Fujiwara Mai, Anstadt Emily J, Khanna Kamal M, Clark Robert B
Department of Immunology, University of Connecticut Health Center, Farmington, CT 06032, USA.
Department of Immunology, University of Connecticut Health Center, Farmington, CT 06032, USA; Department of Medicine, University of Connecticut Health Center, Farmington, CT 06032, USA.
Clin Immunol. 2015 May;158(1):103-13. doi: 10.1016/j.clim.2015.03.018. Epub 2015 Mar 28.
The variable response to therapy in multiple sclerosis (MS) suggests a need for personalized approaches based on individual genetic differences. GWAS have linked CBLB gene polymorphisms with MS and recent evidence demonstrated that these polymorphisms can be associated with abnormalities in T cell function and response to interferon-β therapy. Cbl-b is an E3 ubiquitin ligase that regulates T cell activation and Cbl-b-deficient (Cbl-b(-/-)) mice show T cell abnormalities described in MS patients. We now show that Cbl-b(-/-) T cells demonstrate significant lymph node trafficking abnormalities. We thus asked whether the MS-approved drug, FTY720, postulated to trap T cells in lymphoid tissues, is less effective in the context of Cbl-b dysfunction. We now report that FTY720 significantly inhibits EAE in Cbl-b(-/-) mice. Our results newly document a role for Cbl-b in T cell trafficking but suggest nevertheless that MS patients with Cbl-b abnormalities may still be excellent candidates for FTY720 treatment.
多发性硬化症（MS）患者对治疗的反应存在差异，这表明需要基于个体基因差异采取个性化治疗方法。全基因组关联研究（GWAS）已将CBLB基因多态性与MS联系起来，最近有证据表明，这些多态性可能与T细胞功能异常以及对干扰素-β治疗的反应有关。Cbl-b是一种E3泛素连接酶，可调节T细胞活化，而Cbl-b基因缺陷（Cbl-b(-/-)）小鼠表现出MS患者中所描述的T细胞异常。我们现在发现，Cbl-b(-/-) T细胞表现出明显的淋巴结归巢异常。因此，我们提出疑问，MS批准药物FTY720被认为可将T细胞滞留在淋巴组织中，在Cbl-b功能障碍的情况下其效果是否会降低。我们现在报告，FTY720可显著抑制Cbl-b(-/-)小鼠的实验性自身免疫性脑脊髓炎（EAE）。我们的结果首次证明了Cbl-b在T细胞归巢中的作用，但同时也表明，Cbl-b异常的MS患者仍可能是FTY720治疗的理想候选者。
