Steroid resistance: Experimental Autoimmune Encephalomyelitis/Multiple Sclerosis

描述(申请人提供)：糖皮质激素(GC)仍然是治疗急性MS发作的主要药物。然而，同样清楚的是，GC不能防止MS的复发和疾病的进展，而且似乎对患者对髓鞘抗原的长期T细胞反应几乎没有影响。类似地，GC治疗有效地下调了啮齿动物的EAE，但无法防止随后的复发。重要的是，GC不能抑制炎症部位T细胞的增殖和细胞因子的产生，这可能与CMS特别相关，因为MIF在包括神经元在内的多种细胞类型中的表达可能有助于这一观察。我们自己的初步数据和Powell及其同事最近的一份报告有力地支持了EAE中MIF和糖皮质激素之间的联系。我们发现，停止地塞米松治疗后，Wt小鼠表现出EAE的恶化和复发，但MIF-/-小鼠没有。此外，在用糖皮质激素受体抑制剂米非司酮(RU-486)治疗的MIF-/-小鼠中，EAE显著恶化。此外，当在体内用抗MIF抗体中和MIF时，髓鞘特异性T细胞的频率和功能亲和力降低。根据这些结果和文献，MIF很可能干扰GC介导的免疫抑制、诱导细胞凋亡和/或炎性细胞向CMS的迁移。这项提议将验证这样的假设：MIF通过反向调节糖皮质激素对T细胞和巨噬细胞凋亡、效应功能和CMS迁移的免疫抑制效应来促进EAE。这一假说将通过以下特定目的进行验证：目的1.确定MIF是否干扰EAE中糖皮质激素介导的脑源性T细胞和APC的凋亡。目的2.确定MIF是否对糖皮质激素介导的免疫抑制在EAE中的T细胞效应功能起到反调节作用。目的3.探讨MIF干预细胞凋亡的机制。

DESCRIPTION (provided by applicant): Glucocorticoids (GC) remain the mainstay of therapy for acute MS episodes. However, it is also clear that GC fail to prevent MS relapses and disease progression, and appear to have little effect on long-term T cell responses to myelin antigens in patients. Similarly, GC treatment efficiently down-regulates EAE in rodents, but fails to prevent subsequent relapses. Importantly, GC fail to inhibit proliferation and cytokine production by T cells at inflammatory sites, which could be particularly relevant in the CMS where expression of MIF in a number of cell types including neurons could contribute to this observation. Our own preliminary data and a recent report by Powell and colleagues strongly support a link between MIF and glucocorticoids in EAE. We found that Wt mice show exacerbation of EAE and relapsing disease upon termination of Dexamethasone treatment, but not MIF-/- mice. Furthermore, EAE is substantially exacerbated in MIF-/- mice treated with the glucocorticoid receptor inhibitor Mifepristone (RU-486). Furthermore, the frequencies and functional avidity of myelin-specific T cells were decreased when MIF was neutralized in vivo with anti-MIF antibodies. Based on these results and the literature it is highly likely that MIF interferes with GC-mediated immunosuppression, induction of apoptosis, and/or migration of inflammatory cells to the CMS. This proposal will test the hypothesis that: MIF promotes EAE by counter-regulating the immunosuppressive effects of glucocorticoids on T cell and macrophage apoptosis, effector functions, and CMS migration. This hypothesis will be tested with the following specific aims: Aim 1. To determine whether MIF interferes with glucocorticoid-mediated apoptosis of encephalitogenic T cells and APCs in EAE. Aim 2. To determine whether MIF counter-regulates glucocorticoid-mediated immunosuppression of T cell effector functions in EAE. Aim 3. To determine the mechanism of MIF interference with apoptosis.