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：
8660612
负责人：
Amitinder Kaur
金额：
$ 9.55万
依托单位：
HARVARD MEDICAL SCHOOL
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 2015-01-05
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8660612
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）：艾滋病流行病的30年，估计有3400万HIV感染者在全球范围内，近70％居住在撒哈拉以南非洲。尽管针对开发艾滋病疫苗的深入研究仍在继续，但目前尚无有效的HIV疫苗。为了使HIV疫苗成功，它应该能够诱导粘膜免疫，引起有效的细胞溶液和多功能HIV特异性T细胞反应以及具有广泛定向中性活性的抗HIV抗体，并具有广泛的中性化活性和抗体依赖性的细胞细胞毒性（ADCC）活性。先天免疫系统是适应性免疫的重要调节剂，可以塑造系统性和粘膜部位的病原体特异性免疫反应的大小，质量和耐用性。天然杀伤剂（NKT）细胞是先天免疫系统的独特T细胞，具有有效的免疫调节特性，可能会影响T和B细胞免疫。在此赠款应用中，我们建议使用SIV感染猕猴模型来研究NKT激活将改善疫苗免疫原性并改善疫苗介导的对SIV感染的获取和控制的保护。相反，NKT细胞的不存在可能会降低保护性活衰减SIV（LASIV）疫苗的功效。我们的具体目标是：＃1。确定用于体内施用NKT耗尽和NKT激活mAb的最佳剂量方案，并表征它们在cynomolgus猕猴的血液和组织中的作用。＃2。研究了NKT激活的辅助作用将增强异源促进重组AD26/AD5-SIV疫苗方案的保护效果的假设。＃3。研究假设NKT耗竭的疫苗接种将消除高度保护性LASIV疫苗的保护作用。