Anti-Inflammatory Approaches

项目总结（见说明）： 我们最近的数据表明，食蟹猴移植受体对嵌合体和移植耐受的诱导具有抗性，直到在移植前后出现并持续数周至数月的促炎状态减弱。项目1和2着重强调炎症在影响同种异体移植物反应朝向或远离移植耐受中的作用。根据该逻辑，核心B将通过QRT-PCR监测和表征食蟹猴同种异体移植物受体的炎症和免疫状态，与所有项目1和2体内模型相互作用。使用一组专门用于食蟹猴的定制试剂和强大的预扩增技术，我们可以评估小组织样本中超过65个基因的转录。展望未来，我们将进一步开发单细胞PCR方法，以提供有关受体血液或组织中T细胞亚群频率的详细信息。 其目标是通过控制不良炎症，使免疫平衡向同种异体移植物保护和耐受倾斜。T α 1抗胰蛋白酶（AAT），一种急性期反应物和丝氨酸蛋白酶阻断剂是实现这种平衡的潜在试剂。它已被安全地作为AAT基因缺陷患者的替代疗法。这种蛋白质具有有趣的抗炎和抗血栓形成作用。它是一种有效的胰岛细胞保护剂，虽然对T细胞缺乏直接作用，但可促进T细胞耐受性。将在项目1和2模型中使用的核心B中对该药物和其他新型药物进行表征。

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.