Negative effects on organ transplant rejection and tolerance induced by diet

 描述(申请人提供)：心脏移植第一年以后的死亡率在过去的二十年中没有明显的改善。我们假设，未能改善长期结果可能与该领域对排斥反应动物模型的依赖有关，这些动物模型没有捕捉到人类移植人群中存在的先前存在的或伴随的健康状况。一个可能影响移植结果的伴随情况是高脂血症，这是一种在5年内在95%的患者中发展起来的共病。高脂血症导致动脉粥样硬化的主要原因是血清胆固醇水平升高，但现在也很明显，高脂血症通过改变获得性免疫和先天免疫来推动人类和小鼠的全身炎症。我们推测，高脂血症引起的获得性免疫改变可能会影响移植结果。为了验证这一假设，我们研究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，并通过促进一种在正常血脂水平的小鼠中未观察到的强大的Th17成分来改变参与排斥反应的T细胞亚群。这些变化共同导致了利用共刺激分子阻断诱导耐受的抗性。因此，我们的数据显示，高脂血症深刻地影响排斥反应和使用临床相关策略诱导耐受的能力。因此，在拒绝的背景下研究拒绝是至关重要的 高脂血症，以开发新的战略，以改善结果。我们的中心目标是通过验证高脂血症通过改变参与排斥反应的T细胞亚群的性质和改变Tregs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械性理解。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Th17系细胞在高脂血症小鼠中介导排斥反应的作用和塑造其反应的机制；以及3)确定高脂血症如何促进对耐受诱导的抵抗。这些研究提供了新的见解，通过揭示高脂血症对排斥反应、其调节和诱导耐受的能力，将从根本上改变我们看待移植排斥和耐受的方式。

 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.