Understanding the impact of human NKT cells on hematopoiesis

 描述（由申请人提供）：人脐带血造血干细胞（HSC）移植已成为治疗高风险血液恶性肿瘤以及其他血液疾病的标准程序，也有望成为某些感染性疾病（例如HIV）的治疗方法。然而，在临床环境中脐带血移植后的造血植入通常是次优的，由于转移的CD 34+干细胞的数量少，并且中性粒细胞的缓慢重建通常与移植后并发症相关。先前在小鼠模型和人类患者的相关研究中的工作已经确定，不变的自然杀伤T（iNKT）细胞在促进移植后的HSC植入和骨髓生成中起重要作用，但它们介导这些作用的机制仍然知之甚少。初步研究表明，iNKT细胞产生细胞因子，如GM-CSF，触发CD 40信号传导，并激活嘌呤能信号传导和其他细胞产生PGE 2-所有这些都涉及促进关键造血活动，如HSC自我更新，迁移和骨髓分化。本文提出的研究的总体目标是了解iNKT细胞在移植后造血过程中参与的细胞相互作用和分子信号传导途径，并将这些与特定的造血结果相关联。我们将使用互补的体外和体内模型系统来剖析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小鼠后对人脐带血HSC的植入和分化的影响。由于iNKT细胞可能与多种不同的细胞类型相互作用，并参与多种不同的分子途径来影响造血结果，因此Aim 1将确定与iNKT与其他细胞类型相互作用期间产生的可溶性造血因子的间接作用相比，直接iNKT-HSC相互作用的影响，Aim 2将确定可用于直接或间接途径的iNKT细胞参与的特定信号传导途径的影响。这些研究将通过区分iNKT介导的途径如何促进HSC移植后的不同结果来推进该领域，这将进一步提高我们设计参与这些独特的先天T淋巴细胞的治疗策略的能力。PHS 398/2590（Rev.06/09）

 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