请人提供）：心脏移植第一年后的死亡率在过去二十年中没有显着改善。我们假设，未能改善长期结果可能与该领域依赖于排斥反应的动物模型有关，这些模型没有捕获人类移植人群中存在的预先存在或伴随的健康状况。可能影响移植结果的伴随疾病的一个例子是高脂血症，95%的患者在5年内发生这种合并症。高脂血症导致动脉粥样硬化的发展，主要是由于血清胆固醇水平升高，然而，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。我们推测高脂血症引起的适应性免疫改变可能影响移植结果。为了验证这一假设，我们研究了高血压小鼠的心脏移植排斥反应。我们观察到高脂血症促进同种异体心脏移植的排斥反应。我们的数据表明，高脂血症对调节性T细胞（Treg）功能有负面影响，并通过促进在正常脂质水平的小鼠中未观察到的强Th 17组分来改变参与排斥反应的T细胞亚群。这些变化共同导致对使用共刺激分子阻断的耐受诱导的抗性。因此，我们的数据表明，高脂血症深刻地影响排斥反应和能力，诱导耐受性使用临床相关的策略。因此，在以下背景下研究拒绝是至关重要的 高脂血症，以开发新的策略，以改善结果。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细胞亚群的性质和通过改变T细胞亚群来改变适应性同种异体免疫反应的假设，来发展对高脂血症如何影响同种异体反应性和移植排斥反应的机制性理解。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Th 17谱系细胞在高脂血症小鼠中介导排斥反应的作用和形成其反应的机制;和3）确定高脂血症如何促进对耐受诱导的抗性。这些研究提供了新的见解，将从根本上改变我们如何看待移植排斥反应和耐受性，揭示了以前不受重视的高脂血症对排斥反应的影响，其调节，以及诱导耐受的能力。

 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.