Morin Florence, Kavian Niloufar, Marut Wioleta, Chéreau Christiane, Cerles Olivier, Grange Philippe, Weill Bernard, Nicco Carole, Batteux Frédéric
INSERM U 1016, Institut Cochin, Université Paris Descartes Sorbonne Paris Cité, Faculté de Médecine, Paris, France; Laboratoire d'Immunologie biologique, Hôpital Cochin, AP-HP, Paris, France.
INSERM U 1016, Institut Cochin, Université Paris Descartes Sorbonne Paris Cité, Faculté de Médecine, Paris, France.
J Invest Dermatol. 2015 Oct;135(10):2385-2393. doi: 10.1038/jid.2015.174. Epub 2015 May 4.
Chronic graft-versus-host disease (GVHD) follows allogeneic hematopoietic stem cell transplantation. It results from alloreactive processes induced by minor histocompatibility antigen incompatibilities leading to the activation of CD4 T cells and the development of fibrosis and inflammation of the skin and visceral organs and autoimmunity that resemble systemic sclerosis. EGFR is a ubiquitous cell receptor deeply involved in cell proliferation, differentiation, and motility. EGFR has recently been implicated in autoimmune and fibrotic diseases. Therefore, we tested whether Erlotinib, an EGFR tyrosine kinase inhibitor, can prevent sclerodermatous GVHD (Scl-GVHD). Scl-GVHD was induced in BALB/c mice by B10.D2 bone marrow and spleen cell transplantation. Transplanted mice displayed severe clinical symptoms including alopecia, fibrosis of the skin and visceral organs, vasculitis, and diarrhea. The symptoms were reversed in mice treated with Erlotinib. These beneficial effects were mediated by the decreased production of activated/memory CD4(+) T cells and the reduction in T-cell infiltration of the skin and visceral organs along with a decrease in IFN-γ and IL-13 production and autoimmune B-cell activation. The improvement provided by Erlotinib in the mouse model of Scl-GVHD supplies a rationale for the evaluation of Erlotinib in the management of patients affected by chronic GVHD.
慢性移植物抗宿主病（GVHD）发生于异基因造血干细胞移植后。它是由次要组织相容性抗原不相容性诱导的同种异体反应过程导致的，会引发CD4 T细胞活化，进而出现皮肤和内脏器官的纤维化、炎症以及类似系统性硬化症的自身免疫反应。表皮生长因子受体（EGFR）是一种广泛存在的细胞受体，深度参与细胞增殖、分化和运动过程。最近研究表明EGFR与自身免疫性疾病和纤维化疾病有关。因此，我们测试了表皮生长因子受体酪氨酸激酶抑制剂厄洛替尼是否能够预防硬皮病样移植物抗宿主病（Scl-GVHD）。通过将B10.D2骨髓和脾细胞移植到BALB/c小鼠体内来诱导Scl-GVHD。移植后的小鼠出现了严重的临床症状，包括脱发、皮肤和内脏器官纤维化、血管炎以及腹泻。而用厄洛替尼治疗的小鼠症状得到了缓解。这些有益效果是通过减少活化/记忆CD4(+) T细胞的产生、降低皮肤和内脏器官的T细胞浸润，同时减少IFN-γ和IL-13的产生以及自身免疫性B细胞活化来实现的。厄洛替尼在Scl-GVHD小鼠模型中所带来的改善为评估其在慢性移植物抗宿主病患者治疗中的应用提供了理论依据。
