Antigen specific T cell activation by anti-CD3 coated nanoparticles

抗 CD3 涂层纳米粒子激活抗原特异性 T 细胞

• 批准号: 8515676
• 负责人: MICHAEL A EDIDIN
• 金额: $ 46.63万
• 依托单位: JOHNS HOPKINS UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2012
• 资助国家: 美国
• 起止时间: 2012-08-02 至 2014-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8515676
• 关键词: Affect; Agonist; Animals; Antibodies; Antigens; Binding; Biological Process; CD3 Antigens; CD8B1 gene; Cancer Vaccines; Cells; Collaborations; Couples; Development; Dipeptides; Dose; Engineering; Fc Receptor; HIV; Hepatitis C; Immunity; Individual; Infectious Agent; Ligands; Lipid Bilayers; Malaria; Monoclonal Antibodies; Monoclonal Antibody HuM291; Mus; Nanotubes; Pharmaceutical Preparations; Populations at Risk; Quantum Dots; Receptor Signaling; Scientist; Secondary to; Signal Transduction; Specificity; Surface; T cell response; T-Cell Activation; T-Cell Receptor; T-Lymphocyte; Testing; Vaccines; base; cell type; experience; improved; in vivo; influenza virus vaccine; influenzavirus; interest; mouse model; nanoparticle; novel; pathogen; receptor; response; tumor; vaccine efficacy

DESCRIPTION (provided by applicant): Ligand-receptor interactions impart specificity to biological processes. Therefore, the development of specific agonists and antagonists, so called targeted therapy, offers the potential of selectively inhibiting or enhancing biological processes. However, since specific receptors are rarely expressed solely on the target cell of interest, much of the specificity of targeted therapy can be lost. The correct receptor may be specifically targeted but not necessarily solely on the cells of interest. For example, anti-CD3 antibodies are potent T cell agonists which activate the T Cell Receptor (TCR) signaling cascade. However, attempts to enhance specific T cell responses in vivo are marked by dramatic sequelae secondary to general and non-specific T cell activation. There are too many targets for anti-CD3. Hence, the potent ability of anti-CD3 to activate T cells has not yet been leveraged to enhance anti-pathogen or anti-tumor responses in vivo. Therefore a strategy to enhance the selectivity of targeted therapy to restrict it to the cells of interest is desirable. Recently, ourgroup has found that anti-CD3, when constrained to the surface of a nanoparticle, a quantum dot, selectively activates previously antigen-stimulated T cells, without activating na¿ve cells. The "nanoboost" to specific T cells may reflect the spatial matching of QD/CD3 to the clustered TCR of antigen-stimulated T cells, or may involve other mechanisms that selectively target activated over na¿ve T cells. In this proposal we aim to i) test mechanisms of the enhanced T cell responses to anti-CD3 on quantum dots ii) engineer other, novel, nanoparticles for nanoboost and iii) test the ability of anti-CD3 constrained on optimized nanoparticles to selectively boost protective vaccine responses to influenza virus in vivo.

描述(由申请人提供)：配体-受体相互作用赋予生物过程特异性。因此，开发特定的激动剂和拮抗剂，即所谓的靶向治疗，提供了选择性地抑制或增强生物过程的潜力。 然而，由于特定受体很少仅在感兴趣的靶细胞上表达，靶向治疗的大部分特异性可能会丧失。正确的受体可能是特定的靶点，但不一定只针对感兴趣的细胞。例如，抗CD3抗体是有效的T细胞激动剂，可以激活T细胞受体(TCR)信号级联反应。然而，试图在体内增强特异性T细胞反应的标志是戏剧性的后遗症，继发于一般和非特异性T细胞激活。抗CD3的靶点太多了。因此，抗CD3激活T细胞的强大能力尚未被用来增强体内的抗病原体或抗肿瘤反应。因此，需要一种策略来提高靶向治疗的选择性，将其限制在感兴趣的细胞中。最近，我们的团队发现，当抗CD3被限制在纳米粒子(量子点)的表面时，可以选择性地激活先前抗原刺激的T细胞，而不会激活NA细胞。对特定T细胞的“纳米增强”可能反映了QD/CD3与抗原刺激的T细胞聚集的TCR的空间匹配，或者可能涉及选择性地靶向NA？ve T细胞激活的其他机制。在这项建议中，我们的目标是：i)在量子点上测试增强T细胞对抗CD3的反应的机制；ii)设计其他新型纳米粒子用于纳米增强；以及iii)测试约束在优化的纳米粒子上的抗CD3的能力，以选择性地增强体内对流感病毒的保护性疫苗反应。