Sugisaki K, Dannenberg A M, Abe Y, Tsuruta J, Su W J, Said W, Feng L, Yoshimura T, Converse P J, Mounts P
Department of Environmental Health Sciences, School of Hygiene and Public Health, The Johns Hopkins University, Baltimore, Maryland 21205, USA.
J Leukoc Biol. 1998 Apr;63(4):440-50. doi: 10.1002/jlb.63.4.440.
To our knowledge, this is the first sequential study of cytokines in tissue sections of developing and healing tuberculous (BCG) lesions. In situ hybridization, immunohistochemical, and RT-PCR techniques were used. Cytokine mRNAs showed a biphasic pattern. The percentage of mononuclear cells (MN) containing IL-1beta, TNF-alpha, MCP-1, and IL-8 mRNAs was highest in 1- to 3-day lesions, apparently because of the nonspecific inflammatory response caused by the tubercle bacilli in the BCG vaccine. At 5 days, this percentage was significantly reduced. With IFN-gamma, the peak and trough were delayed by 2 days. By 9 days, the percentage of MN containing the mRNAs of all five cytokines had again increased and the rabbits had become tuberculin-positive. In general, MCP-1 and TNF-alpha proteins and the vascular adhesion molecules, ICAM, VCAM, and perhaps ELAM, peaked at about 3 days. Many mononuclear cells surrounding the central areas of solid and liquefied caseous necrosis contained chemokine IL-8 mRNA. IL-8 is known to attract PMN, and PMN were present nearby. In contrast, MN containing chemokine MCP-1 mRNA were present more peripherally in areas rich in macrophages and lymphocytes. The early nonspecific cytokine response seems to be an adjuvant effect of the mycobacteria in BCG vaccine in that it causes a rapid entry of macrophages, lymphocytes, granulocytes, and probably dendritic cells into local sites of antigen deposition. This effect should be considered in developing improved vaccines for the prevention of tuberculosis, because BCG vaccines producing a strong early cytokine response should be more immunogenic than BCG vaccines with similar antigens producing a weak response.
据我们所知，这是对正在发展和愈合的结核（卡介苗）病变组织切片中细胞因子进行的首次序贯研究。使用了原位杂交、免疫组织化学和逆转录聚合酶链反应技术。细胞因子mRNA呈现双相模式。含有白细胞介素-1β、肿瘤坏死因子-α、单核细胞趋化蛋白-1和白细胞介素-8 mRNA的单核细胞百分比在1至3天的病变中最高，显然是由于卡介苗中的结核杆菌引起的非特异性炎症反应。在第5天，这个百分比显著降低。对于干扰素-γ，峰值和谷值延迟了2天。到第9天，含有所有五种细胞因子mRNA的单核细胞百分比再次增加，并且兔子已变为结核菌素阳性。一般来说，单核细胞趋化蛋白-1和肿瘤坏死因子-α蛋白以及血管黏附分子细胞间黏附分子、血管细胞黏附分子，可能还有内皮细胞白细胞黏附分子，在大约3天时达到峰值。许多围绕实性和液化干酪样坏死中心区域的单核细胞含有趋化因子白细胞介素-8 mRNA。已知白细胞介素-8可吸引中性粒细胞，且附近存在中性粒细胞。相比之下，含有趋化因子单核细胞趋化蛋白-1 mRNA的单核细胞更多地存在于富含巨噬细胞和淋巴细胞的外周区域。早期非特异性细胞因子反应似乎是卡介苗中分枝杆菌的一种佐剂效应，因为它会导致巨噬细胞、淋巴细胞、粒细胞以及可能的树突状细胞迅速进入抗原沉积的局部部位。在开发预防结核病的改良疫苗时应考虑这种效应，因为产生强烈早期细胞因子反应的卡介苗应该比具有相似抗原但产生弱反应的卡介苗更具免疫原性。
