Division of Oncology, Section of Leukemia and Stem Cell Transplantation, Department of Medicine, Washington University School of Medicine, St. Louis, MO, United States.
Division of Dermatology, Department of Medicine, Washington University School of Medicine, St. Louis, MO, United States.
Front Immunol. 2023 Sep 6;14:1264496. doi: 10.3389/fimmu.2023.1264496. eCollection 2023.
Solid organ transplant represents a potentially lifesaving procedure for patients suffering from end-stage heart, lung, liver, and kidney failure. However, rejection remains a significant source of morbidity and immunosuppressive medications have significant toxicities. Janus kinase (JAK) inhibitors are effective immunosuppressants in autoimmune diseases and graft versus host disease after allogeneic hematopoietic cell transplantation. Here we examine the role of JAK inhibition in preclinical fully major histocompatibility mismatched skin and heart allograft models. Baricitinib combined with cyclosporine A (CsA) preserved fully major histocompatibility mismatched skin grafts for the entirety of a 111-day experimental period. In baricitinib plus CsA treated mice, circulating CD4T-bet T cells, CD8T-bet T cells, and CD4FOXP3 regulatory T cells were reduced. Single cell RNA sequencing revealed a unique expression profile in immune cells in the skin of baricitinib plus CsA treated mice, including decreased inflammatory neutrophils and increased CCR2 macrophages. In a fully major histocompatibility mismatched mismatched heart allograft model, baricitinib plus CsA prevented graft rejection for the entire 28-day treatment period compared with 9 days in controls. Our findings establish that the combination of baricitinib and CsA prevents rejection in allogeneic skin and heart graft models and supports the study of JAK inhibitors in human solid organ transplantation.
实体器官移植为患有终末期心力衰竭、肺病、肝病和肾病的患者提供了一种潜在的救生程序。然而，排斥反应仍然是发病率的一个重要来源，免疫抑制药物具有显著的毒性。Janus 激酶 (JAK) 抑制剂在自身免疫性疾病和同种异体造血细胞移植后的移植物抗宿主病中是有效的免疫抑制剂。在这里，我们研究了 JAK 抑制在临床前完全主要组织相容性不合的皮肤和心脏同种异体移植模型中的作用。巴利昔替尼联合环孢素 A (CsA) 在 111 天的实验期间完全保留了完全主要组织相容性不合的皮肤移植物。在巴利昔替尼加 CsA 治疗的小鼠中，循环 CD4T-bet T 细胞、CD8T-bet T 细胞和 CD4FOXP3 调节性 T 细胞减少。单细胞 RNA 测序揭示了巴利昔替尼加 CsA 治疗的小鼠皮肤中免疫细胞的独特表达谱，包括炎症性中性粒细胞减少和 CCR2 巨噬细胞增加。在完全主要组织相容性不合的心脏同种异体移植模型中，巴利昔替尼加 CsA 与对照组的 9 天相比，可预防整个 28 天治疗期间的移植物排斥反应。我们的研究结果表明，巴利昔替尼和 CsA 的联合使用可预防同种异体皮肤和心脏移植物排斥反应，并支持在人类实体器官移植中研究 JAK 抑制剂。
