S1P Receptor subtypes: Regulating lymphocyte trafficking

S1P 受体亚型：调节淋巴细胞运输

• 批准号: 7021389
• 负责人: HUGH ROSEN
• 金额: $ 45.82万
• 依托单位: SCRIPPS RESEARCH INSTITUTE, THE
• 依托单位国家: 美国
• 财政年份: 2004
• 资助国家: 美国
• 起止时间: 2004-03-01 至 2009-02-28
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7021389
• 关键词: antireceptor antibody; artificial immunosuppression; biological signal transduction; cell migration; cell surface receptors; clinical research; flow cytometry; genetically modified animals; human tissue; immune response; immunocytochemistry; immunosuppression; in situ hybridization; laboratory mouse; leukocyte activation /transformation; lymphatic tissue; lymphocyte; lymphopenia; lysophospholipids; ovalbumin; receptor expression; stimulant /agonist

DESCRIPTION (provided by applicant): This proposal is focused on understanding the regulation of lymphocyte trafficking as a fundamental therapeutic approach to autoimmunity and transplantation rejection. Immunosuppressive regimens generally impact upon both lymphoid and myeloid hemopoietic lineages, rendering patients highly susceptible to bacterial, fungal and viral infection, as well as to the long term toxicities of current drug classes, which include significant nephrotoxicity and bone loss. The project brings together chemical and biological approaches to activation of the receptors for the lysophospholipid sphingosine 1-phosphate (S1P) that result in the sequestration of lymphocytes by inhibiting their egress from lymphnodes. The reversible disappearance of lymphocytes from blood results in immunosuppression to peripheral antigen and protects from autoimmune tissue damage, transplant rejection and graft versus host disease. Potential advantages to autoimmune patients are based on broadening therapeutic window by retaining myelomonocytic cell function to enhance host defense, and the relative absence of nephrotoxicity or metabolic sequelae. This proposal will focus on improving the understanding of the mechanism by which S1P receptor agonism produces clinically useful immunosuppression, and will attempt to separate the mechanism of inhibition of lymphocyte egress from the pleiotropic effects of S1P upon pressor and cardiac function. Specific aims of the proposal are to (1) Determine the detailed tissue expression of SIP receptors in lymphoid tissues. This will be done by in situ hybridization and immunohistology; (2) Determine receptor selectivity for alteration of lymphocyte trafficking using receptor selective agonists and S1P receptor subtype null mice. Receptor selective agonists will be defined and used in wild-type and S1P receptor deletant mice, to determine the role of specific receptors in producing lymphopenia and other physiological effects of S1P. (3) Identify the cellular site of action of S1P agonists in lymphocyte sequestration. The study on receptor distribution and evaluation of surrogate marker changes in situ in lymphoid organs will determine whether the effect of S1P receptor agonists is on lymphocytes, endothelium or both. (4) Establish the quantitative changes in immune responses induced by S1P receptor agonism. Local and systemic functional effects of S1P agonism will be studied quantitatively for immunosuppression or potentiation of immune responses in transgenic mice responding to ovalbumin peptide, to understand the roles of the S1P system in control of lymphocyte recirculation. These studies will yield an enhanced understanding of the basic mechanisms by which S1P receptor agonism induces clinically useful immunosuppression of potential use in autoimmunity.

描述（由申请人提供）：该提案的重点是理解对淋巴细胞贩运作为自身免疫和移植拒绝的基本治疗方法的调节。免疫抑制方案通常会影响淋巴样和髓样血有性谱系，使患者高度容易受到细菌，真菌和病毒感染的影响，以及当前药物类别的长期毒性，包括明显的肾毒性和骨质流失。该项目汇集了化学和生物学方法来激活1-磷酸溶血磷脂鞘氨酸（S1P）的受体，从而通过抑制其从淋巴结中的出口来导致淋巴细胞的隔离。淋巴细胞从血液中的可逆消失导致免疫抑制作用到周围抗原，并保护免受自身免疫组织损伤，移植排斥和移植物与宿主疾病的侵害。自身免疫性患者的潜在优势是基于拓宽治疗窗口，通过保留脊髓细胞细胞功能来增强宿主防御，并相对缺乏肾毒性或代谢后遗症。该提案将着重于提高对S1P受体激动剂产生临床有用的免疫抑制的机制的理解，并将尝试将抑制淋巴细胞出口的机制与S1P对压力机和心动功能的多效作用的抑制机制分开。该提案的具体目的是（1）确定淋巴组织中SIP受体的详细组织表达。这将通过原位杂交和免疫组织学来完成； （2）确定使用受体选择性激动剂和S1P受体亚型NULL小鼠改变淋巴细胞运输的受体选择性。受体选择性激动剂将被定义并用于野生型和S1P受体缺失小鼠，以确定特定受体在产生淋巴细胞减少症和S1P的其他生理作用中的作用。 （3）确定S1P激动剂在淋巴细胞隔离中的作用的细胞位点。淋巴器官中替代标记物变化的受体分布和评估的研究将确定S1P受体激动剂的影响是否对淋巴细胞，内皮或两者兼而有之。 （4）确定由S1P受体激动剂诱导的免疫反应的定量变化。将对S1P激动剂的局部和全身功能作用进行定量研究，以在对卵巢蛋白肽作出反应的转基因小鼠中免疫抑制或增强免疫反应，以了解S1P系统在控制淋巴细胞再循环的控制中的作用。这些研究将增强对S1P受体激动剂诱导临床有用的免疫抑制的基本机制的理解。