Regulation of Memory B Cell Responses to Polysaccharide Antigens

 描述(由申请人提供)：在美国，肺炎链球菌导致的死亡人数超过所有其他疫苗可预防疾病的总和，每年导致全球超过160万人死亡。目前用于成人的本土肺炎球菌疫苗由来自23个不同血清型的荚膜多糖(PPS)组成，因此提供了广泛的覆盖范围，可预防侵袭性疾病。尽管如此，随着抗体效价的下降，保护力最终会减弱，通常是在接种疫苗后10年。不幸的是，PPS增强并不能引发回忆反应。这是大多数多糖(Ps)抗原的典型特征。考虑到对肺炎球菌感染的保护作用可能减弱，这是一个重大关切。与在幼儿中观察到的情况相反，PPS-蛋白质结合疫苗在成人中并不能有效地提高或产生比天然PPS更高的滴度。这一点，再加上结合疫苗的高成本和有限的血清型覆盖范围，表明需要替代策略来提高PPS疫苗的效力。为了改进本土的Ps疫苗，必须从机制上理解阻止Ps特异性抗体召回反应的因素。我们的数据支持记忆B细胞是对Ps抗原产生的，但当感染或重新接种后再次遇到抗原时，它们基本上没有反应。抗原特异性的免疫球蛋白可能通过抑制Ps特异性的IgM回忆反应而发挥作用。然而，我们的数据支持额外的抑制机制，不仅有助于受损的IgM，而且有助于促进Ps抗原的免疫球蛋白G。在这个提议中，我们将检验这样一个假设，即受体介导的免疫抑制的活跃机制限制了Ps特异性记忆B细胞的生成和对次级抗原相遇的功能反应。此外，我们将检验这样一种假设，即通过类TLR(TLR)提供的强“危险”信号 而C型凝集素受体(CLR)可以克服这种抑制。在目标1中，我们将研究B7：CD28超家族抑制性受体和配体在抑制Ps特异性记忆B细胞形成和效应功能中的内在和外在作用。在目标2中，我们将研究Ps特异性抗体抑制启动子的机制。在目标3中，我们将研究TLR4/RP105和Mincle激动剂在多大程度上协同促进Ps特异性记忆B细胞的生成和增强过程中的功能反应。我们将研究实现这一目标的机制，包括这些激动剂克服AIMS 1和AIMS 2中检查的抑制途径的程度。这些研究的完成有望提供关于对天然P蛋白的二次抗体反应被抑制的机制以及使用TLR和CLR佐剂组合来克服有效疫苗接种这一障碍的可行性的关键知识。我们的结果预计将对使用本地Ps的Prime-Boost策略的使用产生重大影响，以及未来设计更负担得起、更有效的具有最高血清型覆盖率的Ps疫苗。

 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.