探討CoPP對於小鼠骨髓樹突細胞的免疫耐受性作用

前言：第一型血紅素氧化酶（heme oxygenase-1）具有保護細胞對抗氧化傷害及發炎壓力的功能，在先前的研究中被報導在器官異體移植的實驗中與器官接受者免疫耐受性的增加有關，但是HO-1在樹突細胞上是否具有免疫調控的功能還並不清楚。實驗方法：利用CoPP藥物誘導小鼠骨髓樹突細胞產生HO-1分子，並加入LPS做為刺激因子，分析細胞內HO-1蛋白質的表現情形以及樹突細胞分泌細胞激素的種類與表現量，並進一步探就CoPP對於骨髓樹突細胞表面分子與對T細胞功能的影響。結果：CoPP確實可以使得樹突細胞內HO-1的表現量增加，且隨著CoPP濃度的提升，可顯著的抑制由LPS所誘導的促發炎細胞激素的表現（IL-6、IL-12、TNF-?悀呰L-23），並使IL-10表現量上升。在樹突細胞成熟度方面，CoPP同樣可抑制由LPS所引起的樹突細胞表面分子的增加，可抑制CD80、CD86及CD40的表現，但對MHC Class II無影響。此外經CoPP處理過之樹突細胞無論在allo-response或antigen-specific上都對CD4+ T細胞的增生有抑制的效果，且抗原特異性CD4+ T細胞所分泌的IFN-?蚺呰L-17有降低的現象。結論：實驗結果顯示，CoPP可以誘導HO-1的大量表現，且可以讓樹突細胞產生耐受性，下一步我們將研究此特性是否與調節性T細胞族群的分化與功能有相關，這些研究將可發展自體免疫疾病（如SLE）之抗原特異性免疫療法。

關鍵字

樹突細胞；耐受性；調節性T細胞

並列摘要

BACKGROUD: Heme oxygenase-1 (HO-1) is known for its cytoprotective effect against oxidative stress and inflammation. It suggests that HO-1 HO-1 induction in organ donors could lead to prolonged allogenic graft survival and associated with the tolerogenicity in recipients. However, the role of HO-1 in the function of dendritic cells is still not clear. METHODS: Murine bone marrow derived dendritic cells (BM-DCs) were treated with HO-1 inducer - cobalt protoporphyrin (CoPP) and cultured with LPS as a stimulus. We analyzed the HO-1 protein expression level and different cytokines secreted by BM-DCs. Furthermore, we analyze the phenotype and T cell function affected by CoPP. RESULTS: CoPP could surly upregulate HO-1 protein expression level in BM-DCs. CoPP inhibited the BM-DCs expression of proinflammatory cytokines induced by LPS (IL-6, IL-12, TNF?? and IL-23) and stimulated IL-10 expression in a dose-dependent manner. CoPP also suppressed the maturation of BM-DCs induced by LPS (lower CD80, CD86, CD40 expression, but retained high level of MHC class II). In addition, CoPP inhibited the ability of BM-DCs to stimulate allo- and antigen-specific- T cell response in vitro. CoPP treated BM-DCs also suppressed IFN-?? and IL-17 secretion of antigen specific CD4+ T cells. CONCLUSIONS: Our data suggests that CoPP may modulate BM-DCs to express HO-1 and to exhibit tolerogenic properties in vitro. This study will facilitate to examine the cellular and molecular mechanisms involved in the differentiation of tolerogenic dendritic cells. It helps to develop the antigen-specific immunotherapy in autoimmune diseases (such as systemic lupus erythematosus).