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Mechanisms of DDO Adjuvancy

DDO 辅助机制

基本信息

批准号：
9757694
负责人：
Carolina B. Lopez
金额：
$ 47.05万
依托单位：
UNIVERSITY OF PENNSYLVANIA
依托单位国家：
美国
项目类别：
财政年份：
2018
资助国家：
美国
起止时间：
2018-08-15 至 2020-05-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9757694
关键词：
Adjuvant Animal Model Animals Antibodies Antibody Response Antigens Automobile Driving CD4 Positive T Lymphocytes CD8-Positive T-Lymphocytes CD8B1 gene Cells Cellular Immunity Clinical Cytotoxic T-Lymphocytes Data Dendritic Cells Dependence Detection Development Dose Effectiveness Ferrets Generations Helper-Inducer T-Lymphocyte Human Humoral Immunities Immune response Immune system Immunity Immunize Infection Injections Interferon Type II Interferons Knockout Mice Laboratories Lead Leishmania Longevity Lymph Mediating Memory Modeling Molecular Mus Oligonucleotides Parasites Pathway interactions Primates RNA Receptor Signaling Regimen Reporter Role Series Signal Pathway Signal Transduction Site Squalene T cell response T memory cell T-Lymphocyte Testing Tissues Toll-like receptors Transgenic Mice Vaccination Vaccine Adjuvant Vaccines Viral Genome Viral Vaccines Virus Virus Diseases Virus Replication base cell type cellular longevity cytokine cytotoxic experimental study in vivo influenza virus vaccine influenzavirus insight lymph nodes member pathogen prototype receptor response systemic toxicity tool uptake vaccine development

项目摘要

SUMMARY Adjuvants able to induce long lasting type-1 cellular immunity, including both Th1 CD4+ T cells and cytotoxic CD8+ T cells, are highly sought out for the development of vaccines against intracellular pathogens that evade antibodies. We have identified a powerful new class of adjuvant that elicits protective type-1 biased responses. These adjuvants are synthetic RNA oligonucleotides derived from defective viral genomes (DDOs) and trigger strong immune responses by engaging cellular RIG-I-like receptors (RLRs). DDOs contain a unique immunostimulatory motif that we identified as essential for their ability to trigger RLR signaling. In mice, DDOs induce localized expression of type I IFNs and other cytokines and promote accumulation of DCs in the draining lymph node. In addition, DDOs promote a type I IFN-dependent IgG2b/c-biased antibody response able to protect mice from lethal virus challenge and induce IFNγ-producing antigen-specific CD4+ and CD8+ T cells. Moreover, DDOs synergize with the squalene-based adjuvant AddaVax, providing strong type-1 immunity bias to vaccines adjuvanted with AddaVax+DDOs. These data support our central hypothesis that DDOs represent a new class of adjuvants that stimulate the RLR/type I IFN signaling axis to drive optimal long-lived type-1 humoral and cellular immunity. Experiments in this proposal use the combined expertise and unique set of tools of the Lopez and Scott laboratories to assess the quality, longevity, and protective capacity of DDO-induced T cell responses during vaccination, and to characterize specific molecular and cellular mechanisms responsible for directing the type-1 immune response after DDO administration. Specifically, in Aim 1 we will use our ability to track DDOs in vivo, together with a series of reporter and transgenic mice, to identify the early interactions of DDOs with cells of the immune system, in particular DCs, and to identify potential key targets for the development of type -1 biased responses. In Aim 2, we will assess the development and quality of T helper 1 cells, cytotoxic T cells, T follicular helper cells, and tissue resident T cells in response to a vaccine adjuvanted with DDOs alone or in combination with AddaVax, and assess the role of type I IFNs in establishing these responses. In Aim 3, we will test the ability of DDOs to induce CD4+-mediated protection against the intracellular protozoan parasite Leishmania, since protection against this parasite is dependent upon CD4+ Th1 cells and is independent of antibodies, and we will directly assess the ability of DDOs to induce protective T cell responses using a model influenza vaccine in ferrets.

总结