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首页> 外文期刊>Journal of Neuroimmunology: Official Bulletin of the Research Committee on Neuroimmunology of the World Federation of Neurology >Lack of TIMP-1 increases severity of experimental autoimmune encephalomyelitis: Effects of darbepoetin alfa on TIMP-1 null and wild-type mice.
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Lack of TIMP-1 increases severity of experimental autoimmune encephalomyelitis: Effects of darbepoetin alfa on TIMP-1 null and wild-type mice.

机译：缺乏TIMP-1会增加实验性自身免疫性脑脊髓炎的严重程度：达贝泊汀α对TIMP-1无效和野生型小鼠的影响。

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Multiple sclerosis (MS) and experimental autoimmune encephalomyelitis (EAE) are both characterized by the infiltration of myelin-reactive T cells that trigger oligodendrocyte death associated with axonal loss and neurodegeneration in the CNS. Proteolysis of the cerebral vascular extracellular matrix (ECM) resulting in blood-brain barrier (BBB) breakdown is thought to facilitate infiltration of autoreactive T cells in both of these demyelinating disorders. Increased matrix metalloprotease (MMP) activity coupled with reduced levels of tissue inhibitor of metalloproteases (TIMPs) contribute to a loss of BBB integrity. Erythropoietin induces expression of TIMP-1 in endothelial cells suggesting this property may account in part for its ability to maintain BBB integrity and efficacy in a preliminary clinical MS trial. Consistent with this hypothesis, we report here that administration of the erythropoietin analogue darbepoetin alfa at a low dose that did not elevate hematocrit reduced EAE severity in female C57BL/6 mice when administered following the onset of clinical signs. The protective effects of darbepoetin alfa were associated with an increase in the number of astrocytes expressing TIMP-1 in the brain and spinal cord. In keeping with a central role for TIMP-1 in this autoimmune model of acute demyelination, TIMP-1 null mice displayed a more severe EAE phenotype than wild-type littermates. Interestingly, we observed a lack of effect of darbepoetin alfa on EAE severity in TIMP-1 null mice. These findings indicate that TIMP-1 deficiency both enhances disease severity and attenuates the beneficial effects of low dose darbepoetin alfa in a mouse model of EAE.
机译：多发性硬化症（MS）和实验性自身免疫性脑脊髓炎（EAE）均以髓鞘反应性T细胞浸润为特征，这些细胞会触发少突胶质细胞死亡，并与中枢神经系统中的轴突丢失和神经变性相关。人们认为，脑血管细胞外基质（ECM）的蛋白水解会导致血脑屏障（BBB）分解，从而促进这两种脱髓鞘疾病中自身反应性T细胞的浸润。基质金属蛋白酶（MMP）活性增强，金属蛋白酶（TIMPs）组织抑制剂水平降低，导致BBB完整性下降。促红细胞生成素诱导内皮细胞中TIMP-1的表达，提示该特性可能部分解释了其在一项初步的临床MS试验中维持BBB完整性和功效的能力。与该假设一致，我们在此报告，在临床症状发作后给予雌性C57BL / 6小鼠时，以不升高血细胞比容的低剂量施用促红细胞生成素类似物darbepoetin alfa可以降低EAE严重程度。 darbepoetin alfa的保护作用与脑和脊髓中表达TIMP-1的星形胶质细胞数量增加有关。为了保持TIMP-1在这种急性脱髓鞘的自身免疫模型中的重要作用，与野生型同窝仔相比，TIMP-1无效小鼠表现出更严重的EAE表型。有趣的是，我们观察到在TIMP-1缺失小鼠中达比泊汀α对EAE严重程度缺乏影响。这些发现表明TIMP-1缺乏症在EAE小鼠模型中既增加了疾病的严重性又减弱了低剂量达比泊汀α的有益作用。

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