Anti-Inflammatory Approaches

项目总结(见说明)： 我们最近的数据显示，食蟹猴移植受者对嵌合体和移植耐受的诱导具有抵抗力，直到移植围手术期出现的促炎状态减弱，并持续数周至数月。项目1和2非常强调炎症在影响同种异体移植物对移植耐受的反应中的作用。根据这一逻辑，Core B将通过QRT-PCR监测和表征食蟹猴同种异体移植受者的炎症和免疫状态，从而与所有项目1和2的活体模型相互作用。使用一组为食蟹猴定制的试剂和强大的预扩增技术，我们可以评估一个小组织样本中超过65个基因的转录。展望未来，我们将进一步开发一种单细胞聚合酶链式反应方法，以提供有关受者血液或组织中T细胞亚群频率的详细信息。 目标是通过控制不良炎症，有利地使免疫平衡向同种异体移植保护和耐受倾斜。α1抗胰蛋白酶(AAT)是一种急性时相反应物和丝氨酸蛋白酶阻滞剂，是实现这种平衡的潜在药物。它已经安全地作为替代疗法用于AAT基因缺陷的患者。这种蛋白质具有有趣的抗炎和抗血栓作用。它是一种有效的胰岛细胞保护剂，虽然对T细胞没有直接作用，但它促进了T细胞的耐受。这种和其他新型试剂将在核心B中描述，用于项目1和2模型中。

PROJECT SUMMARY (See instructions): Our recent data show that cynomolgus transplant recipients are resistant to the induction of chimerism and transplant tolerance until the pro-inflammatory state that arises in the peri-transplant period and continues for weeks to months thereafter abates. Projects 1 and 2 place heavy emphasis upon the role of inflammation in influencing the allograft response toward or away from transplant tolerance. In accordance with this logic, Core B will interact with all of the Project 1 and 2 in vivo models, by monitoring and characterizing the state of inflammation and immunity via QRT-PCR in the cynomolgus allograft recipients. Using a panel of custom made reagents crafted for use in cynomolgus monkeys and a powerful pre-amplification technique, we can assess transcription of over 65 genes in a small tissue sample. Going forward we will further develop a single cell PCR method to provide detailed information about the frequency of T cell subsets in recipient blood or tissues. The goal is to favorably tilt the balance of immunity toward allograft protection and tolerance by controlling adverse inflammation. T alpha1 antitrypsin (AAT), an acute phase reactant and serine protease blocker is a potential agent for achieving such balance. It has been given safely as replacement therapy to patients with the AAT gene defect. This protein possesses interesting anti-inflammatory and anti-thrombotic effects. It is a potent islet cytoprotectant and although lacking direct effects upon T cells promotes T cell tolerance. This and other novel agents will be characterized in Core B for use in the Project 1 and 2 models.