Steroid resistance: Experimental Autoimmune Encephalomyelitis/Multiple Sclerosis

描述（由申请方提供）：糖皮质激素（GC）仍然是急性MS发作的主要治疗方法。然而，同样清楚的是，GC不能预防MS复发和疾病进展，并且似乎对患者中对髓鞘抗原的长期T细胞应答几乎没有影响。类似地，GC治疗有效地下调啮齿动物中的EAE，但未能防止随后的复发。重要的是，GC不能抑制炎症部位T细胞的增殖和细胞因子产生，这在CMS中可能特别相关，其中包括神经元在内的许多细胞类型中的MIF表达可能有助于这一观察结果。我们自己的初步数据和Powell及其同事最近的一份报告强烈支持EAE中MIF和糖皮质激素之间的联系。我们发现，Wt小鼠在地塞米松治疗终止后表现出EAE加重和疾病复发，但MIF-/-小鼠没有。此外，EAE在用糖皮质激素受体抑制剂米非司酮（RU-486）治疗的MIF-/-小鼠中显著加重。此外，髓鞘特异性T细胞的频率和功能性亲和力下降时，在体内用抗MIF抗体中和MIF。基于这些结果和文献，MIF极有可能干扰GC介导的免疫抑制、诱导凋亡和/或炎性细胞迁移至CMS。该提议将检验以下假设：MIF通过反调节糖皮质激素对T细胞和巨噬细胞凋亡、效应器功能和CMS迁移的免疫抑制作用来促进EAE。这一假设将通过以下具体目标进行检验：目标1。探讨MIF对EAE中糖皮质激素介导的致脑炎性T细胞和APC凋亡的影响。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起反调节作用。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.