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的影响。 系统。我们将使用人源化的小鼠来开发一种功能性的人类免疫系统，这种免疫系统可以 感染EB病毒、淋巴细胞性脉络膜脑膜炎或甲型流感， 与同种异体排斥反应有关的病毒。在C57BL/6小鼠身上，我们已经证明了异源基因 LCMV感染诱导的免疫导致病毒特异性同种交叉反应的CDS T细胞 排斥同种异体皮肤移植，防止共刺激阻断引起的耐受。\n建议测试 病毒感染导致人类病毒产生的人源化小鼠假说 参与同种异体移植排斥反应的特异性同种异体交叉反应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，以量化幼稚和影响人类 同种异体反应T细胞和病毒诱导的同种异体交叉反应T细胞。这些分析将允许直接 测定他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 体内siRNA传递系统阻断CD40-CD154相互作用。目标1是调查 NOD-sc/d lL2rf“”人类免疫系统对同种异体抗原的免疫应答 移植人胰岛或同种异体皮肤的小鼠。我们将量化同种异体免疫反应， 确定移植物渗入和排斥反应的动力学，并建立研究模型。 病毒诱导异种免疫对同种异体移植物存活的影响。目标2是量化病毒特异性和 协同模拟治疗人源化小鼠急性病毒感染期间的同种异体免疫反应 封锁。我们将确定人类对EBV、LCMV和LAV的免疫反应，并量化由于异种免疫而产生的病毒特异性和同种异体特异性T细胞。我们将测试病毒感染产生异种免疫的假设，方法是诱导 参与同种异体移植排斥反应的病毒特异性异体交叉反应T细胞的发展。这些 独特的资源，新颖的技术，以及在移植，人性化小鼠， 病毒学和siRNA技术为研究异源病毒的作用提供了机会 免疫诱导BV病毒感染对人体免疫系统同种异体反应和移植物排斥反应的影响

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.