Multispecies Comparison of the Impact of Obesity on GVHD/GVT

我们建议建立在令人兴奋的初步数据基础上来调节移植物抗宿主病(GVHD)和移植物抗宿主病。 异基因造血干细胞移植后的抗肿瘤效应 了解肥胖在这两个过程中的作用。目前，绝大多数HSCT和 临床前肿瘤研究涉及使用瘦而无特定病原体(SPF)的近交系小鼠。肥胖是一种 已被很好地定义为具有免疫调节作用的动态过程，其特征是包含一种“亚甲基”。 炎性“环境，定义为一种低级别、慢性、自我维持的炎症状态。作为细胞因子 来自炎性细胞因子的风暴在GVHD病理生理学中扮演着关键的组成部分，这项拨款申请 旨在阐明肥胖作为一种先前存在的炎症状态对移植物抗宿主病发病机制和 GVT反应。此外，肥胖对共生微生物生态影响的最新研究 和肠道的定植揭示了微生物多样性和 免疫病理学。我们的应用程序结合使用鼠标和非 加州大学戴维斯分校的人类灵长类研究由于具有获得肥胖的非人类灵长类动物的独特能力：1)评估 肥胖对条件反射诱导的炎症反应和病理的影响 方案及其对小鼠和非小鼠自体/同基因造血干细胞移植后免疫重建的影响 人类灵长类动物模型，2)用小鼠和非小鼠确定肥胖对GVHD发病的影响 异基因造血干细胞移植后的人类灵长类动物模型，以及3)确定肥胖对肿瘤的影响 影响移植物抗宿主病的药物和微生物干预措施的研究进展 目的，将确定对GVT的影响。

We propose to build upon exciting preliminary data to modulate graft-versus-host disease (GVHD) and graft- versus-tumor (GVT) effects following allogeneic hematopoietic stem cell transplantation (HSCT) by understanding the role of obesity in the two processes. Currently, the vast majority of both HSCT and preclinical tumor studies involve the use of lean specific-pathogen-free (SPF) inbred mice. Obesity is a dynamic process that has been well defined to be immunomodulatory, and characteristically contains a “meta- inflammatory” environment, defined as a state of low-grade, chronic, self-sustaining inflammation. As cytokine storms from inflammatory cytokines play a critical component in GVHD pathophysiology, this grant application seeks to delineate the effects obesity as a pre-existing inflammatory condition on GVHD pathogenesis and GVT responses. Additionally recent investigation into the effects of obesity on commensal microbiome ecology and colonization of the gut have shed light onto the relationship between microbial diversity and immunopathology. Our application proposes the following three aims using a combination of mouse and non- human primate studies due to the unique ability to obtain obese non-human primates at UC Davis: 1) Evaluate the impact of obesity on the induction of inflammatory responses and pathology in response to conditioning regimens, and its effect on immune reconstitution post-autologous/syngeneic HSCT using mouse and non- human primate models, 2) to determine the impact of obesity on GVHD pathogenesis using murine and non- human primate models following allogeneic HSCT, and 3) to determine the effects of obesity on tumor progression and using the pharmacological and microbiological interventions affecting GVHD in the second aim, will determine effects on GVT.