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Synthetic Ligands for Directing Immune Responses

用于指导免疫反应的合成配体

基本信息

批准号：
10616486
负责人：
Laura L Kiessling
金额：
$ 48.37万
依托单位：
MASSACHUSETTS INSTITUTE OF TECHNOLOGY
依托单位国家：
美国
项目类别：
财政年份：
2003
资助国家：
美国
起止时间：
2003-04-15 至 2025-04-30
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10616486
关键词：
Affect Animal Model Antigen Presentation Antigen Targeting Antigen-Presenting Cells Antigens Bacteria Binding Biology Cancerous Carbohydrates Cell Shape Cell surface Cells Cellular Immunity Chemicals Collaborations Combinatorics Data Dendritic Cells Disease Elasticity Encapsulated Exhibits Generations Goals Grant Human Humoral Immunities Immune response Immune signaling Immune system Immunity Influentials Lectin Ligands Malignant Neoplasms Mediator Membrane Molecular Natural Immunity Nature Particulate Pathogen detection Pattern Peptides Polysaccharides Property Protein Array Proteins Receptor Signaling Rest Role Shapes Signal Pathway Signal Transduction Specificity Subunit Vaccines T cell differentiation T cell response T-Lymphocyte T-Lymphocyte Subsets Testing Toll-like receptors Tumor Immunity Vaccines Viral load measurement Virus Virus-like particle adaptive immunity anti-cancer anticancer activity antigen binding antigen detection antigen test candidate identification combat combinatorial cytokine dectin 1 design experimental study extracellular feature detection fungus glycosylation human disease in vivo mechanical properties mechanotransduction microbial mouse dectin-2 novel novel strategies particle pathogen pathogenic fungus receptor recruit response trafficking transmission process

项目摘要

Abstract: Dendritic cells (DCs) reside at the interface of innate and adaptive immunity. They can capture antigens, internalize and degrade them, and present antigen-derived peptides to T cells. The signals generated in these steps result in the release of cytokines that shape T cell responses. Due to their roles as critical antigen-presenting cells, DCs are covered with receptors capable of internalizing antigens—especially lectins. The transmembrane lectins on the DC surface can bind and internalize glycosylated antigens to influence DC signaling and the cytokines that drive the differentiation of T cell subsets. As a result, lectins could be exploited to direct vaccines to dendritic cells and to tailor the immune responses they elicit. The goal of this project is to develop an understanding of key DC lectins to capitalize on this potential. Aim 1 focuses on understanding the combinatorics of lectin engagement and signaling. We hypothesize that glycans that can bind the toll-like receptors and lectins will bias DC signaling and therefore T cell responses. We propose to identify candidate glycans with these properties by assessing the selectivity of DC lectins (DC-SIGN, MGL, dectin-1, dectin-2) for microbial glycans using glycan arrays. We also will synthesize ligands that can bridge DC lectins and TLRs to examine the impact of dual engagement directly. In Aim 2, we shall evaluate the hypothesis that the DC lectins function as mechanosensors. Our preliminary results with DC-SIGN suggest that particulate antigens and soluble antigens differ in their trafficking. These data suggest that DC-SIGN can detect differences in stiffness. Pathogens (e.g., viruses, bacteria, fungi) are much stiffer than human cells, so antigen mechanosensing may be a means of distinguishing foreign from self. Understanding how antigen stiffness influences lectin and TLR signaling could lead to new strategies to modulate immunity. In Aim 3, we examine immune responses to antigens that target DC lectins and TLRs in vivo. The proposed experiments leverage our expertise in chemical biology to test novel hypotheses regarding the signaling pathways and molecular mechanisms that underlie how DCs shape T cell responses and, therefore, immunity. Progress on the proposed Aims is designed to yield new strategies to recruit the immune system to treat human disease.

文摘:

项目成果

期刊论文数量（20）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

Glycan-Modified Virus-like Particles Evoke T Helper Type 1-like Immune Responses.

DOI：
10.1021/acsnano.0c03023
发表时间：
2021-01-26
期刊：
ACS nano
影响因子：
17.1
作者：
Alam MM;Jarvis CM;Hincapie R;McKay CS;Schimer J;Sanhueza CA;Xu K;Diehl RC;Finn MG;Kiessling LL
通讯作者：
Kiessling LL

Lectin Fingerprinting Distinguishes Antibody Neutralization in SARS-CoV-2.

DOI：
10.1021/acscentsci.2c01471
发表时间：
2023-05-24
期刊：
ACS CENTRAL SCIENCE
影响因子：
18.2
作者：
Wuo, Michael G.;Dugan, Amanda E.;Halim, Melanie;Hauser, Blake M.;Feldman, Jared;Caradonna, Timothy M.;Zhang, Shuting;Pepi, Lauren E.;Atyeo, Caroline;Fischinger, Stephanie;Alter, Galit;Garcia-Beltran, Wilfredo F.;Azadi, Parastoo;Hung, Deb;Schmidt, Aaron G.;Kiessling, Laura L.
通讯作者：
Kiessling, Laura L.

Lectin-Seq: A method to profile lectin-microbe interactions in native communities.