NKT cells as modulators of AIDS vaccine efficacy

NKT 细胞作为艾滋病疫苗功效的调节剂

基本信息

批准号：
8846538
负责人：
Amitinder Kaur
金额：
$ 79.49万
依托单位：
TULANE UNIVERSITY OF LOUISIANA
依托单位国家：
美国
项目类别：
财政年份：
2012
资助国家：
美国
起止时间：
2012-06-19 至 2018-05-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8846538
关键词：
AIDS Vaccines Acquired Immunodeficiency Syndrome Adenovirus Vector Adjuvant Africa South of the Sahara Antigens Applications Grants Attenuated B-Lymphocytes Blood Cells Cellular Immunity Collaborations Consensus Cytomegalovirus Data Dendritic Cells Developing Countries Development Dose Epidemic Frequencies Future Glycolipids Grant HIV HIV Antibodies HIV vaccine Herpesviridae Human Humoral Immunities Immune Immune response Immune system Immunity Infection Infection Control Infusion procedures Laboratories Letters Life Macaca Macaca mulatta Mediating Modeling Monitor Mucosal Immunity Mucous Membrane Natural Killer Cells Play Property Recombinants Regimen Research Role SIV SIV Vaccines Shapes Sterility T cell response T-Cell Activation T-Lymphocyte T-Lymphocyte Subsets Techniques Testing Therapeutic Tissues Vaccinated Vaccination Vaccine Adjuvant Vaccines Viral adaptive immunity antibody-dependent cell cytotoxicity base humanized monoclonal antibodies immunogenicity improved in vivo innovation killer T cell killings mucosal site neutralizing antibody nonhuman primate novel pathogen peripheral blood prevent protective efficacy research study vaccine development vaccine efficacy vector vaccine

项目摘要

DESCRIPTION (provided by applicant): Thirty years into the AIDS epidemic, there are an estimated 34 million HIV-infected people worldwide and almost 70% reside in sub-Saharan Africa. Although intensive research towards developing an AIDS vaccine is continuing, there are as yet no effective HIV vaccines on the horizon. For a HIV vaccine to be successful, it is widely accepted that it should be able to induce mucosal immunity, elicit an effective cytolytic and polyfunctional HIV-specific T cell response along with anti-HIV antibodies that have broadly directed neutralization activity and antibody dependent cellular cytotoxicity (ADCC) activity. The innate immune system is an important modulator of adaptive immunity and can shape the magnitude, quality, and durability of pathogen-specific immune responses at systemic and mucosal sites. Natural killer T (NKT) cells are unique T cells of the innate immune system with potent immunoregulatory properties that can impact T and B cell immunity. In this grant application we propose to use the SIV infection macaque model to investigate the hypothesis that NKT activation will improve vaccine immunogenicity and improve vaccine-mediated protection against acquisition and control of SIV infection. Conversely, the absence of NKT cells may reduce the efficacy of a protective live attenuated SIV (LASIV) vaccine. Our specific aims are: #1. Determine the optimal dosing regimen for in vivo administration of the NKT-depleting and NKT-activating mAbs and characterize their effect in blood and tissues of cynomolgus macaques. #2. Investigate the hypothesis that the adjuvant effect of NKT activation will enhance the protective efficacy of a heterologous prime-boost recombinant Ad26/Ad5-SIV vaccine regimen. #3. Investigate the hypothesis that vaccination in the setting of NKT depletion will abrogate the protective efficacy of a highly protective LASIV vaccine.

描述（由申请人提供）：艾滋病流行三十年来，全世界估计有 3400 万艾滋病毒感染者，其中近 70% 居住在撒哈拉以南非洲地区。尽管针对开发艾滋病疫苗的深入研究仍在继续，但目前还没有有效的艾滋病毒疫苗。 HIV疫苗要想获得成功，人们普遍认为它应该能够诱导粘膜免疫，引发有效的细胞溶解和多功能HIV特异性T细胞反应，以及具有广泛定向中和活性和抗体依赖性细胞免疫反应的抗HIV抗体。细胞毒性（ADCC）活性。先天免疫系统是适应性免疫的重要调节剂，可以影响全身和粘膜部位病原体特异性免疫反应的程度、质量和持久性。自然杀伤 T (NKT) 细胞是先天免疫系统中独特的 T 细胞，具有强大的免疫调节特性，可影响 T 细胞和 B 细胞免疫。在本次拨款申请中，我们建议使用 SIV 感染猕猴模型来研究 NKT 激活将提高疫苗免疫原性并改善疫苗介导的针对 SIV 感染获得和控制的保护的假设。相反，NKT 细胞的缺失可能会降低保护性减毒活 SIV (LASIV) 疫苗的功效。我们的具体目标是：#1。确定 NKT 消耗和 NKT 激活 mAb 体内给药的最佳给药方案，并表征它们在食蟹猴血液和组织中的作用。 #2.研究以下假设：NKT 激活的佐剂作用将增强异源初免-加强重组 Ad26/Ad5-SIV 疫苗方案的保护功效。＃3。研究这样的假设：在 NKT 耗尽的情况下接种疫苗将消除高度保护性 LASIV 疫苗的保护功效。