EBV and Heterologous Alloimmunity in Humanized Mice

人源化小鼠中的 EBV 和异源同种免疫

• 批准号: 8279394
• 负责人: Liisa Kaarina Selin
• 金额: $ 47.58万
• 依托单位: UNIV OF MASSACHUSETTS MED SCH WORCESTER
• 依托单位国家: 美国
• 财政年份: 2011
• 资助国家: 美国
• 起止时间: 2011-06-01 至 2015-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8279394
• 关键词: Acute; Aftercare; Alloantigen; Allografting; C57BL/6 Mouse; Engraftment; Generations; Goals; HLA-A2 Antigen; Hematopoietic stem cells; Human; Human Herpesvirus 4; Human Virus; Immune; Immune response; Immune system; Immunity; Infection; Infiltration; Influenza; Laboratories; Lymphocytic Choriomeningitis; Lymphocytic choriomeningitis virus; Mus; Newborn Infant; Research; Resources; Role; Satellite Viruses; Small Interfering RNA; Study models; System; T Virus; T-Lymphocyte; TNFRSF5 gene; TNFSF5 gene; Technology; Testing; Transplantation; Transplantation Tolerance; Umbilical Cord Blood; Viral; Virus; Virus Diseases; allograft rejection; in vivo; innovation; islet allograft; isoimmunity; new technology; prevent; programs; response; skin allograft; virology; virus development

Our goal is to investigate the impact of viral infecfion on alloreactivity on a human immune system. We will use humanized mice that develop a funcfional human immune system that can be infected with Epstein Barr Virus (EBV), lymphocytic choriomeningitis (LCMV), or influenza A (lAV), viruses associated with allograft rejecfion. In C57BL/6 mice, we have shown that heterologous immunity induced by LCMV infection leads to virus-specific allo-cross-reactive CDS T cells that can reject skin allografts and prevent tolerance induced by costimulation blockade. \Ne propose to test the hypothesis in humanized mice that virus infection leads to the generation of human virus specific allo-cross-reactive T cells that participate in rejection of human allografts. Humanized mice will allow analysis of these viruses using novel technologies to quantify naive and effector human alloreactive T cells and virus-induced allo-cross-reactive T cells. These analyses will permit direct determination of their ability to participate in allograft rejecfion. We also propose use of innovative siRNA in vivo delivery systems to block CD40-CD154 interaction. Aim 1 is to investigate the immune response to alloantigens in human immune system-engrafted NOD-sc/d lL2rf"" HLA-A2 mice transplanted with human islet or skin allografts. We will quantify the alloimmune response, determine kinefics of graft infiltration and allograft rejecfion, and establish models for studies of virus-induced heterologous immunity on allograft survival. Aim 2 is to quantify virus-specific and alloimmune responses during acute virus infection in humanized mice treated with cosfimulation blockade. We will determine human immune responses to EBV, LCMV, and lAV, and quantify virusspecific and allospecific T cells that develop as a consequence of heterologous immunity. We will test the hypothesis that virus infection generates heterologous immunity by inducing the development of virus-specific allo-cross-reactive T cells that participate in allograft rejection. These unique resources, novel technologies, and combined expertise in transplantafion, humanized mice, virology, and siRNA technology provide an opportunity to investigate the role of heterologous immunitv induced bv virus infection on alloreactivity and graft rejecfion in a human immune svstem.

我们的目标是研究病毒感染对人类免疫同种异体反应性的影响 系统。我们将使用人源化小鼠来开发功能性人类免疫系统 感染 Epstein Barr 病毒 (EBV)、淋巴细胞性脉络膜脑膜炎 (LCMV) 或甲型流感 (LAV)， 与同种异体移植排斥相关的病毒。在 C57BL/6 小鼠中，我们发现异源 LCMV 感染诱导的免疫会产生病毒特异性同种异体交叉反应性 CDS T 细胞， 排斥同种异体皮肤移植物并防止共刺激阻断引起的耐受性。 \Ne建议测试 人源化小鼠的假设：病毒感染导致人类病毒的产生 参与人类同种异体移植物排斥的特定同种异体交叉反应性 T 细胞。人源化小鼠 将允许使用新技术对这些病毒进行分析，以量化幼稚病毒和效应人类病毒 同种异体反应性 T 细胞和病毒诱导的同种异体交叉反应性 T 细胞。这些分析将允许直接 确定他们参与同种异体移植排斥的能力。我们还建议使用创新的 siRNA 体内递送系统可阻断 CD40-CD154 相互作用。目标 1 是调查 移植人体免疫系统的 NOD-sc/d lL2rf"" HLA-A2 中对同种异体抗原的免疫反应 移植了人类胰岛或皮肤同种异体移植物的小鼠。我们将量化同种免疫反应， 确定移植物浸润和同种异体移植物排斥的动力学，并建立研究模型 病毒诱导的异源免疫对同种异体移植物的存活。目标 2 是量化病毒特异性和 共刺激治疗的人源化小鼠急性病毒感染期间的同种免疫反应 封锁。我们将确定人类对 EBV、LCMV 和 IAV 的免疫反应，并量化因异源免疫而发育的病毒特异性和同种异体特异性 T 细胞。我们将检验病毒感染通过诱导异源免疫产生异源免疫的假设。 开发参与同种异体移植排斥的病毒特异性同种异体交叉反应性 T 细胞。这些 独特的资源、新技术以及移植、人源化小鼠方面的综合专业知识， 病毒学和 siRNA 技术提供了研究异源病毒作用的机会 免疫诱导bv病毒感染对人体免疫系统的同种反应性和移植物排斥反应。