Division of Hematology and Oncology, Department of Medicine, Freiburg University Medical Center, Albert-Ludwigs-University, Freiburg, Germany.
Haematologica. 2013 Jan;98(1):31-40. doi: 10.3324/haematol.2012.065789. Epub 2012 Jul 16.
Despite advances in immunosuppressive regimens, acute graft-versus-host disease remains a frequent complication of allogeneic hematopoietic cell transplantation. Pathogenic donor T cells are dependent on correct attachment of small GTPases to the cell membrane, mediated by farnesyl- or geranylgeranyl residues, which, therefore, constitute potential targets for graft-versus-host disease prophylaxis. A mouse model was used to study the impact of a farnesyl-transferase inhibitor and a geranylgeranyl-transferase inhibitor on acute graft-versus-host disease, anti-cytomegalovirus T-cell responses and graft-versus-leukemia activity. Treatment of mice undergoing allogeneic hematopoietic cell transplantation with farnesyl-transferase inhibitor and geranylgeranyl-transferase inhibitor reduced the histological severity of graft-versus-host disease and prolonged survival significantly. Mechanistically, farnesyl-transferase inhibitor and geranylgeranyl-transferase inhibitor treatment resulted in reduced alloantigen-driven expansion of CD4 T cells. In vivo treatment led to increased thymic cellularity and polyclonality of the T-cell receptor repertoire by reducing thymic graft-versus-host disease. These effects were absent when squalene production was blocked. The farnesyl-transferase inhibitor and geranylgeranyl-transferase inhibitor did not compromise CD8 function against leukemia cells or reconstitution of T cells that were subsequently responsible for anti-murine cytomegalovirus responses. In summary, we observed an immunomodulatory effect of inhibitors of farnesyl-transferase and geranylgeranyl-transferase on graft-versus-host disease, with enhanced functional immune reconstitution. In the light of the modest toxicity of farnesyl-transferase inhibitors such as tipifarnib in patients and the potent reduction of graft-versus-host disease in mice, farnesyl-transferase and geranylgeranyl-transferase inhibitors could help to reduce graft-versus-host disease significantly without having a negative impact on immune reconstitution.
尽管免疫抑制方案有所进展，但急性移植物抗宿主病仍是异基因造血细胞移植的常见并发症。致病性供体细胞 T 细胞依赖于小 GTP 酶与细胞膜的正确附着，这由法呢基或香叶基残基介导，因此构成移植物抗宿主病预防的潜在靶点。使用小鼠模型研究法尼基转移酶抑制剂和香叶基转移酶抑制剂对急性移植物抗宿主病、抗巨细胞病毒 T 细胞反应和移植物抗白血病活性的影响。用法尼基转移酶抑制剂和香叶基转移酶抑制剂治疗正在接受异基因造血细胞移植的小鼠可降低移植物抗宿主病的组织学严重程度并显著延长存活时间。从机制上讲，法尼基转移酶抑制剂和香叶基转移酶抑制剂治疗可减少同种异体抗原驱动的 CD4 T 细胞扩增。体内治疗通过减少胸腺移植物抗宿主病来增加胸腺细胞的细胞性和 T 细胞受体库的多克隆性。当阻断角鲨烯产生时，这些作用不存在。法尼基转移酶抑制剂和香叶基转移酶抑制剂不会影响 CD8 对抗白血病细胞的功能或随后负责抗鼠巨细胞病毒反应的 T 细胞的重建。总之，我们观察到法尼基转移酶和香叶基转移酶抑制剂对移植物抗宿主病具有免疫调节作用，同时增强了功能性免疫重建。鉴于法尼基转移酶抑制剂（如 tipifarnib）在患者中的适度毒性和在小鼠中对移植物抗宿主病的强烈抑制作用，法尼基转移酶和香叶基转移酶抑制剂可以帮助显著减少移植物抗宿主病，而不会对免疫重建产生负面影响。
