NKT Cells Immunotherapy: Targeting Dendritic Cells with Glycolipid Liposomes

NKT 细胞免疫疗法:用糖脂脂质体靶向树突状细胞

基本信息

  • 批准号:
    7273869
  • 负责人:
  • 金额:
    $ 13.84万
  • 依托单位:
  • 依托单位国家:
    美国
  • 项目类别:
  • 财政年份:
    2006
  • 资助国家:
    美国
  • 起止时间:
    2006-08-08 至 2009-07-31
  • 项目状态:
    已结题

项目摘要

DESCRIPTION (provided by applicant): A. SPECIFIC AIMS This research program combines expertise from three different laboratories at The Ohio State University and an industry partner to work on the first proof of concept for liposomal glycolipid drug delivery to dendritic cells for better harnessing the wide range of immunological functions of natural killer T cells. Conventional CD4+ and CD8+ T cells of the immune system recognize specific peptide antigens bound to major histocompatibility complex (MHC) class II or MHC class I molecules, respectively. In contrast, a specialized subpopulation of T cells called NKT cells recognize glycolipids antigens presented by the MHC class l-like molecule; CD1d. NKT cells represent a distinct population of T cells that express a conserved alpha-beta T cell receptor (TCR) and natural killer (NK) receptors. Mouse (m) Valpha14 and human (h) Valpha24 NKT cells regulate a number of critical biological conditions in vivo, including malignancy and infection, as well as autoimmune diseases, through the rapid secretion of T helper 1 (Th1) and Th2 cytokines and chemokines. A synthetic glycosphingolipid called alpha-galactosylceramide (alpha-GalCer), originally derived from a marine sponge, has been used in research as an exogenous ligand for CD1d to stimulate NKT cells. Moreover, alpha-GalCer is currently being tested in cancer patients. However, no complete objective response has been found in several clinical trials conducted by different teams in the United States, Japan and Europe. One of possible reasons might be that alpha-GalCer is too strong ligand that stuns the NKT cells to bring anergy. So far, a much more successful NKT cell immunotherapy approach is to re-induce human mature dendritic cells pulsed with alpha-GalCer ex vivo into patient to expand NKT cells. However, DCs are a small population of cells, and their isolation and pulsing with antigen can be impractical. Thus, we propose to incorporate alpha-GalCer (or other glycosphingosines) into liposomes to deliver the drug to DCs for optimal immunotherapy. Among many receptors on DCs for targeting, we choose recently discovered DC-specific intercellular adhesion molecule 3 (ICAM-3) grabbing non- integrin (DC-SIGN). Human DC-SIGN is abundantly expressed on DCs residing in lymphoid tissues and at mucosal surfaces, dermal DCs, and by specialized macrophages in placenta and lung. Several laboratories have demonstrated that targeting DC-SIGN by anti-DC-SIGN antibody afford the best strategy to deliver antigens or drug into DCs. High mannose glycans are the ligand for DC-SIGN, but recently it was discovered that DC-SIGN bind the second class of glycans: fucosyl containing oligosaccharides. Thus, this proposed research program will be the first attempt to explore the anti-tumor effect of NKT ligands by targeting the glycosphingosine drug specifically to dendritic cells with liposomes which display fucose containing oligosaccharides such as Le-a and Le-x. Four specific aims are proposed in this program: 1. Synthesis of Le-a and Le-x oligosaccharides, their tetramers and their conjugates with lipids, measurement of their binding with DC-SIGN. 2. Production of two liposomal systems. System A consists of a-GalCer with anti-DC-SIGN antibody displayed; system B consists of alpha-GalCer with fucosylated oligosaccharide displayed (e.g. Le-a and Le-x). 3. Investigation in vitro of the two liposomal systems for their targeting and cytotoxicity. 4. Investigation in vivo of the two liposomal systems for their antitumor effects in mouse models. This exploratory research will open many future possibilities on NKT activation, dendritic cell targeting, and liposomal technology. The proposed DC-targeted liposomal systems incorporated with glycolipids as NKT cell activators can be potentially used in vaccine adjuvant development and in preventing infections, autoimmune diseases and inflammatory diseases. This work will set up a novel platform to better use a wide range of possible medical benefits brought about by our recent understanding on the immunoregulatory and immunomodulatory functions of natural killer T cells.
该研究项目结合了俄亥俄州立大学三个不同实验室和一个行业合作伙伴的专业知识,致力于首次证明脂质体糖脂药物递送到树突状细胞的概念,以更好地利用自然杀伤T细胞的广泛免疫功能。免疫系统的常规CD4+和CD8+ T细胞分别识别与主要组织相容性复合体(MHC) II类或MHC I类分子结合的特异性肽抗原。相反,T细胞的一个特殊亚群称为NKT细胞识别由MHC类分子呈递的糖脂抗原;CD1d。NKT细胞代表了一种独特的T细胞群,表达保守的α - β T细胞受体(TCR)和自然杀伤(NK)受体。小鼠(m) Valpha14和人(h) Valpha24 NKT细胞通过快速分泌T辅助1 (Th1)和Th2细胞因子和趋化因子来调节体内许多关键的生物学状况,包括恶性肿瘤和感染,以及自身免疫性疾病。一种合成的鞘糖脂称为α -半乳糖神经酰胺(α - galcer),最初来源于海绵,已在研究中用作CD1d刺激NKT细胞的外源性配体。此外,alpha-GalCer目前正在癌症患者中进行测试。然而,在美国、日本和欧洲的不同团队进行的几项临床试验中,没有发现完全客观的反应。其中一个可能的原因是,α - galcer是一种太强的配体,它会使NKT细胞昏迷而无法带来能量。到目前为止,一种更成功的NKT细胞免疫治疗方法是在体外将α - galcer脉冲的人类成熟树突状细胞重新诱导到患者体内以扩增NKT细胞。然而,树突状细胞是一小群细胞,它们的分离和与抗原的脉冲可能是不切实际的。因此,我们建议将α - galcer(或其他糖鞘苷)结合到脂质体中,将药物输送到树突细胞中,以获得最佳的免疫治疗。在许多靶向dc的受体中,我们选择了最近发现的dc特异性细胞间粘附分子3 (ICAM-3)捕获非整合素(DC-SIGN)。人类DC-SIGN在淋巴组织和粘膜表面的dc、真皮dc以及胎盘和肺的特化巨噬细胞中大量表达。一些实验室已经证明,通过抗DC-SIGN抗体靶向DC-SIGN是将抗原或药物输送到dc的最佳策略。高甘露糖聚糖是DC-SIGN的配体,但最近发现DC-SIGN结合的是第二类聚糖:含焦酰基的低聚糖。因此,本研究计划将首次尝试探索NKT配体的抗肿瘤作用,通过脂质体特异性地将糖鞘苷药物靶向树突状细胞,这些脂质体显示含有低聚糖(如Le-a和Le-x)的焦点。该方案提出了四个具体目标:1.;Le-a和Le-x寡糖及其四聚体和脂质偶联物的合成及其与DC-SIGN结合的测定。2. 两种脂质体系统的产生。系统A由A - galcer组成,显示抗dc - sign抗体;系统B由α - galcer组成,显示集中的低聚糖(例如Le-a和Le-x)。3. 两种脂质体系统的体外靶向性和细胞毒性研究。4. 两种脂质体系统在小鼠体内抗肿瘤作用的研究。这项探索性研究将为NKT激活、树突状细胞靶向和脂质体技术开辟许多未来的可能性。提出的dc靶向脂质体系统与糖脂结合作为NKT细胞激活剂,可潜在地用于疫苗佐剂开发和预防感染、自身免疫性疾病和炎症性疾病。这项工作将建立一个新的平台,更好地利用我们最近对自然杀伤T细胞的免疫调节和免疫调节功能的理解所带来的广泛的可能的医学效益。

项目成果

期刊论文数量(1)
专著数量(0)
科研奖励数量(0)
会议论文数量(0)
专利数量(0)
Alpha-lactosylceramide as a novel "sugar-capped" CD1d ligand for natural killer T cells: biased cytokine profile and therapeutic activities.
α-乳糖神经酰胺作为自然杀伤 T 细胞的新型“糖帽”CD1d 配体:偏向的细胞因子谱和治疗活性。
  • DOI:
    10.1002/cbic.200700625
  • 发表时间:
    2008
  • 期刊:
  • 影响因子:
    0
  • 作者:
    Zhang,Wenpeng;Zheng,Xincheng;Xia,Chengfeng;Perali,RamuSridhar;Yao,Qingjia;Liu,Yang;Zheng,Pan;Wang,PengGeorge
  • 通讯作者:
    Wang,PengGeorge
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Peng George Wang其他文献

"Armed and disarmed" theory in the addition of an azide radical to glucals
  • DOI:
  • 发表时间:
    2015
  • 期刊:
  • 影响因子:
    3.9
  • 作者:
    Yunyan Zhao;Xiufang Xu;Wei Zhao;Peng George Wang;
  • 通讯作者:
Reply to Delanghe et al, Boudin et al, and Focosi et al
回复 Delanghe 等人、Boudin 等人和 Focosi 等人
  • DOI:
    10.1093/cid/ciaa1477
  • 发表时间:
    2020
  • 期刊:
  • 影响因子:
    11.8
  • 作者:
    Jiao Zhao;Mingzhao Xing;Peng George Wang
  • 通讯作者:
    Peng George Wang
Characterization and application in recombinant emN/em-GlcNAc-protein production of a novel emendo/em-β-emN/em-acetylglucosaminidase from emListeria booriae/em
来自博氏李斯特菌的一种新型内切-β-N-乙酰氨基葡萄糖苷酶的特性及其在重组N-乙酰葡糖胺-蛋白质生产中的应用
  • DOI:
    10.1016/j.bioorg.2025.108290
  • 发表时间:
    2025-04-01
  • 期刊:
  • 影响因子:
    4.700
  • 作者:
    Weian Mao;Yongheng Rong;Hongmei Zhang;Fang Yuan;Yankang Wang;Mei Wang;Linhan Wang;Peng George Wang;Min Chen;Shengjun Wang;Yun Kong
  • 通讯作者:
    Yun Kong
Engineered yeast with PNGase F on cell surface for releasing of <em>N</em>-glycans from glycoproteins
  • DOI:
    10.1016/j.enzmictec.2006.10.029
  • 发表时间:
    2007-05-02
  • 期刊:
  • 影响因子:
  • 作者:
    Yishan Su;Houcheng Zhang;Li Gu;Min Chen;Min Xiao;Peng George Wang;Qingsheng Qi
  • 通讯作者:
    Qingsheng Qi
Bromocoumarinplatin, Targeting Simultaneous Mitochondrion and Cell Nucleus with p53 Apoptosis Pathway to Overcome Cisplatin Resistance.
  • DOI:
    org/10.1016/j.bioorg.2020.103768
  • 发表时间:
    2020
  • 期刊:
  • 影响因子:
  • 作者:
    Jing Ma;Linrong Li;Kexin Yue;Yingguang Li;Hanfang Liu;Peng George Wang;Chaojie Wang;Jiajia Wang;Wen Luo;Songqiang Xie
  • 通讯作者:
    Songqiang Xie

Peng George Wang的其他文献

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{{ truncateString('Peng George Wang', 18)}}的其他基金

Investigation on Oligosaccharides as Antimicrobial and Prebiotics
低聚糖作为抗菌剂和益生元的研究
  • 批准号:
    7741453
  • 财政年份:
    2009
  • 资助金额:
    $ 13.84万
  • 项目类别:
Development of A Novel Strategy to Produce Antibacterial Glycoconjugate Vaccines
开发生产抗菌糖复合物疫苗的新策略
  • 批准号:
    7699611
  • 财政年份:
    2009
  • 资助金额:
    $ 13.84万
  • 项目类别:
Investigation on Oligosaccharides as Antimicrobial and Prebiotics
低聚糖作为抗菌剂和益生元的研究
  • 批准号:
    8322023
  • 财政年份:
    2009
  • 资助金额:
    $ 13.84万
  • 项目类别:
Research and Development of a Novel System to Produce Polysaccharide Conjugate Va
多糖复合物生产新系统的研究与开发
  • 批准号:
    8439987
  • 财政年份:
    2009
  • 资助金额:
    $ 13.84万
  • 项目类别:
Biosynthesis of Polysaccharides
多糖的生物合成
  • 批准号:
    8337381
  • 财政年份:
    2009
  • 资助金额:
    $ 13.84万
  • 项目类别:
Biosynthesis of Polysaccharides
多糖的生物合成
  • 批准号:
    8633090
  • 财政年份:
    2009
  • 资助金额:
    $ 13.84万
  • 项目类别:
Research and Development of a Novel System to Produce Polysaccharide Conjugate Va
多糖复合物生产新系统的研究与开发
  • 批准号:
    7673238
  • 财政年份:
    2009
  • 资助金额:
    $ 13.84万
  • 项目类别:
Development of A Novel Strategy to Produce Antibacterial Glycoconjugate Vaccines
开发生产抗菌糖复合物疫苗的新策略
  • 批准号:
    7932881
  • 财政年份:
    2009
  • 资助金额:
    $ 13.84万
  • 项目类别:
Biosynthesis of Polysaccharides
多糖的生物合成
  • 批准号:
    7906823
  • 财政年份:
    2009
  • 资助金额:
    $ 13.84万
  • 项目类别:
Biosynthesis of Polysaccharides
多糖的生物合成
  • 批准号:
    8319742
  • 财政年份:
    2009
  • 资助金额:
    $ 13.84万
  • 项目类别:

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