Mechanisms of GVHD

目前迫切需要阐明慢性GVHD（cGVHD）的病理生物学相关性，并开发新的策略来预防和治疗cGVHD。这些策略必须控制急性和cGVHD，最大限度地减少机会性感染的风险，并维持GVL。要做到这一点，我们对GVHD病理生物学的理解必须扩大。例如，认识到对HY抗原的抗体应答在cGVHD生理学中是重要的，强调了需要开发更多的工具来鉴定体细胞mHA，作为整合mHA和免疫反应性的遗传决定因素的一个步骤。因此，结合1）临床试验，2）开发相关动物模型以研究病理生物学，并在其中测试新疗法，以及3）进一步阐明人类cGVHD的免疫学基础的协调努力是必不可少的。项目1将开发通过靶向B细胞和调节性T细胞来预防cGVHD的策略。第一种策略是一种新的抗CD 20预防方案，而第二种策略将允许通过消除GVHD预防中的钙调磷酸酶抑制剂来扩增调节性T细胞。第二个目的是通过调整治疗以避免肝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VOD。最后，将评估治疗类固醇抗性GVHD的两种互补方法：1）协调B和T细胞的抑制，和2）用超低剂量IL-2扩增调节性T细胞。项目2将扩大其对一种新的、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，而第二个目标模拟可以在项目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性抗原发现方面的工作，现在从性染色体相关蛋白转向更广泛的抗原发现。该项目还将开发GVHD特异性生物标志物，以更精确地预测谁将发展cGVHD，并允许密切监测治疗以减少毒性。最终，我们设想一个综合的基因组图谱，将确定类型的GVHD预防，将是最有效的。

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.