Activation of semi-invariant and diverse NKT cells with an adjuvant combination

使用佐剂组合激活半不变且多样化的 NKT 细胞

• 批准号: 10291409
• 负责人: Mark L Lang
• 金额: $ 36.71万
• 依托单位: UNIVERSITY OF OKLAHOMA HLTH SCIENCES CTR
• 依托单位国家: 美国
• 财政年份: 2017
• 资助国家: 美国
• 起止时间: 2017-11-06 至 2023-10-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10291409
• 关键词: Adjuvant; Affect; Alhydrogel; Antibody-mediated protection; Antigen Presentation; Antigens; Attenuated; Autoimmunity; B-Lymphocytes; Bacterial Toxins; Binding; Cell surface; Cells; Cellular Immunity; Clostridium difficile; Communities; Complex; Cytotoxic T-Lymphocytes; Equilibrium; FDA approved; Family; Formulation; Glycolipids; Haptens; Health; Human; Humoral Immunities; Immune response; Immune system; Immunity; Immunization; Immunize; In Vitro; Infection prevention; Inflammasome; Inflammatory; Keyhole Limpet Hemocyanin; Knowledge; Life; Ligands; Link; Lipids; Longevity; Malignant Neoplasms; Measurement; Measures; Memory B-Lymphocyte; Mission; Modeling; Modification; Molecular; Monitor; Mus; Natural Immunity; Organ; Patients; Pattern; Peptides; Peripheral Blood Mononuclear Cell; Phase I Clinical Trials; Phosphotransferases; Plasma Cells; Production; Proteins; Public Health; Reporting; Research; Safety; Series; Signal Transduction; Structure; T-Cell Activation; Testing; Tetanus Toxoid; Toxic effect; Toxin; United States National Institutes of Health; Vaccination; Vaccine Adjuvant; Vaccine Antigen; Vaccines; Work; adaptive immune response; adaptive immunity; alpha-galactosylceramide; aluminum sulfate; cytokine; experimental study; in vivo; innovation; knowledge base; pathogen; recruit; response; single cell analysis; transcription factor; vaccine candidate

ABSTRACT There are several safe candidate adjuvants that potentiate beneficial immunity following vaccination. However, single adjuvant formulations have performed quite modestly in terms of stimulating the desired blend of humoral versus cellular immunity and/or Th1 versus Th2 immunity. Combination adjuvants offer a possible way forward, but the mechanisms of action of such combinations remain poorly defined. Therefore, we will combine the FDA-approved adjuvant Alum (alhydrogel) with the CD1d-binding glycolipid adjuvant α-galactosylceramide (α-GC) and delineate the mechanisms of action with a particular emphasis on CD1d-restricted Natural Killer T (NKT) cells and humoral immunity. Alum is safe and stimulates excellent Th2 but poor Th1 immunity. We discovered that the Th2 response to Alum depends in large part upon diverse TCR-expressing Type II NKT cells (dNKT) which recognize CD1d/glycolipid complexes but do not recognize the α-GC adjuvant. The α-GC adjuvant stimulates semi-invariant TCR-expressing Type I NKT cells (iNKT) and results in a mixed Th1/Th2 response. It is already known from Phase I clinical trials in patients with cancer that α-GC is well-tolerated and safe. Furthermore, modification of the α-GC structure can readily be employed to skew the Type I NKT- dependent Th1/Th2 balance. Our objective for this proposal is to test the central hypothesis that the combination of Alum and α-GC leads to CD1d/glycolipid presentation and a coordinated dNKT and iNKT- driven mixed Th1/Th2 response against vaccine antigens. In Specific Aim 1, we will perform a series of in vitro studies in primary murine and human cells to determine how the adjuvant combination affects CD1d Ag presentation and activation and functional differentiation of NKT cells into different effector subsets. We will also examine the effect of adjuvant combination on class I and class II presentation of co-administered protein antigens. In Specific Aim 2, we will undertake a series of in vivo experiments in mice to examine the functional consequences of adjuvant combination for Ab-mediated protection against bacterial toxins. Experiments to analyze cellular as well as humoral immunity will be included as the project develops and in vivo toxicity (or lack thereof) will be determined by measurement of pro-inflammatory cytokines as well as markers of autoimmunity and organ damage. We feel this project is innovative because it will provide the vaccine community with mechanistic information when CD1d-binding adjuvants are combined with Alum adjuvant and give careful consideration to NKT cell- driven components of the immune response. We feel the project is significant because it will illuminate potential avenues for inclusion of CD1d-binding glycolipids in mixed adjuvant platforms.

摘要 有几种安全的候选佐剂可增强疫苗接种后的有益免疫力。然而，在这方面， 单一佐剂制剂在刺激所需的佐剂共混物方面表现得相当温和。 体液免疫对细胞免疫和/或Th 1免疫对Th 2免疫。联合佐剂提供了一种可能的方法 向前发展，但这种组合的作用机制仍然不清楚。因此，我们将联合收割机 FDA批准的佐剂明矾（铝胶）与CD 1d结合糖脂佐剂α-半乳糖神经酰胺 （α-GC），并描述了作用机制，特别强调CD 1d限制性自然杀伤T细胞（NK） (NKT)细胞和体液免疫。明矾是安全的，刺激良好的Th 2，但差的Th 1免疫。我们 发现Th 2对明矾的反应在很大程度上取决于不同的表达TCR的II型NKT 识别CD 1d/糖脂复合物但不识别α-GC佐剂的dNKT细胞。α-GC 佐剂刺激表达半恒定TCR的I型NKT细胞（iNKT）并导致混合的Th 1/Th 2 反应从癌症患者的I期临床试验中已经知道，α-GC耐受性良好， 安全了此外，α-GC结构的修饰可以容易地用于使I型NKT-1发生偏斜。 Th 1/Th 2平衡。我们提出这一建议的目的是检验中心假设， 明矾和α-GC的组合导致CD 1d/糖脂呈递和协调的dNKT和iNKT- 驱动针对疫苗抗原的混合Th 1/Th 2应答。 在具体目标1中，我们将在原代鼠和人细胞中进行一系列体外研究，以确定 佐剂组合如何影响CD 1d Ag呈递和活化以及 NKT细胞分成不同的效应子亚群。我们还将检查佐剂组合对I类和II类肿瘤的作用。 共施用的蛋白抗原的II类呈递。 在具体目标2中，我们将在小鼠中进行一系列体内实验，以检查 佐剂组合对于Ab介导的针对细菌毒素的保护的结果。实验来 分析细胞和体液免疫将包括作为该项目的发展和体内毒性（或 缺乏）将通过测量促炎细胞因子以及 自身免疫和器官损伤。 我们认为这个项目是创新的，因为它将为疫苗界提供机制信息 当CD 1d结合佐剂与明矾佐剂组合并仔细考虑NKT细胞时， 免疫反应的驱动成分。我们觉得这个项目意义重大，因为它将阐明 在混合佐剂平台中包含CD 1d结合糖脂的潜在途径。

项目成果

Antigen presentation and interferon signatures in B cells driven by localized ablative cancer immunotherapy correlate with extended survival.

• DOI: 10.7150/thno.65773
• 发表时间: 2022
• 期刊: Theranostics
• 影响因子: 12.4
• 作者: Liu K;Hoover AR;Krawic JR;DeVette CI;Sun XH;Hildebrand WH;Lang ML;Axtell RC;Chen WR
• 通讯作者: Chen WR

Immunization-Expanded NKT Follicular Helper Cells Drive IgG1 Isotype Switch against an Exogenous T-Independent Polysaccharide but Do Not Promote Recall Responses.

免疫扩增的 NKT 滤泡辅助细胞驱动针对外源 T 依赖性多糖的 IgG1 同种型转换，但不促进回忆反应。

• DOI: 10.4049/immunohorizons.1800081
• 发表时间: 2019
• 期刊: ImmunoHorizons
• 作者: Lang,GillianA;AmadouAmani,Souwelimatou;Quinn,JamesL;Axtell,RobertC;Lang,MarkL
• 通讯作者: Lang,MarkL

The Influence of Invariant Natural Killer T Cells on Humoral Immunity to T-Dependent and -Independent Antigens.

• DOI: 10.3389/fimmu.2018.00305
• 发表时间: 2018
• 期刊: Frontiers in immunology
• 影响因子: 7.3
• 作者: Lang ML

Use of a Clostridioides difficile Murine Immunization and Challenge Model to Evaluate Single and Combination Vaccine Adjuvants Consisting of Alum and NKT Cell-Activating Ligands.

• DOI: 10.3389/fimmu.2021.818734
• 发表时间: 2021
• 期刊: Frontiers in immunology
• 影响因子: 7.3
• 作者: Lang GA;Norman K;Amadou Amani S;Shadid TM;Ballard JD;Lang ML
• 通讯作者: Lang ML

Bacteria That Cause Enteric Diseases Stimulate Distinct Humoral Immune Responses.

• DOI: 10.3389/fimmu.2020.565648
• 发表时间: 2020
• 期刊: Frontiers in immunology
• 影响因子: 7.3
• 作者: Amadou Amani S;Lang ML
• 通讯作者: Lang ML