The role of autophagy gene Atg16L1 in allogeneic hematopoietic stem cell transplantation - Resubmission - 1

描述(申请人提供)：异基因造血干细胞移植(allo-HSCT)用于治疗各种恶性和非恶性疾病，涉及从不同捐赠者的骨髓、血液或脐带移植干细胞。移植物抗宿主病(GVHD)是一种由来自移植的同种异体反应性T细胞介导的危及生命的疾病，它的广泛应用受到了移植物抗宿主病(GVHD)的高发生率的限制。改进这一过程依赖于确定导致这种破坏性T细胞反应性的机制。自噬是一种细胞过程，通过这种过程胞浆物质被运送到溶酶体进行降解，作为促进平衡免疫反应的一种途径，自噬正受到越来越多的关注。此外，自噬基因Atg16L1的一个非常常见的多态性与炎症性肠病(IBD)有关，这表明该基因和途径在炎症条件下发挥了作用。为了测试Atg16L1在GVHD中的作用，我们用Atg16L1突变受体小鼠进行了allo-HSCT，发现该基因的缺失显著增加了移植后的死亡率和疾病。这种增强的GVHD与供者来源的T细胞增殖和肠道屏障破坏有关，最可能是因为Atg16L1在抑制树突状细胞过度激活方面发挥了意想不到的作用。此外，初步数据表明，Atg16L1的IBD风险多态与人类移植相关死亡率的较高发生率相关，从而支持我们在临床前小鼠模型中的观察结果。在这项研究中，我们将进一步明确Atg16L1和自噬在allo-HSCT中的作用，并阐明其机制。我们将确定导致GVHD增强的因素，检查移植物抗肿瘤反应，并了解Atg16L1如何抑制树突状细胞过度活动。我们预计，这些结果将对allo-HSCT产生重要的洞察力，并揭示炎症性疾病的基础过程。

DESCRIPTION (provided by applicant): Allogeneic hematopoietic stem cell transplantation (allo-HSCT) is used to treat a variety of malignant and non-malignant disorders, and involves the transfer of stem cells from the bone marrow, blood, or umbilical cord from a non-identical donor. The widespread application of this procedure is limited by the high rate of graft-versus-host disease (GVHD), a life-threatening condition that is mediated by alloreactive T cells from the transplant. Improving the procedure is dependent on identifying the mechanisms that contribute to this damaging T cell reactivity. Autophagy, a cellular process by which cytosolic material is delivered to the lysosome for degradation, is receiving increasing attention as a pathway that contributes to a balanced immune response. Additionally, a highly common polymorphism in the autophagy gene Atg16L1 is associated with inflammatory bowel disease (IBD), suggesting a role for this gene and pathway in inflammatory conditions. To test the role of Atg16L1 in GVHD, we performed an allo-HSCT using Atg16L1 mutant recipient mice and found that deficiency in this gene significantly increased lethality and disease following the transplant This enhanced GVHD is associated with increased donor-derived T cell proliferation and intestinal barrier disruption, most likely due to an unexpected role of Atg16L1 in suppressing dendritic cell hyperactivation. Moreover, preliminary data indicates that the IBD risk polymorphism of Atg16L1 is associated with a higher incidence of transplant-related mortality in humans, thus supporting our observations in a preclinical mouse model. In this proposal, we will further define the role of Atg16L1 and autophagy during allo-HSCT and elucidate mechanism. We will identify the factors that contribute to enhanced GVHD, examine graft-versus-tumor reactions, and understand how Atg16L1 suppresses dendritic cell hyperactivity. We anticipate that these results will yield significant insight into allo-HSCT as well as reveal processes that ae fundamental to inflammatory disease.