小鼠HLA错配喉移植模型中免疫排斥的多维分析

文献信息

中文摘要

目的： 建立单HLA-A2错配的小鼠异位喉移植（LT）模型，并构建用于动态评估免疫排斥和移植物损伤的多维框架。
方法： 将HLA-A2转基因小鼠的喉移植物移植到C57BL/6受者中，以建立HLA错配LT模型，并以同基因C57BL/6→C57BL/6移植作为对照。建立多维评估体系，整合生理监测（存活、体重、移植物外观、颈围、计算机断层扫描和超声）、免疫学分析（组织病理学、免疫组织化学和流式细胞术）以及炎症评估（细胞因子和生化参数），时间范围为移植后第0天至12周。
结果： 与同基因移植相比，HLA错配组表现出加重的免疫排斥和移植物损伤。进行性移植物体积缩小是早期鉴别指标，在移植后1周即可检测到，并与移植物表面变暗和溃疡相关。免疫表型分析显示，CD4+和CD8+ T细胞浸润从1周开始早期出现，而调节性T细胞在3天时增加，随后显著下降。细胞因子谱显示，从4周起MIP-1β、G-CSF和IL-10升高，与免疫激活和移植物损伤一致。
结论： 建立了HLA-A2错配的小鼠异位LT模型，证明单一HLA I类差异足以驱动LT中的进行性免疫排斥和移植物损伤。观察到一组与不良移植物结局相关的生物标志物，为监测HLA驱动的免疫损伤提供了指标。
证据等级： 不适用。

英文摘要

OBJECTIVE: To establish a murine heterotopic laryngeal transplantation (LT) model with a single HLA-A2 mismatch and to develop a multidimensional framework for dynamic evaluation of immune rejection and graft injury.
METHODS: Laryngeal grafts from HLA-A2 transgenic mice were transplanted into C57BL/6 recipients to generate an HLA-mismatched LT model, with syngeneic C57BL/6 → C57BL/6 transplants as controls. A multidimensional evaluation system was established, integrating physiological monitoring (survival, body weight, graft appearance, neck circumference, computed tomography, and ultrasonography), immunological profiling (histopathology, immunohistochemistry, and flow cytometry), and inflammatory assessments (cytokines and biochemical parameters) from Day 0 to 12 weeks posttransplantation.
RESULTS: Compared with syngeneic transplantation, the HLA-mismatched group showed aggravated immune rejection and graft injury. Progressive graft volume reduction was an early discriminator, detectable at 1 week posttransplantation and correlating with graft surface darkening and ulceration. Immunophenotyping revealed early CD4+ and CD8+ T-cell infiltration beginning at 1 week, whereas regulatory T cells increased at 3 days before markedly declining. Cytokine profiling showed elevations of MIP-1β, G-CSF, and IL-10 from 4 weeks onward, consistent with immune activation and graft injury.
CONCLUSION: A murine heterotopic LT model with an HLA-A2 mismatch was established, demonstrating that a single HLA Class I disparity was sufficient to drive progressive immune rejection and graft injury in LT. A panel of biomarkers associated with adverse graft outcomes was observed, providing indicators for monitoring HLA-driven immune injury.
LEVEL OF EVIDENCE: N/A.