Use of a non-human primate model to define the role of T cell immune responses in persistent Kaposi sarcoma-associated herpesvirus infection and Kaposi sarcoma pathogenesis

使用非人灵长类动物模型来定义 T 细胞免疫反应在持续性卡波西肉瘤相关疱疹病毒感染和卡波西肉瘤发病机制中的作用

• 批准号: 10667986
• 负责人: Lorraine Zvichapera Mutsvunguma
• 金额: $ 34.55万
• 依托单位: BECKMAN RESEARCH INSTITUTE/CITY OF HOPE
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-02-01 至 2025-01-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10667986
• 关键词: AIDS with Kaposi' s sarcoma; Animal Experiments; Animal Model; Animals; Antibodies; Antibody Response; B-Lymphocytes; Biochemical; Blood Pressure; CD4 Positive T Lymphocytes; CD8-Positive T-Lymphocytes; CD8B1 gene; Callithrix; Callithrix jacchus jacchus; Cancer Etiology; Case Study; Cell Count; Cells; Chemicals; Collaborations; Complex; Defect; Development; Dose; Drops; Drug Kinetics; Etiology; Excision; Exhibits; Frequencies; HIV; HIV Seronegativity; HIV/AIDS; Herpesviridae Infections; Human; Human Herpesvirus 8; Immune; Immune response; Immune system; Immunocompetent; Immunocompromised Host; Immunologic Deficiency Syndromes; Immunosuppression; In Vitro; Individual; Infection; Intravenous; Japan; Kaposi Sarcoma; Laboratories; Lesion; Light; Malignant Neoplasms; Mediating; Methods; Modeling; Monkeys; Monoclonal Antibodies; Mus; Newly Diagnosed; Pathogenesis; Peripheral Blood Mononuclear Cell; Persons; Play; Population; Predisposition; Primates; Property; Reagent; Research; Resolution; Resources; Role; Serum; Splenocyte; T cell reconstitution; T cell response; T-Cell Depletion; T-Lymphocyte; Tacrolimus; Toxic effect; Urea; Viral Load result; Virus; Virus Diseases; Wisconsin; cell mediated immune response; cytotoxic CD8 T cells; frontier; high risk; human pathogen; immunosuppressed; improved; in vivo; in vivo Model; murine monoclonal antibody; nonhuman primate; oral infection; permissiveness; reconstitution; respiratory; response; side effect; skin lesion; tool

PROJECT ABSTRACT Kaposi sarcoma-associated herpesvirus (KSHV) is the causative agent of several human malignancies including Kaposi sarcoma (KS). KS is the most common KSHV-associated malignancy, with >44,000 new cases reported worldwide each year. The population most vulnerable to KSHV/KS are immunocompromised individuals such as people infected with HIV. Individuals with HIV/AIDS have a higher risk of developing KS when compared to HIV-negative individuals. The adaptive T cell immune response, especially CD4+ and CD8+ T cells, has been shown to play a crucial role in KSHV infection and subsequent KS pathogenesis. Although correlations between CD4+ and CD8+ T cell levels and KS development have been observed, this relationship has not been experimentally validated due to the lack of a suitable animal model. The recent development of the common marmoset (Callithrix jacchus) as a non-human primate (NHP) model that is susceptible to KSHV infection and capable of developing KS-like lesions under immunosuppression opens new frontiers to experimentally validate the role immune cells play in KS development. Thus, our objective is to define the role of reduced CD4+ and CD8+ T cell levels in persistent KSHV infection and subsequent KS pathogenesis in the marmoset NHP model. Anti-CD4 and anti-CD8 monoclonal antibodies (mAbs) have been used to deplete T cells and induce immunosuppression in both murine and NHP animal models, enabling study of CD4+/CD8+ T cells in controlling replication of several viruses. To avoid any adverse responses to murine mAbs when administered into marmosets, we will chimerize (murine-marmoset) anti-CD4/CD8 mAbs and characterize their biochemical and pharmacokinetic properties in vitro and in mice, then we will determine the effects of antibody-mediated T cell depletion on various immune cell populations (Aim 1). We will then challenge immunosuppressed marmosets with KSHV.219 virus and determine the extent to which antibody-mediated depletion of CD4+ and/or CD8+ T cells enables persistent KSHV infection and KS pathogenesis in immunocompromised marmosets (Aim 2). The successful completion of this project will validate the common marmoset as a tool for understanding the etiology of KS and uncover the critical role that CD4+ and/or CD8+ T cell depletion plays in allowing persistent KSHV infection and subsequent KS pathogenesis in immunocompromised animals.

项目摘要 卡波西肉瘤相关疱疹病毒 (KSHV) 是多种人类恶性肿瘤的病原体，包括 卡波西肉瘤（KS）。 KS 是最常见的 KSHV 相关恶性肿瘤，已报告超过 44,000 例新病例 每年在全球范围内。最容易感染 KSHV/KS 的人群是免疫功能低下的个体，例如 作为艾滋病毒感染者。与其他人相比，艾滋病毒/艾滋病患者患 KS 的风险更高 HIV 阴性个体。适应性 T 细胞免疫反应，特别是 CD4+ 和 CD8+ T 细胞，已被 研究显示在 KSHV 感染和随后的 KS 发病机制中发挥着至关重要的作用。虽然之间的相关性 已观察到 CD4+ 和 CD8+ T 细胞水平与 KS 发育的关系，但这种关系尚未得到证实 由于缺乏合适的动物模型而无法通过实验验证。共同的最新发展 狨猴 (Callithrix jacchus) 作为一种易受 KSHV 感染的非人类灵长类动物 (NHP) 模型 能够在免疫抑制下形成 KS 样病变，开辟了实验验证的新领域 免疫细胞在 KS 发育中的作用。因此，我们的目标是定义减少的 CD4+ 和 狨猴 NHP 模型中持续 KSHV 感染和随后的 KS 发病机制中的 CD8+ T 细胞水平。 抗 CD4 和抗 CD8 单克隆抗体 (mAb) 已用于消耗 T 细胞并诱导 小鼠和 NHP 动物模型中的免疫抑制，使得能够研究 CD4+/CD8+ T 细胞控制 多种病毒的复制。为了避免鼠单克隆抗体在给药时出现任何不良反应 狨猴，我们将嵌合（鼠狨猴）抗 CD4/CD8 mAb，并表征其生化和 体外和小鼠体内的药代动力学特性，然后我们将确定抗体介导的 T 细胞的作用 各种免疫细胞群的耗竭（目标 1）。然后我们将挑战免疫抑制的狨猴 使用 KSHV.219 病毒并确定抗体介导的 CD4+ 和/或 CD8+ T 耗竭程度 细胞能够在免疫功能低下的狨猴中实现持续的 KSHV 感染和 KS 发病机制（目标 2）。这 该项目的成功完成将验证普通狨猴作为了解病因学的工具 KS 并揭示 CD4+ 和/或 CD8+ T 细胞耗竭在允许持续 KSHV 中发挥的关键作用 免疫功能低下动物的感染和随后的 KS 发病机制。