Hussain S Farzana, Yang David, Suki Dima, Grimm Elizabeth, Heimberger Amy B
Department of Neurosurgery-Unit 442, The University of Texas M.D. Anderson Cancer Center, 1515 Holcombe Blvd, Houston, TX 77030, USA.
J Transl Med. 2006 Mar 30;4:15. doi: 10.1186/1479-5876-4-15.
Innate immunity is considered the first line of host defense and microglia presumably play a critical role in mediating potent innate immune responses to traumatic and infectious challenges in the human brain. Fundamental impairments of the adaptive immune system in glioma patients have been investigated; however, it is unknown whether microglia are capable of innate immunity and subsequent adaptive anti-tumor immune responses within the immunosuppressive tumor micro-environment of human glioma patients. We therefore undertook a novel characterization of the innate immune phenotype and function of freshly isolated human glioma-infiltrating microglia (GIM).
GIM were isolated by sequential Percoll purification from patient tumors immediately after surgical resection. Flow cytometry, phagocytosis and tumor cytotoxicity assays were used to analyze the phenotype and function of these cells.
GIM expressed significant levels of Toll-like receptors (TLRs), however they do not secrete any of the cytokines (IL-1beta, IL-6, TNF-alpha) critical in developing effective innate immune responses. Similar to innate macrophage functions, GIM can mediate phagocytosis and non-MHC restricted cytotoxicity. However, they were statistically less able to mediate tumor cytotoxicity compared to microglia isolated from normal brain. In addition, the expression of Fas ligand (FasL) was low to absent, indicating that apoptosis of the incoming lymphocyte population may not be a predominant mode of immunosuppression by microglia.
We show for the first time that despite the immunosuppressive environment of human gliomas, GIM are capable of innate immune responses such as phagocytosis, cytotoxicity and TLR expression but yet are not competent in secreting key cytokines. Further understanding of these innate immune functions could play a critical role in understanding and developing effective immunotherapies to malignant human gliomas.
固有免疫被认为是宿主防御的第一道防线，小胶质细胞可能在介导对人脑创伤和感染挑战的强大固有免疫反应中发挥关键作用。胶质瘤患者适应性免疫系统的基本损害已得到研究；然而，尚不清楚在人类胶质瘤患者免疫抑制性肿瘤微环境中，小胶质细胞是否能够产生固有免疫以及随后的适应性抗肿瘤免疫反应。因此，我们对新鲜分离的人胶质瘤浸润小胶质细胞（GIM）的固有免疫表型和功能进行了新的表征。
手术切除后立即从患者肿瘤中通过连续Percoll纯化分离GIM。使用流式细胞术、吞噬作用和肿瘤细胞毒性测定法分析这些细胞的表型和功能。
GIM表达显著水平的Toll样受体（TLR），然而它们不分泌对产生有效的固有免疫反应至关重要的任何细胞因子（IL-1β、IL-6、TNF-α）。与固有巨噬细胞功能相似，GIM可介导吞噬作用和非MHC限制的细胞毒性。然而，与从正常脑分离的小胶质细胞相比，它们在介导肿瘤细胞毒性方面在统计学上能力较弱。此外，Fas配体（FasL）的表达很低或不存在，这表明进入的淋巴细胞群体的凋亡可能不是小胶质细胞免疫抑制的主要模式。
我们首次表明，尽管人类胶质瘤存在免疫抑制环境，但GIM能够产生诸如吞噬作用、细胞毒性和TLR表达等固有免疫反应，但在分泌关键细胞因子方面能力不足。对这些固有免疫功能的进一步了解可能在理解和开发针对恶性人类胶质瘤的有效免疫疗法中发挥关键作用。
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