EBV and Heterologous Alloimmunity in Humanized Mice

我们的目标是研究病毒感染对人类免疫系统同种异体反应性的影响， 系统我们将使用人源化小鼠，这些小鼠开发出一种功能性的人类免疫系统， 感染爱泼斯坦巴尔病毒（EBV）、淋巴细胞性脉络丛脑膜炎（LCMV）或甲型流感（IAV）， 与同种异体移植排斥相关的病毒。在C57 BL/6小鼠中，我们已经证明， 由LCMV感染诱导的免疫导致病毒特异性同种异体交叉反应性CDS T细胞， 排斥皮肤同种异体移植物和防止由共刺激阻断诱导的耐受。我不打算测试 在人源化小鼠中病毒感染导致人病毒产生的假设 特异性同种异体交叉反应性T细胞参与人类同种异体移植物的排斥反应。人源化小鼠 将允许使用新技术分析这些病毒，以定量初始和效应人类 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。这些分析将使直接 确定它们参与同种异体移植排斥反应的能力。我们还建议使用创新的 siRNA体内递送系统阻断CD 40-CD 154相互作用。目的1是研究 移植NOD-sc/d1 L2 rf””HLA-A2人免疫系统对同种抗原免疫应答 移植人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， 确定移植物浸润和移植物排斥的动力学，并建立研究移植物浸润和排斥的模型。 病毒诱导的异源免疫对同种异体移植物存活的影响。目的2是定量病毒特异性和 用共刺激处理的人源化小鼠在急性病毒感染期间的同种免疫应答 封锁我们将确定人类对EBV，LCMV和IAV的免疫应答，并定量作为异源免疫的结果而发展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免疫系统产生异源免疫的假设。 病毒特异性同种异体交叉反应性T细胞参与同种异体排斥反应的发展。这些 独特的资源，新的技术，以及在移植，人源化小鼠， 病毒学和siRNA技术提供了一个机会，研究异源性 免疫诱导bv病毒感染对人体免疫系统同种异体反应性和移植排斥反应影响

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.