Immature myeloid cells as targets for therapeutics to bacterial infection

描述（由申请人提供）：该提案将确定髓源性抑制细胞（MDSC）作为抗感染的新治疗靶点的潜力。MDSC因其在癌症中明确的免疫抑制作用而受到了大量的关注。MDSC在感染中的反应不像在癌症中的反应那样明确，但研究确实显示出与感染部位MDSC浸润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具有向炎性单核细胞、巨噬细胞、骨髓树突状细胞和中性粒细胞分化所必需的可塑性。因此，MDSC反应的双重性质（免疫抑制或保护）可能是由于这些细胞的形态和生物标志物的异质性，因此MDSC在感染期间任何点的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，证明MDSC在感染细菌病原体肠沙门氏菌血清型鼠伤寒沙门氏菌（S. Typhimurium）的小鼠中有很大的反应。此外，我们已经获得的初步证据表明，虽然这些细胞可能具有与先天免疫作用一致的初始保护作用，但它们也对T细胞具有强大的抑制作用，与抑制适应性免疫的作用一致，这是鼠伤寒沙门氏菌感染的标志。这一应用的前提是MDSC可以在感染期间以一种暂时的方式靶向，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阶段降低它们的抑制活性。在特异性目标1中，我们将描述MDSC在鼠伤寒沙门氏菌感染小鼠中的反应和作用。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来抑制T细胞功能。在Specific Aim 2中，我们将使用鼠伤寒沙门氏菌感染的小鼠模型来确定趋化因子受体CCR2是否需要MDSC从骨髓中迁移，以及MDSC是否可以在感染鼠伤寒沙门氏菌的小鼠外周血中扩增和成熟。在Specific Aim 3中，我们将专门针对MDSC在从先天免疫反应到适应性免疫反应转变过程中的扩增、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.