Targeting IL-12/23 p40 Pathways for the Control of GVHD

描述（由申请人提供）：造血细胞移植（HCT）可以治愈各种良性和恶性造血系统疾病，但移植物抗宿主病（GVHD）仍然是移植相关死亡率和发病率的重要来源。干细胞移植物中的供体T细胞识别广泛分布的错配的主要（MHC）和/或次要组织相容性抗原（miHAg），在受体内经历稳健的扩增和功能分化，并且可对宿主组织造成严重损伤。传统上，Th 1细胞被认为在GVHD的诱导中起关键作用;尽管最近我们和其他人表明Th 17细胞也可以引起GVHD。通过靶向Th 1和Th 17特异性转录因子（T-bet和ROR？t），我们证明了Th 1和Th 17亚群都有助于GVHD的发展，但单独的任一谱系都足以诱导GVHD，因此必须阻断这两种谱系以控制GVHD。靶向转录因子被用来证明这一原理，但基本上缺乏翻译潜力。在我们目前的应用中，我们将扩展这些发现，并评估靶向T细胞分化的临床适用方法。具体而言，我们假设靶向p40、IL-12 R？1或其下游信号传导事件将破坏Th 1/Th 17分化，从而控制GVHD。p40是与p35或p19配对以形成IL-12或IL-23的共同亚基; IL-12 R1是IL-12和IL-23受体的共享亚基。支持这一假设的基本原理是，IL-12信号对于 IL-23信号是维持Th 17亚群的关键，而Th 1亚群中的任何一个亚群都可能导致急性GVHD。因此，阻断p40、IL-12 R1或其下游信号传导事件可能足以破坏Th 1和Th 17分化，从而导致GVHD预防。具体目标是：1）通过靶向p40来预防GVHD; 2）通过靶向IL-12 R1来控制GVHD;和3）表征和靶向IL-12 R1的下游信号传导事件。这些研究将在细胞因子、受体和下游信号水平上验证IL-12/23通路作为GVHD预防的治疗靶点。由于目前可获得用于中和p40或阻断IL-12 R1亚基的临床级抗体和用于IL-12/23 R信号传导的小分子抑制剂，因此从这些临床前研究中获得的信息可以容易地转化为临床应用。

DESCRIPTION (provided by applicant): Hematopoietic cell transplantation (HCT) can cure a variety of benign and malignant hematopoietic disorders, but graft-versus-host disease (GVHD) remains a significant source of transplant-related mortality and morbidity. Donor T cells in the stem cell grafts recognize widely distributed mismatched major (MHC) and/or minor histocompatibility antigens (miHAg), undergo robust expansion and functional differentiation within recipients, and can cause severe damage to host tissues. Classically, Th1 cells are believed to play a critical role in the induction of GVHD; although recently we and others showed that Th17 cells can also cause GVHD. By targeting Th1 and Th17 specific transcription factors (T-bet and ROR?t), we demonstrated that both the Th1 and Th17 subsets contribute to GVHD development, but either lineage alone is sufficient to induce GVHD, and thus both lineages must to be blocked in order to control GVHD. Targeting transcription factors was used to prove the principle, but essentially lacks translational potential. In our current application, e will extend these findings and evaluate clinically applicable approaches to target T cell differentiation. Specifically, we hypothesize that targeting p40, IL-12R¿1 or their downstream signaling events will disrupt Th1/Th17 differentiation and thus control GVHD. p40 is a common subunit that pairs with p35 or p19 to form IL-12 or IL-23; IL-12R¿1 is a shared subunit for IL-12 and IL-23 receptors. The rationale to support this hypothesis is that IL-12 signal is essential for Th1 differentiation whereas IL-23 signal is critical for the maintenance of Th17 subset, and either subset can cause acute GVHD. Thus, blocking p40, IL-12R¿1 or their downstream signaling events may be sufficient to disrupt Th1 and Th17 differentiation leading to GVHD prevention. Specific Aims are: 1) To prevent GVHD by targeting p40; 2) To control GVHD by targeting IL-12R¿1; and 3) To characterize and target downstream signaling events of IL-12R¿1. These studies will validate IL-12/23 pathway as a therapeutic target for GVHD prevention at the cytokine, receptor and downstream signaling level. Because clinical grade antibodies for neutralizing p40 or blocking IL-12R¿1 subunit and small molecular inhibitor for IL-12/23R signaling are currently available, the information learned from these pre-clinical studies can be readily translated into clinical application.