Deuse Tobias, Schrepfer Sonja, Reichenspurner Hermann, Hoyt Grant, Fischbein Michael P, Robbins Robert C, Pelletier Marc P
University Heart Center Hamburg, Department of Cardiovascular Surgery, Martinistr. 52, 20246, Hamburg, Germany.
Transpl Immunol. 2007 Jun;17(4):255-61. doi: 10.1016/j.trim.2007.01.009. Epub 2007 Feb 6.
Different animal models have been developed to study the pathogenesis and treatment of obliterative airway disease (OAD). Here we describe the techniques of heterotopic and orthotopic tracheal transplantations in the rat, comparing the kinetics of systemic host immune response and of histopathologic OAD development.
Heterotopic and orthotopic tracheal transplantations were performed in both allogeneic (Brown Norway-to-Lewis) and syngeneic (Lewis-to-Lewis) models. Grafts were harvested after 7, 30, and 60 days post-transplant for histologic evaluation and analysis of host cellular and humoral response.
Syngeneic tracheal grafts did not develop luminal obliteration and were morphologically indistinguishable from native tracheas. In heterotopic allografts, airway epithelium was rapidly destroyed and OAD progressed with complete luminal occlusion by 30 days. Orthotopic allografts showed enhanced early infiltration (1298+/-45 vs. 674+/-75 cells/high power field, p<0.001) with concomitant greater day 7 luminal narrowing (45+/-6% vs. 14+/-3%, p<0.001). In this model, donor-type BN epithelium (62+/-17%, 21+/-19%, and 1+/-1% on days 7, 30, and 60) was gradually replaced by recipient-type epithelial cells (2+/-4%, 70+/-22%, and 98+/-2%). OAD developed with circular orientation of cells and connective tissue fibers to 45+/-6% obliteration by day 60. Cellular host response, as determined by IFN-gamma-ELISPOT assay (548+/-132 vs. 402+/-197 spots, p=0.046) and anti-donor alloreactive IgM antibody production (2827+/-148 vs. 1565+/-393 mean channel fluorescence, p<0.001) were significantly stronger in rats bearing orthotopic vs. heterotopic allografts.
The orthotopic tracheal transplantation model may be more representative of OAD found in human lung transplant recipients and we therefore encourage the wider use of this model.
已建立不同的动物模型来研究闭塞性气道疾病（OAD）的发病机制和治疗方法。在此，我们描述大鼠异位和原位气管移植技术，比较全身宿主免疫反应动力学和组织病理学OAD发展情况。
在同种异体（棕色挪威大鼠到刘易斯大鼠）和同基因（刘易斯大鼠到刘易斯大鼠）模型中进行异位和原位气管移植。移植后7天、30天和60天收获移植物，进行组织学评估并分析宿主细胞和体液反应。
同基因气管移植物未发生管腔闭塞，形态上与天然气管无差异。在异位同种异体移植物中，气道上皮迅速被破坏，OAD进展，到30天时管腔完全闭塞。原位同种异体移植物早期浸润增强（1298±45对674±75个细胞/高倍视野，p<0.001），同时第7天管腔狭窄更明显（45±6%对14±3%，p<0.001）。在该模型中，供体型BN上皮（第7天、30天和60天分别为62±17%、21±19%和1±1%）逐渐被受体型上皮细胞取代（分别为2±4%、70±22%和98±2%）。到第60天时，OAD发展为细胞和结缔组织纤维呈环形排列，管腔闭塞达45±6%。通过IFN-γ-ELISPOT分析（548±132对402±197个斑点，p=0.046）和抗供体同种异体反应性IgM抗体产生（平均通道荧光2827±148对1565±393，p<0.001）确定，原位同种异体移植大鼠的细胞宿主反应明显强于异位同种异体移植大鼠。
原位气管移植模型可能更能代表人类肺移植受者中发现的OAD，因此我们鼓励更广泛地使用该模型。
