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）是一种潜在的治疗性疗法，用于治疗几种造血干细胞移植。 恶性疾病，其中最常见的是急性髓性白血病（AML）。多达8000人中的一半 每年在美国进行的aHSCT将导致GVHD，因此移植物抗宿主病（GVHD）仍然是一个严重的问题。 是接受aHSCT患者发病率和死亡率的重要原因。移植前预处理，包括 放疗和化疗治疗血液肿瘤，会导致分裂细胞的广泛死亡， 内源性危险信号和由于胃肠（GI）上皮屏障功能障碍引起的细菌移位。 这些事件促进了由先天性巨噬细胞活化介导的促炎细胞因子风暴的产生。 免疫传感器，其驱动同种异体反应性供体T细胞的分化和扩增。活化的供体 然后，抗宿主T细胞可以损伤GVHD特征的特定受体组织，以及介导抗- 靶向同种异体抗原和肿瘤抗原的肿瘤免疫。我之前的发现表明， 干扰素基因刺激因子（STING）是一种先天性免疫传感器，可促进炎症和GVHD， 预处理和MHC匹配的鼠aHSCT。接受aHSCT的好处是伴随的“移植- 抗白血病”（GVL）反应，由供体T/NK细胞介导，以靶向和根除残留疾病。 因此，本提案F99阶段的主要目标是确定STING途径如何影响 临床前GVL应答，并且如果在不存在受体STING的情况下减少GVHD，则可以促进肿瘤生长。 疫苗接种策略。减少移植前条件反射的炎症反应的其他策略包括 降低强度调节（RIC）方案的发展，比传统的毒性更小 化疗和放疗，降低移植相关死亡率和GVHD的风险，但由于 RIC后复发风险显著增加。由于AML诊断的中位年龄-最 aHSCT的常见适应症是68岁，虚弱和与年龄增加相关的合并症的频率 通常排除了在许多aHSCT接受者中使用毒性清髓性预处理（MAC）方案。作为 因此，本提案K 00阶段的研究将确定是否有多种临床前RIC方案 与先天免疫传感器的激活降低、GVHD减少和免疫功能改善相关。 小鼠aHSCT后的重建。实验还将确定预防性移植后抗白血病药物 靶向残余AML的策略在RIC与MAC之后促进相当或改善的抗肿瘤免疫。 本提案中的研究将提供有关STING和其他先天性疾病参与的新信息。 aHSCT背景下的传感器。我研究的长期目标是开发新的疗法， 可以转化为临床，以预防或减少GVHD而不减少GVL，从而增加GVHD的发生率。 潜在的移植受者总数，以增加aHSCT的使用。

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.