Studies on the role of IL-23p19/IL-17 cascade in the pathogenesis of acute GVHD

描述(由申请人提供)： 摘要目前公认的aGVHD是由T细胞对抗原异质性的识别引发的，体外清除T细胞是降低其发病率和严重程度的最有效方法。本研究拟验证两个假设：1)IL-23p19/IL-17细胞因子轴通过调节促进或抑制aGVHD的关键细胞因子基因的表达，在aGVHD的炎症反应中发挥重要作用。2)IL-23p19/1L-17细胞因子轴与TNF1、IL-12、IL-6级联反应密切但不完全相互作用，放大了aGVHD的病理过程。为了解决这些问题，我们设计了三个目标，它们源于我们的观察，即移植了IL-23 p19/p40异二聚体p19二聚体缺陷突变小鼠的骨髓(BM)加含T细胞的脾(SCs)的BALB/c小鼠与移植正常野生型C57BL/6 BM+SCs的BALB/c小鼠相比，发生aGVHD的频率和严重程度更低。在同时移植WT和p19缺陷细胞的BALB/c小鼠中，CD8 Th17细胞产生的IL-17mRNA和血清细胞因子水平升高，但在WT动物中显著升高。P19-/-小鼠Th17细胞产生IL-17的诱生作用来源于宿主BALB/c动物全身照射所诱导的TGF2、IL-6和IL23p19。第一个目标是确定供体接种中分离的T细胞和其他细胞对诱导aGVHD的影响。第二个目标是确定Th17细胞产物在aGVHD发病机制中的作用。第三个目标是确定IL-23/IL17-21-22级联与TNF1-IL-12-IL-6级联在aGVHD病理中的相对作用。使用缺乏IL-23p19、RORGamma t(对Th17细胞发育至关重要)和TNF1的靶突变动物提供了分析aGVHD病理成分的独特模型。 公共卫生相关性： 与退伍军人事务部使命相关：每天都有大量不幸的退伍军人患上新的癌症。除了白血病、骨髓异常增生症和多发性骨髓瘤，其他癌症也可以接受干细胞移植。诚然，有些癌症可能不会从这种疗法中受益，但实现免疫系统恢复的能力可能是对他们的护理的重要补充。然而，如上所述，目前发生移植相关毒性、移植物抗宿主病和压倒性感染的风险太大，不能为更广泛类型的癌症患者提供干细胞移植。拟议的研究是为了探索一种将GVHD降至最低的新方法

DESCRIPTION (provided by applicant): Abstract It is firmly established that aGVHD is initiated by T-cell recognition of antigenic foreignness and ex vivo depletion of T-cells has been the most effective method to reduce its incidence and severity. The proposed studies are to test 2 hyptheses: 1) The IL-23p19/IL-17 cytokine axis plays a major role in the inflammatory reactions characteristic of aGVHD by regulating the expression of key cytokine genes that may promote or inhibit aGVHD. 2) The IL -23p19/1L-17 cytokine axis interacts closely but not completely with the TNF1, IL-12, and IL-6 cascade to amplify the pathology of aGVHD. Three objectives are designed to address these They are derived from our observation that BALB/c mice transplanted with bone marrow (BM) plus T- containing spleens (SCs) from mutant mice deficient in the p19 dimer of the IL-23 p19/p40 heterodimer develop aGVHD less frequently and less severely than BALB/c transplanted with normal wild type C57BL/6 BM + SCs. IL-17 mRNA and serum cytokine produced by CD8 Th17 cells are elevated in BALB/c mice transplanted with both WT and p19 deficient cells but to significantly higher levels in the WT animals. Induction of Th17 producing IL-17 in the p19-/- mice was shown to be derived from TGF2, IL-6 and IL23p19 induced by total body irradiation of the host BALB/c animals. The first objective is to determine the effect on the induction of aGVHD by isolated T and other cells in the donor inoculum. The second objective is to determine the role of the products of Th17 cells in the pathogenesis of aGVHD. The third objective is to determine the relative roles of the IL-23/IL17-21-22 cascade versus the TNF1-IL-12-IL-6 cascade in the pathology of aGVHD. Use of target mutant animals deficient in IL-23p19, RORgamma t (critical for Th17 cell development) and TNF1 provide unique models in which to dissect the components of aGVHD pathology. PUBLIC HEALTH RELEVANCE: Relevance to VA Mission: Every day large numbers of unfortunate veterans present with new cancers. In addition to the leukemias, myelodysplasia and multiple myeloma, other cancers could be amenable to stem cell transplantation. Admittedly, there are some cancers that probably would not benefit from this therapy but the ability to achieve a revitalized immune system could be an important addition to their care. However, as stated above, the current risk of developing transplant related toxicities, GVHD and overwhelming infection are too great to offer stem cell transplantation to patents with a wider variety of cancers. The proposed studies are to investigate a new approach to minimize GVHD