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血管化复合组织同种异体移植的慢性排斥模型

Chronic rejection models for vascularized composite tissue allotransplantation.

作者信息

Fisher Daniel T, Mackey Emily, Kononov Eugene, Bogner Paul N, Sharma Umesh, Yu Han, Cetrulo Curtis L, Seshadri Mukund, Kalinski Pawel, Skitzki Joseph J, Repasky Elizabeth A, Kim Minhyung

机构信息

Department of Immunology, Roswell Park Comprehensive Cancer Center, Buffalo, NY, USA.

Comparative Oncology Shared Resource, Roswell Park Comprehensive Cancer Center, Buffalo, NY, USA.

出版信息

Sci Rep. 2025 May 15;15(1):16882. doi: 10.1038/s41598-025-01803-8.

Abstract

Vascularized composite tissue allotransplantation (VCA) has transformed patients' lives by enabling limb, face, abdominal wall, and penile transplants. Despite advancements in screening and immunosuppression, chronic rejection continues to limit the success of VCA. Lack of reliable preclinical models exacerbates this challenge. Here, we report on new mouse models of chronic rejection following heterotopic hind limb VCA. We employed different levels of MHC mismatch using CD8 knockout C57BL/6 mice as recipients along with BALB/c or B6 H2-Ab1 mice as donors. Transient CD4 T cell depletion was induced to allow graft maturation. Evaluation included gross findings, changes in immune status changes, production of donor-specific antibodies (DSA), C4d levels, and histopathological alterations. Two chronic rejection models displayed common features of clinical chronic graft rejection, such as skin stricture, hair loss, adnexal atrophy, extensive fibrosis and mast cell infiltration without widespread necrotic changes common in acute rejection. Similar to chronic rejection patients, large populations of activated B and plasma cells were detected in the recipient's immune system as well as increased DSA and C4d production. Collectively, our models closely replicate the immunological and histopathological aspects of chronic graft rejection post-VCA, and could provide a new platform for evaluation of novel therapeutic interventions prior to clinical evaluation.

摘要

血管化复合组织同种异体移植(VCA)通过实现肢体、面部、腹壁和阴茎移植改变了患者的生活。尽管在筛查和免疫抑制方面取得了进展,但慢性排斥反应仍然限制了VCA的成功。缺乏可靠的临床前模型加剧了这一挑战。在此,我们报告了异位后肢VCA后慢性排斥反应的新小鼠模型。我们使用CD8基因敲除的C57BL/6小鼠作为受体,以及BALB/c或B6 H2-Ab1小鼠作为供体,采用不同程度的主要组织相容性复合体(MHC)错配。诱导短暂的CD4 T细胞耗竭以促进移植物成熟。评估包括大体观察结果、免疫状态变化、供体特异性抗体(DSA)产生、C4d水平和组织病理学改变。两种慢性排斥反应模型表现出临床慢性移植物排斥反应的共同特征,如皮肤狭窄、脱发、附件萎缩、广泛纤维化和肥大细胞浸润,而无急性排斥反应中常见的广泛坏死变化。与慢性排斥反应患者相似,在受体免疫系统中检测到大量活化的B细胞和浆细胞,同时DSA产生和C4d水平增加。总体而言,我们的模型密切复制了VCA后慢性移植物排斥反应的免疫学和组织病理学方面,并可为临床评估前新型治疗干预措施的评估提供新平台。

https://cdn.ncbi.nlm.nih.gov/pmc/blobs/eb6a/12081738/3345049d52c4/41598_2025_1803_Fig1_HTML.jpg

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