M-1/M-2 Macrophages

M-1/M-2巨噬细胞

• 批准号: 6474178
• 负责人: CHARLES D MILLS
• 金额: $ 11.14万
• 依托单位: UNIVERSITY OF MINNESOTA
• 依托单位国家: 美国
• 财政年份: 2002
• 资助国家: 美国
• 起止时间: 2002-08-01 至 2004-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6474178
• 关键词: B lymphocyte; SCID mouse; T lymphocyte; aminoacid metabolism; antineoplastics; arginine; athymic mouse; cell proliferation; cytotoxic T lymphocyte; enzyme linked immunosorbent assay; free radical oxygen; helper T lymphocyte; immune tolerance /unresponsiveness; immunoregulation; inflammation; interferon alpha; interferon beta; interferon gamma; interleukin 12; interleukin 8; leukocyte activation /transformation; macrophage; natural killer cells; nitric oxide; ornithine; phenotype

Description (provided by applicant): The goal of this investigation is to more clearly defme M- 1 and M-2 macrophages and how they influence immune responses. The concept of M-1 and M-2 fomented from observations in this laboratory that with the same stimuli, macrophages from certain mice (C57BL/6, B1OD2) preferentially metabolize argimne to NO while other mice (Balb/c, DBAI2) increase ornithine production. NO inhibits cell replication while omithine (via polyamines) promotes cell replication. Therefore, M-1/M-2 does not simply represent activated or unactivated macrophages, but macrophages that have upregulated qualitatively different metabolic programs. M-1/M-2 propensities are also observed in C57BL/6 and Balb/c SCID mice and are thus independent of T or B lymphocytes. Indeed, other evidence indicates that M-1/M-2 macrophages can shepherd T lymphocytes into Thi or Th2 responses, respectively. Macrophages are a major precursor of dendritic cells, which have been reported to influence the Thl/Th2 balance. Therefore, our results suggest that macrophages play much a more important role in orchestrating immune responses than is currently appreciated. The Main Hypothesis is that M-1 is associated with destructive products and Thl responses, while M-2 is associated with the constructive products involved in healing/regeneration and with Th2 responses. It is also hypothesized that overexpression of the M-l phenotype (e.g. NO) can inhibit specific immune responses. To test these hypotheses Specific Aim 1 will more clearly define products and properties of M-1/M-2 macrophages including a) arginine metabolites (NO/ornithine); b) oxygen radicals (O2-, ONOO-, H2O2); and c) cytokines/growth factors (e.g. IL- 12, IFN-g, IL-8, IFN a/b, macrophage stimulating protein). Specific Aim I will also determine if M-1/M-2 macrophage phenotypes are expressed at the single cell level using double color ELISPOT. Specific Aim 2 will determine how M-l/M-2 macrophage responses influence non-specific or specific immune responses in vivo. Specific Aim 2a will determine how M-1/M-2 macrophage responses influence non-specific inflammation associated with injury/danger. Specific Aim 2b will compare innate immunity in M-l/M-2-dominant mice. Specific Aim 2c will determine how M- 1 /M-2 macrophages influence tumor specific or allo specific immune responses. M1 (C578L/6) and M-2 (Balb/c) SCID mice will be used extensively as test subjects and as sources of macrophages for adoptive transfer to directly determine effects due to M-1/M-2 macrophages. Together, this investigation will result in a major increase in our understanding of M-1/M-2 macrophages and how they influence immune responses.

描述（由申请人提供）：本次调查的目的是为了更多 清楚地定义M- 1和M-2巨噬细胞以及它们如何影响免疫反应。 M-1和M-2的概念是从这个实验室的观测中产生的， 在相同的刺激下，某些小鼠（C57 BL/6，B1 OD 2）的巨噬细胞 Balb/c、DBAI 2小鼠优先代谢精氨酸为NO， 增加鸟氨酸产量。NO抑制细胞复制，而omithine（通过 多胺）促进细胞复制。因此，M-1/M-2不只是 代表活化或未活化的巨噬细胞，但巨噬细胞 上调不同性质的代谢程序。M-1/M-2倾向 在C57 BL/6和Balb/c SCID小鼠中也观察到，因此不依赖于T 或B淋巴细胞。事实上，其他证据表明M-1/M-2巨噬细胞可以 分别引导T淋巴细胞进入Th 1或Th 2应答。巨噬细胞是 树突状细胞的主要前体，据报道，它会影响 Thl/Th 2平衡。因此，我们的研究结果表明，巨噬细胞发挥了很大的作用， 在协调免疫反应中的作用比现在更重要 赞赏.主要假设是，M-1与破坏性有关。 产品和Thl反应，而M-2与建设性的 参与愈合/再生和Th 2应答的产物。也是 假设M-I表型（例如NO）的过表达可以抑制 特异性免疫反应。为了验证这些假设，具体目标1将更多 明确定义M-1/M-2巨噬细胞的产物和性质，包括a） 精氨酸代谢物（NO/鸟氨酸）; B）氧自由基（O2-、ONOO-、H2 O2）;和 c）细胞因子/生长因子（例如IL- 12、IFN-g、IL-8、IFN a/B、巨噬细胞 刺激蛋白）。特定目标I还将确定M-1/M-2巨噬细胞 使用双色ELISPOT在单细胞水平表达表型。 具体目标2将确定M-1/M-2巨噬细胞应答如何影响 体内非特异性或特异性免疫应答。具体目标2a将 确定M-1/M-2巨噬细胞反应如何影响非特异性炎症 与伤害/危险有关。具体目标2b将比较先天免疫， M-1/M-2-显性小鼠。特定目标2c将决定M- 1 /M-2巨噬细胞如何 影响肿瘤特异性或同种特异性免疫应答。M1（C578 L/6）和 M-2（Balb/c）SCID小鼠将被广泛用作试验对象和来源 用于过继转移的巨噬细胞，以直接确定 M-1/M-2巨噬细胞。总之，这次调查将导致 我们对M-1/M-2巨噬细胞及其影响方式的了解增加 免疫反应。