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.

我们的目标是调查病毒不安对同种反应性对人免疫的影响 系统。我们将使用人性化的小鼠，该小鼠可以开发一种可能是可能是的人类免疫系统 感染了爱泼斯坦Barr病毒（EBV），淋巴细胞绒毛膜炎（LCMV）或流感A（LAV）， 与同种异体恢复有关的病毒。在C57BL/6小鼠中，我们已经表明了异源 LCMV感染诱导的免疫力导致病毒特异性的同异质反应性CDS T细胞可以 拒绝皮肤同种异体移植物，并防止共刺激封锁引起的公差。 \ ne建议测试 人性化小鼠的假设是病毒感染导致人类病毒的产生 参与人类同种异体移植物的特定特定的同种异体T细胞。人源化的小鼠 将允许使用新技术对这些病毒进行分析，以量化幼稚和效应人类 同种反应性T细胞和病毒诱导的同异种反应性T细胞。这些分析将允许直接 确定他们参与同种异体恢复的能力。我们还建议使用创新 siRNA在体内递送系统中可阻止CD40-CD154相互作用。目标1是调查 人免疫系统促进剂的nod-sc/d ll2rf“ hla-a2 用人胰岛或皮肤同种异体移植的小鼠。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恢复的动力学，并建立研究模型 病毒诱导的同种异体移植生存的异源免疫。 AIM 2是量化病毒特异性和 在急性病毒感染期间的同种异体免疫反应在人源化小鼠中接受了同摄取的治疗 封锁。我们将确定人类对EBV，LCMV和LAV的免疫反应，并量化由于异源免疫力而发展的Viruss特异性T细胞。我们将检验以下假设，即病毒感染通过诱导诱导而产生异源免疫力 参与同种异体移植排斥反应的病毒特异性同异种反应性T细胞的发展。这些 独特的资源，新颖的技术和移植的专业知识，人性化的小鼠， 病毒学和siRNA技术提供了调查异源作用的机会 免疫诱导人类免疫系统中的同种异体反应性和移植物的诱导BV病毒感染。