Regulation of Memory B Cell Responses to Polysaccharide Antigens

 描述（由申请人提供）：链球菌在美国造成的死亡人数超过所有其他疫苗可预防疾病的总和，并导致全球每年超过160万人死亡。目前用于成人的天然肺炎球菌疫苗由来自23种不同血清型的荚膜多糖（PPS）组成，因此可广泛覆盖侵袭性疾病。然而，随着抗体滴度的降低，保护作用最终会减弱，通常在接种疫苗后10年。不幸的是，PPS提升并不能诱导回忆反应。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可能减少，这是一个重大问题。与在幼儿中观察到的情况相反，PPS-蛋白缀合物疫苗在成人中不能有效地增强或产生比天然PPS更上级的滴度。沿着结合疫苗的高成本和有限的血清型覆盖，这表明需要替代策略来增强PPS疫苗的功效。为了改进天然Ps疫苗，必须对阻止Ps特异性抗体回忆反应的因素进行机械理解。我们的数据支持记忆B细胞是响应Ps抗原而产生的，但当感染或再接种后再次遇到抗原时，它们在很大程度上不响应。抗原特异性IgG可通过抑制Ps特异性IgM回忆应答而发挥作用。然而，我们的数据支持另外的抑制机制不仅导致IgM受损，而且导致IgG增强为Ps抗原。在这个建议中，我们将测试的假设，受体介导的免疫抑制的活性机制限制PS-特异性记忆B细胞的产生和功能的反应，第二抗原遇到。此外，我们将测试的假设，强大的“危险”信号提供通过收费样（TLR） 而C型凝集素受体（C-type lectin receptor，C-Lectin receptor）可以克服这种抑制。在目的1中，我们将研究B7：CD 28超家族抑制性受体和配体在抑制PS特异性记忆B细胞形成和效应器功能中的B细胞内在和外在作用。在目标2中，我们将研究Ps特异性抗体抑制加强的机制。在目的3中，我们将检查TLR 4/RP 105和Mincle激动剂协同促进Ps特异性记忆B细胞生成和加强期间功能反应的程度。我们将研究实现这一目标的机制，包括这些激动剂克服目标1和2中检查的抑制途径的程度。这些研究的完成预计将提供关键知识的机制，负责抑制二抗反应的天然Ps，以及使用TLR和CLR为基础的佐剂组合，以克服这一障碍，有效的疫苗接种的可行性。我们的研究结果预计将有一个显着的影响，使用初免-加强策略，采用本地Ps，以及未来的设计更实惠，更有效的Ps为基础的疫苗，尽可能高的血清型覆盖率。

 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.