M-1/M-2 Macrophages

描述(申请人提供)：本次调查的目的是为了 明确界定M-1和M-2巨噬细胞及其如何影响免疫反应。 M-1和M-2的概念是从这个实验室的观察中产生的 在相同刺激下，某些小鼠(C57BL/6，B1OD2)的巨噬细胞 优先代谢精氨酸为NO，而其他小鼠(Balb/c，DBAI2) 增加鸟氨酸产量。NO抑制细胞复制，而奥美辛(通过 多胺)促进细胞复制。因此，M-1/M-2不是简单的 代表激活或未激活的巨噬细胞，但具有 上调了本质上不同的代谢程序。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细胞 或者B淋巴细胞。事实上，其他证据表明，M-1/M-2巨噬细胞可以 牧羊人T淋巴细胞分别转化为Th1或Th2反应。巨噬细胞 树突状细胞的主要前体，据报道，树突状细胞影响 Th1/Th2平衡。因此，我们的结果表明，巨噬细胞在很大程度上 在协调免疫反应方面的作用比目前更重要 感激不尽。主要的假设是M-1与破坏性有关 产品和THL反应，而M-2与建设性的 参与修复/再生和Th2反应的产品。它也是 假设M-L表型的过表达(例如，NO)可以抑制 特定的免疫反应。为了检验这些假说，《特定目标1》将会有更多 明确定义M-1/M-2巨噬细胞的产品和属性，包括a) 精氨酸代谢物(NO/鸟氨酸)；b)氧自由基(O2-、ONOO-、H2O2)；以及 C)细胞因子/生长因子(如IL-12、干扰素-g、IL-8、干扰素a/b、巨噬细胞 刺激蛋白质)。特异性目标I还将确定M-1/M-2巨噬细胞 利用双色ELISPOT在单细胞水平表达表型。 特异靶2将确定M-L/M-2巨噬细胞反应如何影响 体内的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/危险有关。特定目标2b将比较先天免疫 M-L/M-2显性小鼠。特异靶2c将决定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)及 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的数量以直接确定由于 M-1/M-2巨噬细胞。总之，这次调查将导致一项重大的 增加我们对M-1/M-2巨噬细胞及其影响的了解 免疫反应。

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.