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 Kaposi肉瘤相关的疱疹病毒（KSHV）是几种人类恶性肿瘤的原因 Kaposi肉瘤（KS）。 KS是最常见的KSHV相关的恶性肿瘤，报告了44,000例新病例 每年全球。最容易受到KSHV/KS的人口是免疫强张病的人 作为感染艾滋病毒的人。与艾滋病毒/艾滋病患者相比，患有KS的人的风险更高 艾滋病毒阴性个体。自适应T细胞免疫反应，尤其是CD4+和CD8+ T细胞，已经是 证明在KSHV感染和随后的KS发病机理中起着至关重要的作用。虽然之间的相关性 已经观察到CD4+和CD8+ T细胞水平以及KS的发展，这种关系尚未 由于缺乏合适的动物模型，实验验证了。共同的最新发展 Marmoset（Callithrix Jacchus）作为非人类灵长类动物（NHP）模型，容易受到KSHV感染和 能够在免疫抑制下形成类似KS的病变，为实验验证开辟了新的边界 免疫细胞在KS发育中起作用。因此，我们的目标是定义降低的CD4+和 Marmoset NHP模型中持续的KSHV感染和随后的KS发病机理中的CD8+ T细胞水平。 抗CD4和抗CD8单克隆抗体（mAb）已用于耗尽T细胞并诱导 鼠和NHP动物模型中的免疫抑制，使CD4+/CD8+ T细胞的研究在控制中 复制几种病毒。为了避免对鼠mab的不良反应， marmosets，我们将嵌合（鼠）抗CD4/CD8 mabs，并表征其生化和 在体外和小鼠中的药代动力学特性，然后我们将确定抗体介导的T细胞的作用 各种免疫细胞群体的耗竭（AIM 1）。然后，我们将挑战免疫抑制的marmosets 使用KSHV.219病毒，并确定抗体介导的CD4+和/或CD8+ T的耗竭程度 细胞可以在免疫功能低下的果棒中持续的KSHV感染和KS发病机理（AIM 2）。这 该项目的成功完成将验证共同的marmoset作为理解病因的工具 KS的CD4+和/或CD8+ T细胞耗竭在允许持续的KSHV中发挥作用的关键作用 免疫功能低下动物中的感染和随后的KS发病机理。