Steroid resistance: Experimental Autoimmune Encephalomyelitis/Multiple Sclerosis

描述（由申请人提供）：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不能预防MS复发和疾病进展，并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。同样，GC处理有效地下调啮齿类动物的EAE，但不能防止随后的复发。重要的是，GC不能抑制T细胞在炎症部位的增殖和细胞因子的产生，这可能与CMS特别相关，其中MIF在许多细胞类型（包括神经元）中的表达可能有助于这一观察结果。我们自己的初步数据和Powell及其同事最近的报告强烈支持MIF与EAE中糖皮质激素之间的联系。我们发现Wt小鼠在终止地塞米松治疗后EAE加重和疾病复发，但MIF-/-小鼠没有。此外，糖皮质激素受体抑制剂米非司酮（RU-486）治疗的MIF-/-小鼠EAE显著加重。此外，当MIF在体内被抗MIF抗体中和时，髓磷脂特异性T细胞的频率和功能亲和力降低。基于这些结果和文献，MIF极有可能干扰gc介导的免疫抑制、诱导细胞凋亡和/或炎症细胞向CMS的迁移。本课题将验证MIF通过拮抗糖皮质激素对T细胞和巨噬细胞凋亡、效应物功能和CMS迁移的免疫抑制作用促进EAE的假说。这一假设将通过以下具体目标进行检验：目的1。探讨MIF是否干扰糖皮质激素介导的EAE脑源性T细胞和APCs凋亡。目标2。确定MIF是否对EAE中糖皮质激素介导的T细胞效应功能的免疫抑制进行反调控。目标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.