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aGVHD是由T细胞识别外源性抗原引起的，体外清除T细胞是降低其发生率和严重程度的最有效方法。拟开展的研究旨在验证2个假设：1）IL-23 p19/IL-17细胞因子轴通过调节可能促进或抑制aGVHD的关键细胞因子基因的表达，在aGVHD的炎症反应特征中发挥主要作用。2)IL-23 p19/1 L-17细胞因子轴与TNF 1、IL-12和IL-6级联密切但不完全相互作用，以放大aGVHD的病理学。设计了三个目标来解决这些问题。它们来源于我们的观察结果，即移植了来自IL-23 p19/p40异源二聚体的p19二聚体缺陷的突变小鼠的骨髓（BM）加含T脾脏（SC）的BALB/c小鼠比移植了正常野生型C57 BL/6 BM + SC的BALB/c小鼠发生aGVHD的频率更低且更不严重。由CD 8 Th 17细胞产生的IL-17 mRNA和血清细胞因子在移植有WT和p19缺陷细胞的BALB/c小鼠中升高，但在WT动物中达到显著更高的水平。在p19-/-小鼠中诱导产生IL-17的Th 17被证明来源于宿主BALB/c动物的全身照射诱导的TGF 2、IL-6和IL 23 p19。第一个目的是确定供体接种物中分离的T细胞和其他细胞对aGVHD诱导的影响。第二个目的是确定Th 17细胞产物在aGVHD发病机制中的作用。第三个目的是确定IL-23/IL 17 -21-22级联与TNF 1-IL-12-IL-6级联在aGVHD病理学中的相对作用。使用IL-23 p19、ROR γ t（对Th 17细胞发育至关重要）和TNF 1缺陷的靶突变动物提供了独特的模型，其中剖析了aGVHD病理学的组分。 公共卫生相关性： 与退伍军人事务部使命的相关性：每天都有大量不幸的退伍军人患上新的癌症。除了白血病、骨髓增生异常和多发性骨髓瘤，其他癌症也可以接受干细胞移植。诚然，有一些癌症可能不会受益于这种疗法，但实现免疫系统振兴的能力可能是他们护理的重要补充。然而，如上所述，目前发生移植相关毒性、GVHD和压倒性感染的风险太大，无法为患有更广泛癌症的患者提供干细胞移植。这些研究旨在探索一种新的方法来减少GVHD

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