Mechanisms of GVHD

迫切需要描述慢性移植物抗宿主病(CGVHD)的病理生物学相关性，并开发新的策略来预防和治疗cGVHD。这些策略必须同时控制急性和慢性移植物抗宿主病，将机会性感染的风险降至最低，并维持移植物抗宿主病。要做到这一点，我们必须扩大对GVHD病理生物学的理解。例如，认识到对HY抗原的抗体反应在cGVHD生理学中很重要，强调了开发更多工具来识别体细胞MHA的必要性，以此作为整合MHA和免疫反应性的遗传决定因素的一步。因此，1)临床试验，2)发展相关的动物模型来研究病理生物学并在其中测试新的治疗方法，以及3)进一步阐明人类cGVHD的免疫学基础是必要的。项目1将制定通过靶向B细胞和调节性T细胞来预防cGVHD的策略。第一个策略是一种新的抗CD20预防方案，而第二个策略将允许通过消除GVHD预防中的钙调神经磷酸酶抑制剂来扩大调节性T细胞。第二个目的是通过调整治疗方法以避免肝脏损伤或通过使用新型药物去纤肽预防血管并发症来预防肝脏VOD。最后，将评估两种治疗类固醇耐药GVHD的互补方法：1)协调抑制B和T细胞，以及2)用超低剂量IL-2扩增调节性T细胞。项目2将扩大对一种新的、临床相关的cGVHD小鼠模型的研究。这将允许在第一个目标中探索cGVHD的病理生物学，而第二个目标建立可在项目1中进行临床评估的治疗方法。项目3将继续其在次要组织相容抗原发现方面的工作，现在从性染色体相关蛋白转移到更广泛的抗原发现。该项目还将开发GVHD特异性生物标记物，以便更准确地预测谁将患上cGVHD，并允许密切监测治疗以减少毒性。最终，我们设想了一个完整的基因组图谱，它将决定最有效的GVHD预防类型。

There is a critical need to delineate pathobiological correlates of chronic GVHD (cGVHD) and to develop new strategies to prevent and treat cGVHD. These strategies must control both acute and cGVHD, minimize risk of opportunistic infection, and maintain GVL. To do this our understanding of GVHD pathobiology must be broadened. For instance, recognizing that antibody responses to HY antigens are important in cGVHD physiology underscores the need to develop more tools to identify somatic mHA as a step toward the integration of mHA and genetic determinates of immune reactivity. Thus, a coordinated effort combining 1) clinical trials, 2) the development of a relevant animal model to study pathobiology and in which new therapies can be tested, and 3) further elucidation of the immunologic basis of human cGVHD is essential. Project 1 will develop strategies to prevent cGVHD by targeting B cells and regulatory T cells. The first strategy is a novel anti-CD20 prophylaxis regimen, while the second strategy will allow the expansion of regulatory T cells by eliminating calineurin inhibitors from GVHD prophylaxis. The second aim is to prevent hepatic VOD by adjusting the therapy to avoid hepatic injury or by preventing vascular complications using the novel agent, defibrotide. Finally, two complementary approaches to treat steroid-resistant GVHD will be assessed: 1) coordinate inhibition of both B and T cells, and 2) expansion of regulatory T cells with ultra low dose IL-2. Project 2 will expand its studies of a new, clinically relevant mouse model of cGVHD. This will allow the pathobiology of cGVHD to be explored in the first aim, while the second aim models therapeutic approaches that can be clinically assessed in Project 1. Project 3 will continue its work in minor histocompatitbility antigen discovery moving now from sex-chromosome associated proteins to more generalized antigen discovery. This project will also develop GVHD-specific biomarkers that will allow more precise prediction of who will develop cGVHD as well as allow the therapy to be closely monitored to reduce toxicity. Ultimately we envision an integrated genomic profile that will determine the type of GVHD prophylaxis that will be most effective.