Role of Fc Receptor Polymorphisms in Antibody-Mediated Protection

Fc 受体多态性在抗体介导的保护中的作用

• 批准号: 8410766
• 负责人: Joern E. Schmitz
• 金额: $ 87.45万
• 依托单位: BETH ISRAEL DEACONESS MEDICAL CENTER
• 依托单位国家: 美国
• 财政年份: 2012
• 资助国家: 美国
• 起止时间: 2012-03-01 至 2015-02-28
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8410766
• 关键词: Acquired Immunodeficiency Syndrome; Affect; Affinity; Animal Model; Animals; Antibodies; Antibody-mediated protection; Binding; Biological Assay; Cell Line; Clinical; Complex; Data; Data Analyses; Disease; Dose; Evaluation; Fc Receptor; Genetic; Genetic Polymorphism; Genetic Variation; HIV; HIV Infections; Human; Immune; Immune system; Infection; Inferior; Investigation; Macaca; Macaca mulatta; Mediating; Modeling; Monkeys; Monoclonal Antibodies; Pathway interactions; Patients; Publishing; Relative (related person); Research; Research Personnel; Role; SIV; Sequence Analysis; Sterility; Vagina; Viremia; Virus; cellular transduction; in vivo; neutralizing antibody; nonhuman primate; prospective; receptor; research study; simian human immunodeficiency virus; success; tumor

DESCRIPTION (provided by investigator): Recent investigations have suggested that efficient neutralization of AIDS viruses in vivo goes well beyond steric inhibition of the virus by antibodies. Efficient neutralization also depends on additional functional activities such as Fc? receptor-mediated deactivation of the virus. It is well established in humans that the action of antibodies depends on multiple pathways that enhance efficient extermination of its target. However, as the full potential of antibodies requires additional components of the host's immune system, antibody-mediated immune control gets more complex. In fact, the same potent monoclonal antibody may show a different in vivo efficacy depending on specific polymorphisms within the host's immune system. This has been demonstrated in detail for as Fc? receptor polymorphisms where a particular antibody treatment in some tumor patients has resulted in an inferior likelihood of clinical success because the downstream functional activities for the antibody were less efficient due to genetic variation between patients. In HIV infection, limited research has suggested that as Fc? receptor polymorphisms may also affect the progression to AIDS. However, until to date there is no published information available whether as Fc? receptor polymorphisms may affect SIV infection in rhesus macaques that are the most utilized animal model to study an AIDS-like disease in nonhuman primates. We have recently determined as Fc? receptor polymorphisms in rhesus macaques and have gained statistical evidence that as Fc? receptor polymorphisms also affect the in vivo efficacy of antibodies in this nonhuman primate species. Our preliminary data also suggest that as Fc? receptor polymorphisms may be correlated with a differential ability to contain SIV setpoint viremia. While these preliminary data are very encouraging, these observations need more scrutiny. Here we propose studies that (Aim 1) will determine the functional activity of different polymorphic forms of the as Fc? receptors in rhesus macaques. We will conduct (Aim 2) a prospective low dose neutralizing antibody administration and low dose mucosal challenge study to investigate whether as Fc? receptor polymorphisms may impact the efficacy of the neutralizing antibody b12 in protecting the animals from vaginal challenges.

描述（由研究者提供）：最近的研究表明，体内艾滋病病毒的有效中和远远超出了抗体对病毒的立体抑制。有效中和还取决于其他功能活动，如Fc？受体介导的病毒失活。在人类中，抗体的作用依赖于多种途径，从而提高对其靶标的有效消灭。然而，由于抗体的全部潜力需要宿主免疫系统的额外成分，抗体介导的免疫控制变得更加复杂。事实上，同一种有效的单克隆抗体可能根据宿主免疫系统内的特定多态性而显示出不同的体内功效。这已经在Fc？受体多态性，在某些肿瘤患者中，特定的抗体治疗导致临床成功的可能性较低，因为由于患者之间的遗传变异，抗体的下游功能活动效率较低。在艾滋病毒感染中，有限的研究表明，作为Fc？受体多态性也可能影响艾滋病的进展。然而，到目前为止，还没有公布的信息，是否为Fc？受体多态性可能影响恒河猴的SIV感染，恒河猴是研究非人类灵长类类艾滋病疾病最常用的动物模型。我们最近确定为Fc？在恒河猴的受体多态性，并获得了统计证据，作为Fc？受体多态性也会影响这种非人灵长类动物体内抗体的功效。我们的初步数据还表明，当Fc？受体多态性可能与抑制SIV设定点病毒血症的能力差异有关。虽然这些初步数据非常令人鼓舞，但这些观察结果需要更多的审查。在这里，我们提出的研究（Aim 1）将确定不同多态形式的as Fc？恒河猴的受体。我们将进行（目标2）一项前瞻性低剂量中和抗体给药和低剂量粘膜激发研究，以调查是否作为Fc？受体多态性可能影响中和抗体b12保护动物免受阴道攻击的功效。