Hansen Max, Stahl Lilly, Heider Andreas, Hilger Nadja, Sack Ulrich, Kirschner Andreas, Cross Michael, Fricke Stephan
Vita 34 AG, Leipzig, Germany; Institute of Clinical Immunology, Medical Faculty, University of Leipzig, Leipzig, Germany.
Tcell Tolerance GmbH, Leipzig, Germany; Fraunhofer Institute for Cell Therapy and Immunology, Leipzig, Germany.
Transplant Cell Ther. 2021 Aug;27(8):658.e1-658.e10. doi: 10.1016/j.jtct.2021.04.018. Epub 2021 May 5.
Graft-versus-host disease (GVHD) is one of the major complications following hematopoietic stem cell transplantation, which remains the sole curative therapy for many malignant diseases of the hematopoietic system. The immunomodulatory potential of mesenchymal stromal cells (MSCs) to treat GVHD is currently being tested in various preclinical and clinical trials. Because the results of the preclinical and clinical trials on the use of MSCs to treat GVHD have not been consistent, we analyzed the potential beneficial effects of syngeneic versus allogenic treatment, culture expansion of MSCs, and various MSC cell doses and time points of MSC transplantation in a murine GVHD model. We established the murine GVHD model based on the transplantation of umbilical cord blood-derived hematopoietic stem cells (UC-HSCs) and used this model to assess the therapeutic potential of umbilical cord blood-derived MSCs (UC-MSCs). The use of HSC and MSC populations derived from the same donor allowed us to exclude third-party cells and test the UC-HSCs and UC-MSCs in a matched setting. Moreover, we were able to compare various doses, transplantation time points, and the influence of culture expansion of MSCs on the impact of treatment. This resulted in 16 different treatment groups. The most efficient setting for treatment of UC-HSC-induced GVHD reactions was based on the simultaneous administration of 1 × 10 culture-expanded, syngeneically matched UC-MSCs. This therapy effectively reduced the number of CD8 T cells in the blood, protected the mice from weight loss, and prolonged their survival until the end of observation period. Taken together, our data show beneficial effects of (1) syngeneic over allogeneic UC-HSCs and UC-MSCs, (2) culture-expanded cells over freshly isolated primary cells, (3) simultaneous over sequential administration, and (4) high doses of UC-MSCs. The animal model of GVHD established here is now available for more detailed studies, including a comparative analysis of the efficacy of MSCs derived from alternative sources, such as adipose tissue and bone marrow.
移植物抗宿主病（GVHD）是造血干细胞移植后的主要并发症之一，造血干细胞移植仍是许多造血系统恶性疾病的唯一治愈性疗法。间充质基质细胞（MSCs）治疗GVHD的免疫调节潜力目前正在各种临床前和临床试验中进行测试。由于使用MSCs治疗GVHD的临床前和临床试验结果并不一致，我们在小鼠GVHD模型中分析了同基因与异基因治疗、MSCs的培养扩增、不同MSC细胞剂量以及MSC移植时间点的潜在有益效果。我们基于脐带血来源的造血干细胞（UC-HSCs）移植建立了小鼠GVHD模型，并使用该模型评估脐带血来源的MSCs（UC-MSCs）的治疗潜力。使用来自同一供体的HSC和MSC群体使我们能够排除第三方细胞，并在匹配的环境中测试UC-HSCs和UC-MSCs。此外，我们能够比较不同剂量、移植时间点以及MSCs培养扩增对治疗效果的影响。这产生了16个不同的治疗组。治疗UC-HSC诱导的GVHD反应的最有效方案是同时给予1×10个经培养扩增的、同基因匹配的UC-MSCs。这种疗法有效地减少了血液中CD8 T细胞的数量，保护小鼠免于体重减轻，并延长了它们的生存期直至观察期结束。综上所述，我们的数据显示了以下有益效果：（1）同基因的UC-HSCs和UC-MSCs优于异基因的；（2）经培养扩增的细胞优于新鲜分离的原代细胞；（3）同时给药优于序贯给药；（4）高剂量的UC-MSCs。这里建立的GVHD动物模型现在可用于更详细的研究，包括对来自替代来源（如脂肪组织和骨髓）的MSCs疗效的比较分析。
