Hollmén Maria, Tikkanen Jussi M, Nykänen Antti I, Koskinen Petri K, Lemström Karl B
Cardiopulmonary Research Group, Transplantation Laboratory, University of Helsinki, Helsinki, Finland.
J Heart Lung Transplant. 2008 Aug;27(8):856-64. doi: 10.1016/j.healun.2008.05.018. Epub 2008 Jul 3.
Obliterative bronchiolitis (OB) is the most prominent cause of morbidity and mortality among lung transplant patients. No effective treatment for OB exists, but preliminary clinical studies have suggested that a calcineurin inhibitor, tacrolimus, may delay the development of OB when compared with standard cyclosporine-based immunosuppression.
Using a murine tracheal transplantation model, we examined the effects of tacrolimus prophylaxis and treatment on the development of obliterative airway disease (OAD). Tracheal allografts were transplanted heterotopically from BALB/c to C57 black mice into a subcutaneous pouch. The mice received different doses of tacrolimus monotherapy, ranging from 0 to 3 mg/kg/day, subcutaneously initiated at 0 (prophylaxis), 7 (early treatment) or 14 (late treatment) days. We harvested the grafts 30 days after transplantation for histologic and immunohistochemical analyses.
We found that tacrolimus prophylaxis dose-dependently inhibited OAD, and that early treatment halts OAD progression and that late treatment delays progression. Syngeneic grafts showed no obliterative changes. Tacrolimus prophylaxis was associated with inhibition of recruitment of CD4+, CD8+ and interleukin-2R+ inflammatory cells into the allografts, suggesting a central role for interleukin-2 in the development of OAD. In addition, a dose-dependent correlation between epithelial necrosis and tracheal occlusion was observed, suggesting that epithelial injury is required for the development of OAD. When tacrolimus treatment was initiated at the time the obliterative lesion had already started to develop, it inhibited the progression of OAD significantly.
The findings from this study suggest that tacrolimus therapy is effective during the early stages of clinical OB.
闭塞性细支气管炎（OB）是肺移植患者发病和死亡的最主要原因。目前尚无针对OB的有效治疗方法，但初步临床研究表明，与基于环孢素的标准免疫抑制相比，钙调神经磷酸酶抑制剂他克莫司可能会延缓OB的发展。
我们使用小鼠气管移植模型，研究了他克莫司预防和治疗对闭塞性气道疾病（OAD）发展的影响。将气管同种异体移植物从BALB/c异位移植到C57黑小鼠的皮下袋中。小鼠接受不同剂量的他克莫司单药治疗，剂量范围为0至3mg/kg/天，分别在第0天（预防）、第7天（早期治疗）或第14天（晚期治疗）开始皮下给药。移植30天后收获移植物进行组织学和免疫组织化学分析。
我们发现他克莫司预防剂量依赖性地抑制OAD，早期治疗可阻止OAD进展，晚期治疗可延缓进展。同基因移植物未显示闭塞性改变。他克莫司预防与抑制CD4+、CD8+和白细胞介素-2受体+炎症细胞募集到同种异体移植物中有关，提示白细胞介素-2在OAD发展中起核心作用。此外，观察到上皮坏死与气管闭塞之间存在剂量依赖性相关性，提示上皮损伤是OAD发展所必需的。当在闭塞性病变已经开始发展时开始他克莫司治疗，可显著抑制OAD进展。
本研究结果表明，他克莫司治疗在临床OB的早期阶段有效。
