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)是几种人类恶性肿瘤的病原体，包括 卡波西肉瘤(KS)。KS是最常见的与KSHV相关的恶性肿瘤，报告了44,000例新病例 每年在全球范围内。最易感染KSHV/KS的人群是免疫受损的人，如 作为感染艾滋病毒的人。与感染艾滋病毒/艾滋病的人相比，他们患KS的风险更高 HIV阴性的个人。适应性T细胞免疫反应，特别是CD4+和CD8+T细胞 已证明在KSHV感染和随后的KS发病中起着关键作用。尽管两者之间的相关性 已经观察到了CD4+和CD8+T细胞水平与KS的发展，这种关系尚未被观察到 由于缺乏合适的动物模型而进行了实验验证。公用事业的最新发展 绒猴(Callithrix Jacchus)是一种非人类灵长类动物模型，对KSHV感染和 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发生中的作用。因此，我们的目标是定义减少的CD4+和 在恒河猴NHP模型中持续感染KSHV和随后的KS发病中CD8+T细胞水平。 抗CD4和抗CD8的单抗已被用来耗尽T细胞并诱导 在小鼠和NHP动物模型中的免疫抑制，使研究CD4+/CD8+T细胞在控制 复制几种病毒。为了避免对小鼠单抗在体内注射时的任何不良反应 ，我们将嵌合(小鼠绒猴)抗CD4/CD8单抗，并鉴定其生化和 在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细胞的效果 消耗各种免疫细胞群(目标1)。然后我们将挑战免疫抑制的绒猴 与KSHV.219病毒结合，确定抗体介导的CD4+和/或CD8+T细胞耗尽程度 在免疫受损的绒猴中，细胞使KSHV持续感染和KS发病(目标2)。这个 这个项目的成功完成将验证常见的绒猴作为了解病因学的工具 并揭示了CD4+和/或CD8+T细胞耗竭在导致持续性KSHV中所起的关键作用 免疫受损动物的感染和随后的KS发病机制。