A preclinical acute GVHD mouse model based on chemotherapy conditioning and MHC-matched transplantation
A preclinical acute GVHD mouse model based on chemotherapy conditioning and MHC-matched transplantation
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DOI：
10.1038/bmt.2015.279
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发表时间：
2016-03-01
影响因子：
4.8
通讯作者：
Penack, O.
中科院分区：
文献类型：
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作者：
Riesner, K.;Kalupa, M.;Penack, O.
动物疾病模型因与人类疾病缺乏相似性而受到批评，阻碍了从临床前研究到临床医学的知识转移。在异基因造血干细胞移植（allo-HSCT）领域中，在基于致死性TBI的鼠模型中研究GVHD是标准实践。通常，MHC不匹配的供体用于GVHD模型。相比之下，在临床中，allo-HSCT预处理与化疗（+/- TBI）是常见的，并且供体通常是MHC匹配的。本研究针对临床需要，采用白消安和环磷酰胺预处理，建立了小鼠MHC相合、次要组织相容性抗原不相合的GVHD模型（LP/J [H2k（B）] -> C57 BL/6 [H2k（B）]）。我们发现了典型的急性GVHD的临床和组织学特征。T细胞浸润，GVHD特异性损伤和全身炎症与allo-HSCT后患者的观察结果相似。在急性GVHD的幸存者中，我们发现CD 4 + T细胞的扩增和硬皮病样慢性GVHD的发展。当研究allo-HSCT领域的临床相关问题时，使用基于化疗的、次要组织相容性抗原（miHA）不匹配的GVHD动物模型可能是一个很好的选择。
Animal disease models have been criticized for lack of resemblance to human illnesses, hampering transfer of knowledge from preclinical research to clinical medicine. In the field of allogeneic hematopoietic stem cell transplantation (allo-HSCT), it is standard practice to study GVHD in lethal TBI-based murine models. Frequently, MHC-mismatched donors are used in GVHD models. In contrast, in clinical allo-HSCT conditioning with chemotherapy (+/- TBI) is common and donors are often MHC-matched. Aiming at a more clinically oriented situation, we established and characterized a murine MHC-matched, minor histocompatibility antigen mismatched GVHD model (LP/J [H2k(b)] -> C57BL/6 [H2k(b)]) using busulfan and cyclophosphamide conditioning. We found typical clinical and histological features of acute GVHD. T-cell infiltration, GVHD-specific damage and systemic inflammation were similar to observations made in patients after allo-HSCT. In survivors of acute GVHD, we found expansion of CD4+ T cells and the development of scleroderma-like chronic GVHD. The use of chemotherapy-based, minor histocompatibility antigen (miHA)-mismatched GVHD animal models may be a good option when studying clinically relevant questions in the field of allo-HSCT.