Ecto-enzyme CD38: Regulator of dendritic cell migration

描述（由申请方提供）：免疫应答依赖于白细胞从抗原沉积部位到次级淋巴器官和感染或炎症部位的协调运动。趋化因子通过引导白细胞在整个身体中的运输在该过程中发挥关键作用。尽管众所周知白细胞表达趋化因子受体并且可以响应于趋化因子梯度定向迁移，但是控制趋化因子受体应答的分子机制仍然在很大程度上未知。CD 38是一种ADP-核糖环化酶，催化钙动员代谢产物环ADP-核糖（cADPR）的产生，似乎是趋化因子受体信号传导和白细胞运输的关键调节剂。我们观察到CD 38缺陷小鼠中性粒细胞迁移受损，导致炎症反应减弱和降低。我们还发现，CD 38产生的cADPPR调节中性粒细胞中的钙动员，这些中性粒细胞已被炎性化学引诱物（如细菌和病毒衍生的肽）激活。此外，我们发现cADPR特异性拮抗剂阻断中性粒细胞对这些肽的迁移反应。这些数据表明，CD 38的小分子抑制剂可能用于阻断嗜中性粒细胞依赖性炎症反应。最近，我们观察到树突状细胞的迁移反应也在CD 38缺陷小鼠中受损。具体来说，我们发现CD 38缺陷型树突状细胞不能响应ELC或SLC而迁移，ELC或SLC是指导树突状细胞从损伤或损伤部位迁移到淋巴组织的趋化因子。在CD 38缺陷树突状细胞中观察到的这种受损的趋化反应导致T细胞引发效率低下，并显著降低了T细胞依赖性免疫反应。基于我们先前的数据，我们现在假设CD 38通过其cADPR的产生，通过调节树突状细胞的迁移来调节细胞依赖性免疫应答。为了验证这一假设，我们提出了以下具体目标：（1）我们将确定CD 38是否调节所有成熟树突状细胞亚群向ELC或SLC的迁移，（2）我们将确定CD 38是否调节树突状细胞向炎性化学引诱物的迁移，（3）我们将确定CD 38产生的cADPR是否控制体内树突状细胞的运输。这些实验将验证CD 38拮抗剂是否具有用作免疫抑制剂的潜力，所述免疫抑制剂通过调节白细胞运输来减弱免疫应答。

DESCRIPTION (provided by applicant): Immune responses are dependent on the coordinated movement of leukocytes from sites of antigen deposition, to secondary lymphoid organs and to sites of infection or inflammation. Chemokines play a critical role in this process by directing leukocyte trafficking throughout the body. Although it is well known that leukocytes express chemokine receptors and can migrate directionally in response to chemokine gradients, the molecular mechanism(s) that control chemokine receptor responses are still largely unknown. CD38, an ADP-ribosyl cyclase, that catalyzes the production of the calcium-mobilizing metabolite cyclic ADP-ribose (cADPR), appears to be a critical regulator of chemokine receptor signaling and leukocyte trafficking. We observed that neutrophil migration is impaired in CD38-deficientmice resulting in attenuated and reduced inflammatory responses. We also found that the cADPPR produced byCD38 modulates calcium mobilization in neutrophils that have been activated with inflammatory chemoattractants such as peptides derived from bacteria and viruses. Furthermore, we showed that cADPR-specific antagonists block the migratory response of neutrophils to these peptides. The data suggest that small molecule inhibitors of CD38could potentially be used to block neutrophil-dependent inflammatory responses. Recently, we observed that the migratory response of dendritic cells is also impaired in CD38 deficient mice. Specifically, we found that CD38-deficient dendritic cells cannot migrate in response to ELC or SLC, chemokines that direct dendritic cells to migrate from sites of damage or injury to lymphoid tissues. This impaired chemotactic response observed inCD38-deficient dendritic cells results in inefficient T cell priming and significantly reduced T cell-dependent immune responses. Based on our previous data, we now hypothesize that CD38, through its production of cADPR, regulates cell-dependent immune responses by modulating the migration of dendritic cells. To test this hypothesis we have proposed the following Specific Aims: (1) we will determine whether CD38 regulates migration of all mature dendritic cell subsets to ELC or SLC, (2) we will determine whether CD38 regulates the migration of dendritic cells to inflammatory chemoattractants and (3) we will determine whether cADPR production by CD38 controls dendritic cell trafficking in vivo. These experiments will validate whether CD38 antagonists have the potential to be used as immunosuppressive agents that attenuate immune responses by modulating leukocyte trafficking.