Higuchi Toru, Jaramillo Andrés, Kaleem Zahid, Patterson G Alexander, Mohanakumar T
Department of Surgery, Washington University School of Medicine, St. Louis, MO 63110, USA.
Transplantation. 2002 Sep 15;74(5):646-51. doi: 10.1097/00007890-200209150-00010.
Both T and B cells have been shown to be implicated in the pathogenesis of bronchiolitis obliterans syndrome, which is considered to represent chronic lung allograft rejection. However, the relative contributions of T cells and alloantibodies in the pathogenesis of the disease are still unknown. In this study, we used an heterotopic murine tracheal transplantation model to determine the contribution of these components of the immune system in the pathogenesis of posttransplant obliterative airway disease (OAD).
Tracheal allografts from BALB/c and HLA-A2-transgenic (HLA-A2+) mice were heterotopically transplanted into C57BL/6, CD4-knockout (KO), CD8-KO, Ig-KO, and Rag1-KO mice. In additional experiments, recipient mice were pretreated with depleting antibodies against CD4+, CD8+, and NK1.1+ cells. Development of OAD was determined by histopathology at days 10, 30, 60, 90, and 180 after transplantation.
HLA-A2+ allografts transplanted into C57BL/6, CD8-KO, and Ig-KO mice demonstrated OAD lesions by day 30. In contrast, allografts transplanted into CD4-KO mice showed no OAD lesions at day 30, partial OAD development by days 60 and 90, and complete OAD development by day 180. No OAD development was observed in allografts transplanted into Rag1-KO mice. Treatment with anti-NK1.1 antibody did not show any effect on posttransplant OAD development. In contrast, anti-CD4+ or anti-CD8+ antibody treatments partially reduced the OAD histopathology and combined anti-CD4/CD8 antibody treatment further abrogated the histopathology of the disease.
These results show that both CD4+ and CD8+ T cells have a role in the pathogenesis of OAD and that natural killer cells and alloantibodies are not necessary for the development of this disease.
T细胞和B细胞均已被证明与闭塞性细支气管炎综合征的发病机制有关，该综合征被认为代表慢性肺移植排斥反应。然而，T细胞和同种异体抗体在该疾病发病机制中的相对作用仍不清楚。在本研究中，我们使用异位小鼠气管移植模型来确定免疫系统的这些组成部分在移植后闭塞性气道疾病（OAD）发病机制中的作用。
将来自BALB/c和HLA-A2转基因（HLA-A2+）小鼠的气管同种异体移植物异位移植到C57BL/6、CD4基因敲除（KO）、CD8基因敲除、Ig基因敲除和Rag1基因敲除小鼠体内。在额外的实验中，受体小鼠用针对CD4+、CD8+和NK1.1+细胞的耗竭抗体进行预处理。在移植后第10、30、60、90和180天通过组织病理学确定OAD的发展情况。
移植到C57BL/6、CD8基因敲除和Ig基因敲除小鼠体内的HLA-A2+同种异体移植物在第30天时出现OAD病变。相比之下，移植到CD4基因敲除小鼠体内的同种异体移植物在第30天时未出现OAD病变，在第60天和第90天时出现部分OAD发展，在第180天时出现完全OAD发展。移植到Rag1基因敲除小鼠体内的同种异体移植物未观察到OAD发展。用抗NK1.1抗体治疗对移植后OAD的发展没有任何影响。相比之下，抗CD4+或抗CD8+抗体治疗部分减轻了OAD组织病理学，联合抗CD4/CD8抗体治疗进一步消除了该疾病的组织病理学。
这些结果表明，CD4+和CD8+ T细胞在OAD的发病机制中均起作用，并且自然杀伤细胞和同种异体抗体对于该疾病的发展不是必需的。
