S1P Receptor subtypes: Regulating lymphocyte trafficking

S1P 受体亚型：调节淋巴细胞运输

• 批准号: 6772930
• 负责人: HUGH ROSEN
• 金额: $ 46.93万
• 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/6772930
• 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)：这项建议的重点是了解作为自身免疫和移植排斥反应的基本治疗方法的淋巴细胞贩运的调节。免疫抑制方案通常同时影响淋巴系和髓系造血系，使患者对细菌、真菌和病毒感染以及当前药物的长期毒性非常敏感，包括显著的肾毒性和骨丢失。该项目结合了化学和生物方法来激活溶血磷脂1-磷酸鞘氨醇(S1P)的受体，这种受体通过抑制淋巴细胞从淋巴结外流出而导致淋巴细胞的隔离。淋巴细胞从血液中的可逆性消失导致对外周抗原的免疫抑制，保护自身免疫组织损伤、移植排斥反应和移植物抗宿主病。自身免疫患者的潜在优势是通过保留骨髓单核细胞功能来增强宿主防御来拓宽治疗窗口，以及相对没有肾毒性或代谢后遗症。这项建议将集中于提高对S1P受体激动剂产生临床有用的免疫抑制的机制的理解，并试图将抑制淋巴细胞出口的机制与S1P对升压和心脏功能的多效性作用分开。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)使用受体选择性激动剂和S1P受体亚型缺失小鼠来确定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的其他生理效应中的作用。(3)确定S1P激动剂在淋巴细胞隔离中的作用部位。对S1P受体激动剂在淋巴器官中的分布和替代标志物原位变化的研究将决定S1P受体激动剂对淋巴细胞、内皮或两者都有作用。(4)建立S1P受体激动剂诱导的免疫应答的量化变化。为了了解S1P系统在控制淋巴细胞再循环中的作用，将定量研究S1P激动剂的局部和全身功能效应，以期在卵蛋白多肽应答的转基因小鼠中抑制或增强免疫反应。这些研究将加深对S1P受体激动剂引起临床上有用的免疫抑制的基本机制的理解，这些免疫抑制可能用于自身免疫。