TOLERANCE AND HOST IMMUNITY TO VIRUS INFECTION

病毒感染通过引起疾病并与移植物抗宿主反应和移植排斥反应相关，一直困扰着人类同种异体移植患者。移植患者易受病毒感染，因为病毒可以通过移植过程转移或重新激活，也因为患者接受免疫抑制治疗以耐受同种异体移植物。我的同事们在同种异体皮肤和胰岛移植的动物模型中表明，在两周的cd40配体（CD154）抗体治疗方案中，受体预先暴露于供体同种异体脾细胞输注（DST），可以绕过持续免疫抑制治疗的需要。这使宿主对同种异体组织产生耐受性，这种耐受性可以持续一年以上。一个重要的问题是病毒感染是否可以克服这种耐受性并诱导移植物排斥，以及DST抗cd154耐受性是否会损害宿主清除病毒感染的能力。我们最近确定淋巴细胞性脉络丛脑膜炎病毒（LCMV）诱导小鼠新移植而非50天移植同种异体皮肤的排斥反应。我们建议在这个模型中研究为什么这种排斥反应发生在移植后早期而不是晚期，小鼠巨细胞病毒和其他几种病毒是否可以诱导这种排斥反应，以及耐受过程是否包括宿主控制这些感染的能力。从这项研究中获得的信息将有助于确定移植患者对病毒感染的脆弱性，并在这项新技术开始临床试验时帮助制定保护弱势患者免受感染的策略。

Viral infections have plagued human allogeneic transplant patients by causing illness and being associated with graft versus host reactions and transplant rejections. Transplant patients are vulnerable to viruses because viruses can be transferred or reactivated by the transplantation procedure and because of the immunosuppressive treatment the patients receive to tolerate the allografts. My colleagues have shown in animal models of allogeneic skin and pancreatic islet transplantation that the need for continued immunosuppressive therapy can be bypassed by pre-exposure of the recipient to a donor allogeneic splenocyte transfusion (DST) in the presence of a two-week regimen of antibody to CD40-ligand (CD154). This tolerizes the host to the allogeneic tissue, and this tolerance lasts well over a year. An important issue is whether viral infections can overcome this tolerance and induce graft rejection and whether the DST anti-CD154 tolerization compromise the host's ability to clear viral infections. We have recently determined that lymphocytic choriomeningitis virus (LCMV) induces the rejection of newly transplanted but not 50-day transplanted skin allografts in mice. We propose to examine in this model why this rejection takes place early but not late after transplantation, whether murine cytomegalovirus and several other viruses can induce such rejection, and whether the tolerization process comprises the host's ability to control these infections. Information gained from this study will help determine the vulnerability of transplant patients to viral infections and aid in developing strategies to shield vulnerable patients from infection as this new technique begins clinical trials.