Koskinen P K, Kallio E A, Krebs R, Lemström K B
Transplantation Laboratory, University of Helsinki, Finland.
Am J Respir Crit Care Med. 1997 Jan;155(1):303-12. doi: 10.1164/ajrccm.155.1.9001329.
Inbred DA and WF rats were used as donors and recipients of heterotopic tracheal allografts. To investigate cellular and molecular mechanisms as well as inhibitory effects of differently acting immunosuppressive drugs on the development of obliterative bronchiolitis (OB), the recipient rats received either cyclosporine A (CsA; 1, 2, or 5 mg/kg/d), 15-deoxyspergualin (DSG; 1 or 2 mg/kg/d), or mycophenolate mofetil (MMF; 20 or 40 mg/kg/d), or were left without immunosuppression. The grafts were removed at various time points for histology and immunohistochemistry. In tracheal allografts removed from nonimmunosuppressed animals, respiratory epithelium was replaced by cuboidal or squamous cell epithelium, with markedly enhanced expression of epithelial major histocompatibility class (MHC) Class II antigens at 3 d after transplantation. This was associated with a pronounced inflammatory episode and proliferation of T cells and macrophages, with the prominence of lymphoid activation markers, MHC Class II antigens and interleukin-2R (IL-2R). Later, total epithelial necrosis developed and intense proliferation of granulation tissue occluded the airway lumen producing a condition resembling OB in humans. In syngeneic tracheal grafts, no such changes could be observed. CsA decreased the development of OB in a dose-dependent fashion, in association with downregulation of epithelial MHC Class II antigen expression, IL-2R expression, and the infiltration of T cells. The new immunosuppressive drugs DSG (suppression of the monocyte/macrophage action and lymphocyte proliferation) and MMF (blocking of the de novo pathway of purine synthesis), in the dose range tested, showed no significant effect on the development of OB. These results suggest that an acute alloimmune response to airway targets, perhaps to epithelium, is the primary cause of OB, since CsA, with a nearly exclusive effect on the transcription of immune cytokines, entirely inhibited the generation of OB, and that preventive intervention for OB must occur early in the T-cell activation pathway.
近交系DA和WF大鼠用作异位气管同种异体移植的供体和受体。为了研究细胞和分子机制以及不同作用的免疫抑制药物对闭塞性细支气管炎（OB）发展的抑制作用，受体大鼠接受环孢素A（CsA；1、2或5mg/kg/天）、15-去氧精胍菌素（DSG；1或2mg/kg/天）或霉酚酸酯（MMF；20或40mg/kg/天）治疗，或不进行免疫抑制。在不同时间点取出移植物进行组织学和免疫组织化学检查。在从未免疫抑制动物身上取出的气管同种异体移植物中，呼吸上皮被立方或鳞状上皮取代，移植后3天上皮主要组织相容性复合体（MHC）II类抗原的表达明显增强。这与明显的炎症发作以及T细胞和巨噬细胞的增殖有关，淋巴激活标志物、MHC II类抗原和白细胞介素-2受体（IL-2R）显著增加。后来，出现了完全的上皮坏死，肉芽组织的强烈增殖阻塞了气道腔，产生了一种类似于人类OB的情况。在同基因气管移植物中，未观察到此类变化。CsA以剂量依赖性方式减少了OB的发展，同时上皮MHC II类抗原表达、IL-2R表达下调以及T细胞浸润减少。新的免疫抑制药物DSG（抑制单核细胞/巨噬细胞作用和淋巴细胞增殖）和MMF（阻断嘌呤合成的从头途径），在所测试的剂量范围内，对OB的发展没有显著影响。这些结果表明，对气道靶点（可能是上皮）的急性同种免疫反应是OB的主要原因，因为CsA几乎只对免疫细胞因子的转录有影响，完全抑制了OB的产生，并且对OB的预防性干预必须在T细胞激活途径的早期进行。
