Proteasome targeting for alloreactive plasma cells

摘要 分泌抗供体组织同种异体抗原抗体的浆细胞的诱导 这是移植成功的主要障碍。此外，由于许多浆细胞是 产生的抗体滴度非常持久，寿命非常长。因此 需要采取策略来消除产生同种异体特异性的长寿命浆细胞 抗体。目前耗尽浆细胞的主要策略集中在 干扰蛋白酶体的化合物。浆细胞被认为是唯一的 需要蛋白酶体功能才能存活。然而，由于不清楚的原因，重大的 同种异体特异性浆细胞数量可抵抗可用蛋白酶体抑制剂的作用 (PIS)。新形成的浆细胞， 由持续的抗原诱导，也贡献了大量的有害物质 抗体。该项目的主要目标是确定绩效指标对新的 形成的与长寿的浆细胞的对比，并定义了生化反应如何 低氧影响线粒体凋亡调节浆细胞对 蛋白酶体阻断。这项工作将利用我们独特的能力来解决和 描述新形成的浆细胞与长期存活的浆细胞的特征。具体来说，我们将：1) 对比PI对新形成的PC和长期使用的PC的影响。2)测试是否 低氧生态位和HIF1-α增强PC对PI的抗性，以及3)识别PI诱导的 长寿PC中的线粒体死亡和抗性机制。这些研究将 对蛋白酶体抑制的机制提供独特和必要的见解 影响同种异体浆细胞的存活和功能。

Abstract The induction of plasma cells that secrete antibodies against donor tissue alloantigens is a major barrier to successful transplantation. Moreover, because many plasma cells are exceptionally long-lived, the resulting antibody titers are exceptionally durable. Hence strategies are needed to eliminate long-lived plasma cells that generate allospecific antibodies. A current dominant strategy for depleting plasma cells centers on compounds that interfere with the proteasome. Plasma cells are thought to uniquely require proteasome function to survive. However, for reasons unclear, substantial numbers of allospecific plasma cells resist the action of available proteasome inhibitors (PIs). This issue is compounded by the possibility that newly formed plasma cells, induced by persisting antigens, also contribute substantial amounts of deleterious antibodies. The chief objective of this project is to establish the impact of PIs on newly formed versus long-lived plasma cells, and define how biochemical responses to hypoxia affect mitochondrial apoptosis regulate responses of plasma cells to proteasome blockade. This work will leverage our unique capacity to resolve and characterize newly formed versus long-lived plasma cells. Specifically, we will: 1) Contrast the impact of PIs on newly formed versus long-lived PCs. 2) Test whether hypoxic niches and HIF1-alpha enhance PC resistance to PIs, and 3) Identify PI-induced mitochondrial death and resistance mechanisms in long-lived PCs. These studies will provide unique and needed insights into the mechanisms whereby proteasome inhibition affects allospecific plasma cell survival and function.