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KSHV相关恶性肿瘤，报告了> 44，000例新病例 全球每年都有。最易感染KSHV/KS的人群是免疫功能低下的个体， 感染艾滋病病毒的人。艾滋病毒/艾滋病感染者患KS的风险高于 艾滋病毒阴性个体。适应性T细胞免疫应答，特别是CD 4+和CD 8 + T细胞，已经被广泛应用。 显示在KSHV感染和随后的KS发病机制中起关键作用。虽然， 已观察到CD 4+和CD 8 + T细胞水平与KS发展，但尚未发现这种关系。 由于缺乏合适的动物模型，最近的发展共同的 绒猴（Callithrix jacchus）作为对KSHV感染易感的非人灵长类动物（NHP）模型， 能够在免疫抑制下发展KS样病变开辟了新的领域， 免疫细胞在KS发展中的作用。因此，我们的目标是确定减少的CD 4+和 在绒猴NHP模型中持续KSHV感染和随后KS发病机制中的CD 8 + T细胞水平 抗-CD 4和抗-CD 8单克隆抗体（mAb）已用于耗尽T细胞并诱导T细胞凋亡。 在小鼠和NHP动物模型中的免疫抑制，使得能够研究CD 4 +/CD 8 + T细胞在控制 几种病毒的复制。为了避免在给药时对鼠mAb产生任何不良反应， 我们将嵌合（鼠-绒猴）抗CD 4/CD 8单克隆抗体，并表征其生化和 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 对各种免疫细胞群体的消耗（目的1）。然后我们将挑战免疫抑制的绒猴 与KSHV.219病毒感染，并确定抗体介导的CD 4+和/或CD 8 + T细胞耗竭的程度， 细胞使KSHV持续感染和KS发病机制免疫受损的绒猴（目的2）。的 本计画的成功完成将验证普通绒猴作为了解病因的工具 揭示了CD 4+和/或CD 8 + T细胞耗竭在持续性KSHV中的关键作用 感染和随后KS发病机制。