Understanding the impact of human NKT cells on hematopoiesis

 描述(申请人提供)：移植人脐血造血干细胞(HSCs)已成为治疗高危恶性血液病和其他血液疾病的标准程序，也有望成为治疗某些传染病(如艾滋病毒)的方法。然而，由于转移的CD34+干细胞数量较少，临床上脐血移植后的造血植入往往不理想，而且中性粒细胞重建缓慢往往与移植后的并发症有关。先前在小鼠模型和对人类患者的相关研究中已经证实，不变自然杀伤T细胞(INKT)在促进移植后HSC植入和骨髓生成方面发挥着重要作用，但它们介导这些作用的机制尚不清楚。初步研究表明，iNKT细胞产生GM-CSF等细胞因子，触发CD40信号，激活嘌呤能信号和其他细胞产生PGE2-所有这些活动都参与促进关键的造血事件，如HSC自我更新、迁移和髓系分化。这些研究的首要目标是了解iNKT细胞在移植后造血过程中的细胞相互作用和分子信号通路，并将其与特定的造血结果联系起来。我们将使用互补的体外和体内模型系统来解剖iNKT介导的机制过程，并测试人iNKT细胞在移植到高度免疫缺陷的NSG小鼠后对人脐血HSCs植入和分化的影响。由于iNKT细胞可能与多种不同类型的细胞相互作用，并参与多种不同的分子途径来影响造血结果，因此Aim 1将确定直接iNKT-HSC相互作用的影响，比较iNKT与其他细胞类型相互作用时产生的可溶性造血因子的间接影响，Aim 2将确定iNKT细胞参与的可用于直接或间接途径的特定信号通路的影响。这些研究将通过区分iNKT介导的途径如何影响HSC移植后的不同结果来推动这一领域的发展，这将进一步促进我们设计利用这些独特的固有T淋巴细胞的治疗策略的能力。PHS 398/2590(06/09版)页面续格式页面

 DESCRIPTION (provided by applicant): Transplantation of human umbilical cord blood hematopoietic stem cells (HSCs) has become a standard procedure to treat high-risk hematologic malignancies as well as other hematological disorders, and also holds promise as a therapy for certain infectious diseases (e.g. HIV). However, hematopoietic engraftment following cord blood transplantation in clinical settings is frequently suboptimal due to low numbers of transferred CD34+ stem cells, and slow reconstitution of neutrophils is often associated with post-transplant complications. Prior work in murine models and correlative studies of human patients have established that invariant Natural Killer T (iNKT) cells play important roles in promoting both HSC engraftment and myelopoiesis after transplantation, yet the mechanisms by which they mediate these effects remain poorly understood. Preliminary studies have demonstrated that iNKT cells produce cytokines such as GM-CSF, trigger CD40 signaling, and activate purinergic signaling and PGE2 production by other cells - all of which are activities that have been implicated in promoting key hematopoietic events such as HSC self-renewal, migration, and myeloid differentiation. The overarching goal of the studies proposed here is to understand the cellular interactions and molecular signaling pathways engaged by iNKT cells during post-transplant hematopoiesis, and to associate these with particular hematopoietic outcomes. We will use complementary in vitro and in vivo model systems to dissect iNKT- mediated mechanistic processes and to test the effects of human iNKT cells on the engraftment and differentiation of human cord blood HSCs after transplantation into highly immune deficient NSG mice. Since iNKT cells might interact with multiple different cell types and engage multiple different molecular pathways to influence hematopoietic outcomes, Aim 1 will determine the impact of direct iNKT-HSC interactions as compared to the indirect effects of soluble hematopoietic factors produced during iNKT interactions with other cell types, and Aim 2 will determine the impact of specific signaling pathways engaged by iNKT cells that could be utilized in either direct or indirect pathways. These studies will advance the field by distinguishing how iNKT-mediated pathways contribute to different outcomes following HSC transplantation, which will further our ability to design therapeutic strategies that engage these unique innate T lymphocytes. PHS 398/2590 (Rev. 06/09) Page Continuation Format Page