The regulation of innate immune sensors to control GVHD and GVL after allogeneic hematopoietic stem cell transplantation

异基因造血干细胞移植(AHSCT)是一种潜在的治疗方法，可用于治疗 恶性疾病，其中最常见的是急性髓系白血病(AML)。多达8000人中的一半 每年在美国进行的aHSCT会导致移植物抗宿主病(GVHD)，因此移植物抗宿主病(GVHD)仍然是 AHSCT患者发病和死亡的重要原因。移植前调理，包括 血液肿瘤的放射和化疗，导致分裂细胞的广泛死亡，释放 内源性危险信号，以及胃肠道(GI)上皮屏障功能障碍导致的细菌易位。 这些事件促进了由先天激活介导的促炎细胞因子风暴的产生 驱动同种异体反应性供者T细胞分化和扩增的免疫感受器。激活的供体 然后，抗宿主T细胞可以损伤GVHD特有的特定受体组织，并介导抗-GVHD 针对同种异体抗原和肿瘤抗原的肿瘤免疫。我之前的发现证明 干扰素基因刺激物(STING)是一种先天免疫感受器，可促进炎症和GVHD 条件化和MHC相合的小鼠aHSCT。接受aHSCT的好处是伴随着“移植物-- 抗白血病“(GVL)反应，由供者T/NK细胞介导，靶向并根除残留疾病。 因此，本提案F99阶段的主要目标是确定刺痛途径如何影响 临床前GVL反应，如果在没有受体叮咬的情况下GVHD减少可以促进肿瘤 疫苗接种策略。减少对移植前条件反应的炎症反应的其他策略包括 降低强度调节(RIC)疗法的发展，这种疗法比传统疗法毒性更小 化疗和放射治疗降低移植相关死亡率和移植物抗宿主病的风险，但由于 RIC后复发风险显著增加。因为急性髓细胞白血病的诊断年龄中位数是 AHSCT-IS-68的常见指征，虚弱和与年龄升高相关的共病频率 通常排除在许多急性造血干细胞移植受者中使用毒性的骨髓清除性调节(MAC)方案。作为一名 结果，该提案K00阶段的研究将确定多个临床前RIC方案是否 与先天免疫感受器激活减少、移植物抗宿主病减少和免疫力提高有关 小鼠aHSCT后的重建。实验还将确定移植后预防性治疗是否能抗白血病 针对残留AML的策略可促进RIC与MAC后类似或改善的抗肿瘤免疫。 这项提案中的研究将提供有关刺痛和其他先天因素参与的新信息。 AHSCT环境中的传感器。我研究的长期目标将是开发新的疗法， 可以转化到临床上，在不减少GVL的情况下预防或减少GVHD，从而增加 增加异基因造血干细胞移植使用的潜在移植受者总数。

Allogeneic hematopoietic stem cell transplantation (aHSCT) is a potentially curative therapy used to treat several malignant diseases, of which the most frequent is acute myeloid leukemia (AML). As many as half of the ~8,000 aHSCTs performed in the U.S. each year will result in GVHD, thus graft-versus-host disease (GVHD) remains a significant cause of morbidity and mortality in patients receiving aHSCTs. Pre-transplant conditioning, including irradiation and chemotherapy for hematological tumors, causes widespread death of dividing cells, release of endogenous danger signals, and bacterial translocation due to gastrointestinal (GI) epithelial barrier dysfunction. These events promote the generation of a pro-inflammatory cytokine storm mediated by the activation of innate immune sensors which drives the differentiation and expansion of allo-reactive donor T cells. Activated donor anti-host T cells can then damage particular recipient tissues characteristic of GVHD, as well as mediate anti- tumor immunity targeted to both allogeneic and tumor-antigens. My previous findings demonstrate that Stimulator of Interferon Genes (STING), an innate immune sensor, promotes inflammation and GVHD following conditioning and MHC-matched murine aHSCT. The benefit of receiving an aHSCT is the accompanying “graft- versus-leukemia” (GVL) response, mediated by donor T/NK cells to target and eradicate residual disease. Therefore, primary objectives of the F99 phase of this proposal are to identify how the STING pathway affects pre-clinical GVL responses, and if reduced GVHD in the absence of recipient STING can promote tumor vaccination strategies. Other strategies to reduce inflammatory responses to pre-transplant conditioning include the development of reduced intensity conditioning (RIC) regimens, which are less toxic than traditional chemoradiotherapy and lower the risks of both transplant-related mortality and GVHD but are limited in use due to the significantly increased risk of relapse after RIC. Since the median age of diagnosis for AML - the most frequent indication for aHSCT - is 68, frailty and the frequency of co-morbidities associated with elevated age often precludes the use of toxic myeloablative conditioning (MAC) regimens in many aHSCT recipients. As a result, studies during the K00 phase of this proposal will determine if multiple pre-clinical RIC regimens are associated with decreased activation of innate immune sensors, reduced GVHD and improved immune reconstitution after murine aHSCT. Experiments will also determine if prophylactic post-transplant antileukemic strategies targeting residual AML promotes comparable or improved anti-tumor immunity after RIC versus MAC. The studies in this proposal will provide new information regarding the involvement of STING and other innate sensors in the context of aHSCT. The long-term objective of my studies will be to develop new therapies that can be translated into the clinic to prevent or reduce GVHD without diminishing GVL, thereby increasing the overall number of potential transplant recipients to augment the use of aHSCT.