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 清楚地定义了 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 的概念源于该实验室的观察： 在相同的刺激下，来自某些小鼠的巨噬细胞（C57BL/6、B1OD2） 优先将精氨酸代谢为 NO，而其他小鼠（Balb/c、DBAI2） 增加鸟氨酸产量。 NO 抑制细胞复制，而鸟氨酸（通过 多胺）促进细胞复制。因此，M-1/M-2不只是简单地 代表激活或未激活的巨噬细胞，但巨噬细胞具有 上调质不同的代谢程序。 M-1/M-2 倾向 在 C57BL/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 Thi 或 Th2 反应。巨噬细胞是 树突状细胞的主要前体，据报道可影响 Thl/Th2 平衡。因此，我们的结果表明巨噬细胞在 在协调免疫反应方面比目前更重要 赞赏。主要假设是 M-1 与破坏性相关 产品和Thl反应，而M-2与建设性相关 涉及愈合/再生和 Th2 反应的产品。这也是 假设 M-l 表型（例如 NO）的过度表达可以抑制 特异性免疫反应。为了检验这些假设，具体目标 1 将更多 明确定义 M-1/M-2 巨噬细胞的产物和特性，包括 a) 精氨酸代谢物（NO/鸟氨酸）； b) 氧自由基（O2-、ONOO-、H2O2）；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）。具体目标 我还将确定 M-1/M-2 巨噬细胞是否 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 巨噬细胞反应如何影响 体内非特异性或特异性免疫反应。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/危险相关。具体目标 2b 将比较先天免疫 M-1/M-2-显性小鼠。具体目标 2c 将确定 M-1/M-2 巨噬细胞如何 影响肿瘤特异性或同种异体特异性免疫反应。 M1 (C578L/6) 和 M-2 (Balb/c) SCID 小鼠将被广泛用作测试对象和来源 巨噬细胞的过继转移直接确定由于 M-1/M-2 巨噬细胞。总之，这项调查将产生重大影响 增加我们对 M-1/M-2 巨噬细胞及其影响方式的了解 免疫反应。