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Regulation of Memory B Cell Responses to Polysaccharide Antigens

记忆 B 细胞对多糖抗原反应的调节

基本信息

批准号：
9465418
负责人：
Karen M Haas
金额：
$ 38.44万
依托单位：
WAKE FOREST UNIVERSITY HEALTH SCIENCES
依托单位国家：
美国
项目类别：
财政年份：
2015
资助国家：
美国
起止时间：
2015-05-01 至 2020-04-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9465418
关键词：
Adjuvant Adult Agonist Antibodies Antibody Formation Antibody Response Antibody titer measurement Antigens B-Lymphocytes Bacteria Binding C Type Lectin Receptors CD22 gene CD28 gene CD80 gene CTLA4 gene Carbohydrates Cell division Cells Cessation of life Child Communicable Diseases Complement Complement Receptor Complex Conjugate Vaccines Cytotoxic T-Lymphocyte-Associated Protein 4 Data Development Disease Encapsulated Functional disorder Future Generations Goals Immune system Immunization Immunoglobulin G Immunoglobulin M Immunoglobulin-Secreting Cells Immunoglobulins Immunosuppression Impairment Individual Infection Knowledge Lead Lectin Lectin Receptors Ligands Link Lipid A Mediating Memory Memory B-Lymphocyte Modification PDCD1LG1 gene Pathway interactions Pattern recognition receptor Play Pneumococcal Infections Pneumococcal vaccine Pneumovax Polysaccharides Polyvalent pneumococcal vaccine Proteins Public Health Regulation Regulatory Pathway Research Research Personnel Role SLEB2 gene Secondary Immunization Secondary to Serotyping Sialic Acids Signal Transduction Streptococcus Streptococcus pneumoniae Suppressor-Effector T-Lymphocytes T-Lymphocyte TLR4 gene Testing Time Toll-like receptors Trehalose Ursidae Family Vaccination Vaccines Work base cancer therapy cost design improved prevent public health relevance receptor response sialic acid binding Ig-like lectin sialic acid receptor sialylation synergism trafficking vaccine efficacy

项目摘要

DESCRIPTION (provided by applicant): Streptococcus neumoniae kills more people in the U.S. than all other vaccine-preventable diseases combined and causes over 1.6 million deaths/year worldwide. The native pneumococcal vaccine currently used in adults consists of capsular polysaccharides (PPS) derived from 23 different serotypes and therefore provides broad coverage against invasive disease. Nonetheless, protection eventually wanes as antibody titers diminish, typically by 10 years post-vaccination. Unfortunately, PPS boosting does not induce recall responses. This is typical of most polysaccharide (Ps) antigens. This is a significant concern given the potential for diminished protection against pneumococcal infections. PPS-protein conjugate vaccines do not effectively boost or yield superior titers to native PPS in adults, in contrast to what is observed in young children. This, along with the high cost and limited serotype coverage of conjugate vaccines, suggests that alternative strategies are needed to enhance PPS vaccine efficacy. To improve native Ps vaccines, it is imperative to develop a mechanistic understanding of the factors preventing Ps-specific antibody recall responses. Our data supports that memory B cells are generated in response to Ps antigens but that they are largely unresponsive when antigen is re- encountered following infection or revaccination. Antigen-specific IgG may play a part by suppressing Ps- specific IgM recall responses. However, our data supports additional mechanisms of suppression contribute to not only to impaired IgM, but IgG, boosting to Ps antigens. In this proposal, we will test the hypothesis that active mechanisms of receptor-mediated immune suppression limit Ps-specific memory B cell generation and functional responsiveness to secondary antigen encounter. In addition, we will test the hypothesis that strong "danger" signals supplied through toll-like (TLR) and C-type lectin receptors (CLR) can overcome this suppression. In Aim 1, we will examine the B cell-intrinsic and -extrinsic roles for B7:CD28 superfamily inhibitory receptors and ligands in suppressing Ps-specific memory B cell formation and effector function. In Aim 2, we will investigate mechanisms by which Ps-specific antibody suppresses boosting. In Aim 3, we will examine the extent to which TLR4/RP105 and Mincle agonists synergize to promote Ps-specific memory B cell generation and functional responsiveness during boosting. We will examine the mechanisms by which this is achieved, including the extent to which these agonists overcome the inhibitory pathways examined in Aims 1 and 2. Completion of these studies is expected to provide critical knowledge regarding the mechanisms responsible for suppressed secondary antibody responses to native Ps as well as the feasibility of using TLR and CLR-based adjuvant combinations to overcome this barrier to effective vaccination. Our results are expected to have a significant impact on the use of prime-boost strategies employing native Ps, as well as the future design of more affordable and efficacious Ps-based vaccines with the highest possible serotype coverage.