Immature myeloid cells as targets for therapeutics to bacterial infection

描述(由申请人提供)：这项提案将确定髓系来源的抑制细胞(MDSC)作为新的抗感染治疗靶点的潜力。MDSC因其在癌症中明确的免疫抑制作用而最近受到了大量的关注。MDSC在感染中的反应不如在癌症中那样好，但研究确实表明，在感染部位与MDSC渗透相关的一致的免疫抑制表型。在某些感染中，MDSC可能具有早期保护作用。MDSC具有分化为炎性单核细胞、巨噬细胞、髓系树突状细胞和中性粒细胞所必需的可塑性。因此，MDSC反应的两面性(免疫抑制或保护)可能是由于这些细胞的形态和生物标记物的异质性，因此在感染过程中任何时候MDSC表型和功能的平衡可能决定结果。我们已经获得了初步数据，表明MDSC在感染了细菌病原体鼠伤寒沙门氏菌(鼠伤寒沙门氏菌)的小鼠中有很大的反应。此外，我们已获得初步证据表明，虽然这些细胞可能具有与先天免疫一致的初步保护作用，但它们对T细胞也具有强大的抑制作用，与抑制获得性免疫的作用一致，这是鼠伤寒沙门氏菌感染的一个特征。这一应用的前提是，MDSC可以在感染期间以临时方式靶向，以利用它们在免疫反应的先天阶段的保护作用，并在免疫反应的适应性阶段减少它们的抑制活动。在特定的目标1中，我们将表征MDSC在感染鼠伤寒沙门氏菌后的反应和作用。这将包括记录鼠伤寒沙门氏菌诱导的MDSC是否通过产生一氧化氮或精氨酸酶-1抑制T细胞功能。在具体目标2中，我们将使用鼠伤寒沙门氏菌感染模型来确定趋化因子受体CCR2是否需要趋化因子受体CCR2才能将MDSC迁移出骨髓，以及MDSC是否能在感染鼠伤寒沙门氏菌的小鼠外周扩增和成熟。在具体目标3中，我们将特别针对MDSC从先天免疫反应向获得性免疫反应的转变过程中的扩增、激活和抑制活性，作为一种新的感染治疗方法。

DESCRIPTION (provided by applicant): This proposal will determine the potential for myeloid-derived suppressor cells (MDSC) as novel therapeutic targets against infection. MDSC have received a significant amount of recent attention for their well-defined immunosuppressive role in cancer. The response of MDSC in infection is not as well characterized as in cancer, but studies do show a consistent immunosuppressive phenotype associated with MDSC infiltration at sites of infection. In some infections, MDSC may have an early protective role. MDSC have the plasticity necessary to differentiate into inflammatory monocytes, macrophages, myeloid dendritic cells and neutrophils. Thus, the dual nature of the MDSC response (immunosuppressive or protective) may be due to the morphologic and biomarker heterogeneity of these cells, such that the balance of MDSC phenotypes and functions at any point during infection may determine the outcome. We have obtained preliminary data demonstrating a large response of MDSC in mice infected with the bacterial pathogen Salmonella enterica serovar Typhimurium (S. Typhimurium). In addition, we have obtained preliminary evidence to suggest that while these cells may have an initial protective effect consistent with a role in innate immunity, they also have a potent inhibitory effect on T cells consistent with a role in suppression of adaptive immunity, which is a hallmark of S. Typhimurium infection. This application is built on the premise that MDSC can be targeted during infection in a temporal manner to capitalize on their protective role during the innate phase of the immune response and decrease their suppressive activity during the adaptive phase of the immune response. In Specific Aim 1, we will characterize the response and role of MDSC in mice infected with S. Typhimurium. This will involve documenting whether S. Typhimurium-induced MDSC suppress T cell function through production of nitric oxide or arginase-1. In Specific Aim 2, we will use a mouse model of infection with S. Typhimurium to determine if chemokine receptor CCR2 is required for emigration of MDSC out of bone marrow, and if MDSC can expand and mature in the periphery of mice infected with S. Typhimurium. In Specific Aim 3, we will specifically target MDSC expansion, activation and suppressive activity at the transition from innate to adaptive immune response as a novel therapeutic approach to infection.