Sparrelid E, Emanuel D, Fehniger T, Andersson U, Andersson J
Department of Immunology, Pathology, Microbiology and Infectious Diseases, Karolinska Institute, Huddinge University Hospital, Sweden.
Transplantation. 1997 Jun 27;63(12):1782-9. doi: 10.1097/00007890-199706270-00013.
Interstitial pneumonitis, especially associated with cytomegalovirus (CMV) infection, is a serious complication after bone marrow transplantation (BMT), with a high fatality rate despite adequate antiviral treatment. The aim of this study was to elucidate the local immunopathogenesis of interstitial pneumonitis caused by CMV or other agents in BMT recipients.
Cryopreserved lung tissue obtained from 12 patients with interstitial pneumonitis following BMT was analyzed for cytokine production at the single-cell level using a cytokine-specific monoclonal antibody and immunohistochemical technique. Cytokine production in individual cells was analyzed using monoclonal antibodies to 23 different human cytokines: interleukin (IL)-1 to IL-13, tumor necrosis factor (TNF)-alpha, TNF-beta, interferon-gamma (IFNgamma), granulocyte colony-stimulating factor, granulocyte-macrophage colony-stimulating factor, and transforming growth factor (TGF)-beta1 to 3.
Marrow transplant patients with interstitial pneumonia had increased numbers of infiltrating alveolar macrophages, CD3+, CD4+ T cells, and CD40+ B cells and significantly increased numbers of IL-4-, IL-10-, IL-1-, TGF-beta1-, TGF-beta2-, and TGF-beta3-producing cells than controls. IL-2-, IFN-gamma-, and TNF-beta-producing cells were undetectable in most patients with CMV pneumonitis (n=7). Neither perforin-positive CD8+ T lymphocytes nor up-regulation of the apoptotic pathway was detected in lung tissue from patients with interstitial pneumonia. In contrast, extensive local production of IgA, IgG, and IgM was demonstrated in all patients. Intracellular and extensive extracellular deposition of CD68, the L-1 antigen synthesized in CD14+ macrophages, was found.
The cytokine profile suggested that Th1-type cytokine production was absent, whereas production of Th2-type cytokines was significantly up-regulated. Interstitial pneumonitis in BMT recipients with fatal outcome (11/12 patients) was associated with dysregulation in the local cytokine network notable for a predominant Th2 immune response with minimal or absent T cell-mediated cytotoxicity.
间质性肺炎，尤其是与巨细胞病毒（CMV）感染相关的间质性肺炎，是骨髓移植（BMT）后的一种严重并发症，尽管进行了充分的抗病毒治疗，死亡率仍很高。本研究的目的是阐明BMT受者中由CMV或其他病原体引起的间质性肺炎的局部免疫发病机制。
使用细胞因子特异性单克隆抗体和免疫组织化学技术，在单细胞水平分析从12例BMT后发生间质性肺炎的患者获取的冻存肺组织中的细胞因子产生情况。使用针对23种不同人类细胞因子的单克隆抗体分析单个细胞中的细胞因子产生情况：白细胞介素（IL）-1至IL-13、肿瘤坏死因子（TNF）-α、TNF-β、干扰素-γ（IFNγ）、粒细胞集落刺激因子、粒细胞-巨噬细胞集落刺激因子以及转化生长因子（TGF）-β1至3。
患有间质性肺炎的骨髓移植患者浸润的肺泡巨噬细胞、CD3⁺、CD4⁺ T细胞和CD40⁺ B细胞数量增加，与对照组相比，产生IL-4、IL-10、IL-1、TGF-β1、TGF-β2和TGF-β3的细胞数量显著增加。在大多数CMV肺炎患者（n = 7）中未检测到产生IL-2、IFN-γ和TNF-β的细胞。在间质性肺炎患者的肺组织中未检测到穿孔素阳性的CD8⁺ T淋巴细胞，也未检测到凋亡途径的上调。相反，在所有患者中均显示出IgA、IgG和IgM的广泛局部产生。发现了在CD14⁺巨噬细胞中合成的L-1抗原CD68的细胞内和广泛的细胞外沉积。
细胞因子谱表明Th1型细胞因子产生缺失，而Th2型细胞因子的产生显著上调。具有致命结局的BMT受者中的间质性肺炎（11/12例患者）与局部细胞因子网络失调有关，其特征是主要为Th2免疫反应，T细胞介导的细胞毒性最小或不存在。
