Prevention of Neonatal Sepsis by Therapeutic Targeting of MDSCs

摘要 新生儿败血症每年导致全球300多万人死亡，是死亡风险最高的国家。 发生在早产儿(≤37周)。这种易感性的增加是由于骨髓生成的改变和固有的 对病原体的低反应性，伴随着持续的免疫抑制机制的激活 母胎耐受性。出生后，新生儿的免疫系统经历了从半 同种异体不育条件对富含微生物的出生后环境的影响，这在一定程度上是由新生儿调节的 髓系来源的抑制细胞(MDSC)和先天免疫效应细胞反应。在新生儿中， MDSCs极具争议性，因为它们不仅可以控制早期微生物定居期间的炎症，而且 通过诱导免疫抑制，也会增加新生儿感染的易感性。先天免疫效应器 细胞功能也在早产儿中异常。我们最重要的假设是，增加的易感性和 早产儿脓毒症的死亡可以部分解释为未成熟的， 免疫抑制髓系细胞与先天免疫异常终末分化 效应细胞(如单核细胞、中性粒细胞)。此外，我们建议预防性给药 生命早期的免疫调节剂可以通过改变MDSC数量和数量来刺激宿主保护性免疫 功能，导致先天免疫效应细胞数量和功能的增加(特别是中性粒细胞)。这 该战略将降低这一脆弱的“过早出生”人群中微生物感染的发生率和严重程度。 两个具体目标如下：(1)检验新生儿早产和早期败血症的假设 诱导MDSC的扩张，这与先天免疫细胞功能呈负相关。循环中的MDSCs (CD33+CD11b+HLADRlow/-)将在出生时和产中对120名早产儿和40名足月儿进行量化 住院治疗和患败血症的患者。我们将确定人类MDSC和PMN表型 受胎龄和脓毒症的影响，以及MDSCs的扩张和PMN功能障碍是否在 生育是有益的，或者增加了感染的易感性。(2)不能进行的免费研究 在人类中，我们假设骨髓生成和髓系功能(特别是MDSCs)可以受到 应用免疫调节剂诱导分化为有功能的终末天然免疫效应细胞 探员们。利用新生儿败血症模型，我们将测试MDSCs在免疫细胞效应功能和 通过诱导非特异性效应(NSE)或“训练有素的免疫”导致败血症。总而言之， 拟议的研究将集中在调节新生儿免疫反应的关键机制上。使用 组学技术的使用，我们希望提供：1)髓系人群所经历的变化的全球视角 住院期间的早产儿和败血症，以及2)对潜在机制的洞察 通过使用佐剂(卡介苗和TLR4激动剂)进行免疫调节会影响髓系细胞并防止 在这一高度脆弱的人群中出现败血症。

ABSTRACT Neonatal sepsis results in more than 3 million deaths per annum worldwide and the highest risk of mortality occurs in preterm infants (≤37 weeks). This increased vulnerability is due to altered myelopoiesis and an intrinsic hypo-responsiveness to pathogens, concomitant with activation of immunosuppressive mechanisms that sustain maternal-fetal tolerance. Following birth, the neonatal immune system undergoes transition from a semi- allogeneic sterile condition to a microbial-rich postnatal environment, which is modulated in part by neonatal myeloid-derived suppressor cell (MDSC) and innate immune effector cell responses. In newborns, the role of MDSCs is highly controversial, as they may not only control inflammation during early microbial colonization, but also contribute to neonatal susceptibility to infection by inducing immunosuppression. Innate immune effector cell function is also aberrant in prematurity. Our overarching hypothesis is that the increased susceptibility to and mortality from sepsis in preterm neonates can be explained in part by the presence of immature, immunosuppressive myeloid cell populations (MDSCs) and deviant terminal differentiation of innate immune effector cells (e.g. monocytes, PMNs). Furthermore, we propose that the prophylactic administration of immunomodulatory agents early in life can stimulate host protective immunity by altering MDSC numbers and function, leading to augmentation of innate immune effector cell numbers and function (especially PMNs). This strategy will reduce the incidence and severity of microbial infections in this fragile ‘born-too-soon’ population. The two specific aims are as follows: (1) to test the hypothesis that neonatal prematurity and sepsis in early life induce MDSC expansion, which is inversely correlated with innate immune cell function. Circulating MDSCs (CD33+CD11b+HLADRlow/-) will be quantified in 120 preterm and 40 full-term infants at birth and during hospitalization and in those who develop sepsis. We will determine how human MDSC and PMN phenotypes are influenced by gestational age and sepsis, as well as whether expansion of MDSCs and PMN dysfunction at birth is beneficial or increases susceptibility to infections. (2) In complimentary studies that cannot be performed in humans, we hypothesize that myelopoiesis and myeloid function (especially MDSCs) can be influenced to differentiate into functional terminal innate immune effector cells by the administration of immunomodulatory agents. Using a model of neonatal sepsis, we will test the role of MDSCs in immune cell effector functions and outcomes to sepsis through the induction of non-specific effects (NSEs) or ‘trained immunity’. In summary, the proposed studies will focus on mechanisms critical to regulate neonatal immune responses in neonates. With the use of -omics technology, we expect to provide: 1) a global view of changes that myeloid populations undergo in preterm neonates during hospitalization and sepsis, and 2) insights into underlying mechanisms of how immunomodulation through the use of adjuvants (BCG and TLR4 agonists) influences myeloid cells and prevents sepsis in this highly vulnerable population.