C-Glycosphingolipids with an exo-methylene substituent: stereocontrolled synthesis and immunostimulation of mouse and human natural killer T lymphocytes.
C-Glycosphingolipids with an exo-methylene substituent: stereocontrolled synthesis and immunostimulation of mouse and human natural killer T lymphocytes.
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DOI：
10.1002/cbic.201200374
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发表时间：
2012-08-13
期刊：
影响因子：
3.2
通讯作者：
Bittman, Robert
中科院分区：
文献类型：
--
作者：
Liu, Zheng;Courtney, Amy N.;Metelitsa, Leonid S.;Bittman, Robert
鞘糖脂（GSL）是控制无数生物和生理过程（包括免疫系统的刺激）的多种脂质。[1]恒定型自然杀伤T（iNKT）细胞是一种进化上保守的T细胞亚系，其特征在于表达恒定的T细胞受体（TCR）α链（人Vα24-Jα18和小鼠Vα14-Jα18）并对由单态HLA I类分子呈递的自身和微生物源性糖脂具有反应性。CD 1d iNKT细胞特异性识别α-半乳糖神经酰胺（1，通常称为α-半乳糖神经酰胺C26：0或α-GalCer;见方案1）及其类似物。[2]当NKT细胞被CD 1d呈递的GSL抗原激活时，它们迅速产生大量的免疫调节细胞因子。由1，CD 1d和iNKT细胞TCR形成的三元复合物具有长半衰期，[3]这导致非选择性产生辅助性T细胞1（Th 1）和辅助性T细胞2（Th 2）细胞因子;此外，1过度刺激iNKT细胞导致iNKT细胞长期无反应性。[4]这些作用阻碍了1的治疗应用，并导致了制备各种结构类似物的努力，所述结构类似物（a）选择性地刺激iNKT细胞分泌Th 1或Th 2细胞因子，和（B）对TCR具有降低的亲和力以使iNKT细胞过度活化最小化。[4]带有截短的植物鞘氨醇链（表示为OCH，2a）[5]或C20：2酰胺链（2b）[6]的α-GalCer衍生物已被鉴定为使iNKT细胞活化以产生Th 2细胞因子的配体。另一方面，Th 1极化配体已经通过在酰胺链的末端安装芳族基团（如3）[7]或半乳糖基6-羟基的衍生化而被发现。[8]然而，配体如1、2a、2b和3的潜在临床有效性在体内细胞内运输期间可能会受到损害，因为O-糖苷易于因内源性糖苷酶活性或内体区室的低pH环境的水解而产生代谢不稳定性。[9]C-糖苷类似物
Glycosphingolipids (GSLs) are a diverse group of lipids that control a myriad of biological and physiological processes, including stimulation of the immune system.[1] The invariant Natural Killer T (iNKT) cells are an evolutionary conserved sub-lineage of T cells that are characterized by the expression of an invariant T cell receptor (TCR) α-chain (Vα24-Jα18 in human and Vα14-Jα18 in mouse) and reactivity to self-and microbial-derived glycolipids presented by monomorphic HLA class-I-like molecule. CD1d iNKT cells specifically recognize α-galactosylceramide (1, commonly referred to as αgalactosylceramide C26: 0 or α-GalCer; see Scheme 1) and its analogues.[2] When NKT cells are activated by GSL antigens presented by CD1d, they rapidly produce large amounts of immunoregulatory cytokines. The ternary complex formed by 1, CD1d, and the iNKT cell TCR has a long half-life,[3] which leads to unselective production of T-helper 1 (Th1) and T-helper 2 (Th2) cytokines; furthermore, overstimulation of iNKT cells by 1 results in a long-term unresponsiveness of iNKT cells.[4] These effects have impeded therapeutic applications of 1 and have led to efforts to prepare various structural analogues that (a) selectively stimulate iNKT cells to secrete either Th1 or Th2 cytokines and (b) have a reduced affinity for the TCR to minimize iNKT cell overactivation.[4] α-GalCer derivatives bearing a truncated phytosphingosine chain (denoted as OCH, 2a)[5] or a C20: 2 amide chain (2b)[6] have been identified as ligands that polarize iNKT cells to produce Th2 cytokines. On the other hand, Th1-polarizing ligands have been found by installation of an aromatic group at the terminus of the amide chain (such as 3)[7] or derivatization of the galactosyl 6-hydroxyl group.[8]Nevertheless, the potential clinical effectiveness of ligands such as 1, 2a, 2b, and 3 may be compromised in vivo during intracellular trafficking because O-glycosides are prone to metabolic instability resulting from hydrolysis by either endogenous glycosidase activity or by the low pH milieu of the endosomal compartment.[9] Therefore, C-glycoside analogues
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影响因子：
3.2
作者：
Lu, Xuequan;Song, Liping;Bittman, Robert
通讯作者：
Bittman, Robert
影响因子：
15
作者：
Harrak, Youssef;Barra, Carolina M.;Llebaria, Amadeu
通讯作者：
Llebaria, Amadeu
影响因子：
4.4
作者：
Forestier, Claire;Takaki, Toshiyuki;Porcelli, Steven A.
通讯作者：
Porcelli, Steven A.
影响因子：
2.2
作者：
Liu, Yang;Goff, Randal D.;Savage, Paul B.
通讯作者：
Savage, Paul B.
DOI：
10.4049/jimmunol.0902880
发表时间：
2010-01-01
期刊：
Journal of immunology (Baltimore, Md. : 1950)
影响因子：
--
作者：
Sullivan BA;Nagarajan NA;Wingender G;Wang J;Scott I;Tsuji M;Franck RW;Porcelli SA;Zajonc DM;Kronenberg M
通讯作者：
Kronenberg M