Cytolytic antibodies:Bridging the gap between the innate and adaptive immune resp

溶细胞抗体：弥合先天免疫和适应性免疫反应之间的差距

• 批准号: 7686615
• 负责人: Galit Alter
• 金额: $ 44.13万
• 依托单位: MASSACHUSETTS GENERAL HOSPITAL
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-04-01 至 2014-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7686615
• 关键词: Acquired Immunodeficiency Syndrome; Acute; Antibodies; Antibody Formation; Antiviral Therapy; B-Lymphocytes; Biological Assay; Blocking Antibodies; CD8B1 gene; Cancer Model; Cell physiology; Cells; Data; Disease Outcome; Disease Progression; Epitopes; Failure; Fc Receptor; Generations; HIV; HIV Infections; HIV envelope protein; HIV-1; Human; Hypergammaglobulinemia; Immune; Immune response; Immune system; Immunity; In Vitro; Infection; Infection prevention; Malignant Neoplasms; Mediating; Modeling; Natural Killer Cells; Nature; Patients; Play; Principal Investigator; Proteins; Receptor Cell; Role; SIV; Specificity; Staging; T-Lymphocyte; Vaccination; Vaccine Design; Vaccines; Viral; Virus; Virus Diseases; antibody-dependent cell cytotoxicity; design; flexibility; improved; in vivo; killer T cell; mucosal site; neutralizing antibody; novel; novel strategies; patient population; prophylactic; public health relevance; response; therapeutic vaccine; vaccine candidate

DESCRIPTION (provided by applicant): Significant advances have been achieved in our understanding of both the humoral and cellular immune response in HIV infection, however the correlates of protection against disease progression have still not been defined. Several lines of evidence suggest that although both CD8+ T cells and neutralizing antibodies seem to play a critical role in suppressing viral replication in vitro, vaccines that induce these responses do not seem to induce protective immunity. HIV-1 infection is associated with a dramatic hypergammaglobulinemia. Despite the induction of these large quantities of antibodies, broadly neutralizing antibodies only seem to develop following years of infection, and always seem to lag behind and poorly neutralize the contemporaneous infecting virus. However a small number of studies have demonstrated that in addition to neutralizing antibodies, non-neutralizing antibodies that can induce cytolytic activity, such as those that induce antibody-dependent cellular cytotoxicity (ADCC), may also play a protective role in the control of HIV-1 infection. ADCC inducing antibodies are detectable as early as acute HIV-1 infection, can be isolated from mucosal sites, and correlate independently of other effector functions with better disease outcome. Furthermore, novel data from the simian model of infection suggests that neutralizing antibodies may largely elicit their protective role in vivo via the induction of ADCC activity. However human studies, aimed at defining the role of ADCC in the control of HIV-1 infection, have been performed on small numbers of poorly characterized patient populations, using varied and incomparable assays. Given the association of ADCC with slower HIV-1 disease progression, data from the SIV model demonstrating that ADCC may be important in preventing infection, the capacity of ADCC inducing antibodies to elicit and focus the effector functions of cells of the innate immune system, the fact that non-neutralizing Abs are flexible and can target multiple epitopes in the HIV envelope gene products, their critical nature in the immune response in the context of other infections and cancer models, and the ease with which antibodies can be induced via vaccination, it is plausible that protective antibodies with cytolytic functions could play a critical role in containing HIV-1 replication. It is therefore imperative that we begin to define the role of cytolytic antibodies to determine whether the induction of these immune responses can improve control of HIV-1 replication in vivo. Thus this application aims to comprehensively define the role of cytolytic ADCC inducing antibody responses in HIV-1 infection and to determine whether the induction of these responses should be a priority in our efforts to design an effective vaccine. PUBLIC HEALTH RELEVANCE: Both killer- T cells and antibodies that block viral infection (neutralizing antibodies) seem to play a critical role in suppressing viral replication in vitro, but vaccines that induce these responses do not induce protection against HIV-1 disease progression. In contrast, non-neutralizing antibodies that bridge the adaptive (B cells) to the innate immune response, via the induction of cytolytic activity by cells of the innate immune system by antibody dependent cellular cytotoxicity (ADCC), have been identified in patients as early as acute HIV-1 infection and correlate significantly with better disease outcome. Given the critical nature of non-neutralizing antibodies in slower HIV-1 disease progression, their flexibility in targeting multiple regions on the HIV envelope protein, as well as their critical role in protection against other pathogenic infections and cancers, it is plausible that antibodies with cytolytic functions could play a central role in controlling HIV-1 replication as well. This proposal therefore aims to define the role of ADCC in HIV- 1 infection to determine whether the generation of these responses should be a priority in our efforts to design an effective prophylactic or therapeutic vaccine.

描述（由申请人提供）：在我们对HIV感染中的体液和细胞免疫反应的理解中，已经取得了重大进展，但是仍未定义保护疾病进展的保护相关性。几条证据表明，尽管CD8+ T细胞和中和抗体似乎在抑制体外病毒复制方面起着至关重要的作用，但诱导这些反应的疫苗似乎并没有诱导保护性免疫。 HIV-1感染与显着的高γ-球素血症有关。尽管诱导了这些大量抗体，但在感染了多年后，广泛中和的抗体似乎才会发展出来，并且似乎总是落后，并且不良中和同时的感染病毒。然而，少量研究表明，除了中和抗体外，非中和抗体可以诱导细胞溶解活性，例如诱导抗体依赖性细胞细胞毒性（ADCC）的抗体，在HIV-1感染的控制中也可能起保护作用。早在急性HIV-1感染时就可以从粘膜部位分离出ADCC诱导抗体，并且可以独立于具有更好疾病结果的其他效应功能。此外，来自猿猴感染模型的新数据表明，中和抗体可能在很大程度上通过诱导ADCC活性引起其在体内的保护作用。然而，使用各种和无与伦比的测定法，旨在定义ADCC在控制HIV-1感染中的作用的人类研究已在少量特征的患者人群中进行。鉴于ADCC与HIV-1疾病进展较慢的关联，SIV模型的数据表明，ADCC可能在防止感染中很重要，ADCC诱导抗体引起并集中了先天免疫系统细胞的效应子的能力，这一事实是，非中性化的ABS可以灵活，并且在HIV中靶向其他eStempect and the Vernation invel Gene eNVELESS的抗衡，这一事实是，它们在hiv中的其他响应，并且在近距离范围内构成了其他范围的启示，并且在范围内构成了范围的范围。模型，以及通过疫苗接种诱导抗体的易感性，具有细胞溶解功能的保护性抗体可能在包含HIV-1复制中起关键作用。因此，我们必须开始定义细胞溶剂抗体的作用，以确定这些免疫反应的诱导是否可以改善体内HIV-1复制的控制。因此，该应用程序旨在全面定义诱导HIV-1感染中抗体反应的细胞溶解ADCC的作用，并确定这些反应的诱导是否应该是我们设计有效疫苗的优先事项。公共卫生相关性：阻断病毒感染（中和抗体）的杀伤细胞和抗体似乎在抑制体外抑制病毒复制方面起着至关重要的作用，但是诱导这些反应的疫苗并不能诱导保护HIV-1疾病进展。相反，通过抗体依赖性细胞毒性（ADCC）通过抗体免疫系统细胞诱导细胞的细胞溶解活性（ADCC），已被确定为急性HIV HIV-1感染和更好的疾病相关性，通过抗体依赖性细胞毒性（ADCC）诱导了先天性免疫系统的细胞溶性活性（ADCC）。鉴于在较慢的HIV-1疾病进展中非中和化抗体的批判性质，它们在针对HIV Invelope蛋白多个区域的灵活性以及它们在保护其他致病感染和癌症的保护中的关键作用，因此具有细胞溶解功能的抗体可以在细胞溶解功能中起到中心作用，可以在Contrication Contrication Contrication Contrication Contrication Contrication Contrication。因此，该提案旨在确定ADCC在HIV-1感染中的作用，以确定这些反应的产生是否应该是我们设计有效的预防性或治疗疫苗的优先事项。