Wuerfel Jens, Tysiak Eva, Prozorovski Timour, Smyth Maureen, Mueller Susanne, Schnorr Joerg, Taupitz Matthias, Zipp Frauke
Cecilie-Vogt-Clinic for Molecular Neurology, Charité - University Medicine Berlin, and Max-Delbrueck-Center for Molecular Medicine, Germany.
Eur J Neurosci. 2007 Jul;26(1):190-8. doi: 10.1111/j.1460-9568.2007.05644.x. Epub 2007 Jun 26.
The value of experimental autoimmune encephalomyelitis (EAE), an animal model of multiple sclerosis, in deriving novel diagnostic and therapeutic input has been subject to recent debate. This study is the first to report a disseminated distribution of plaques including cranial nerves, prior to or at early stages of disease in murine adoptive transfer EAE, irrespective of the development of clinical symptoms. We induced EAE by adoptive proteolipid protein-specific T-cell transfer in 26 female SJL/J mice, and applied high-field-strength magnetic resonance imaging (MRI) scans longitudinally, assessing blood-brain barrier (BBB) disruption by gadopentate dimeglumine enhancement. We visualized inflammatory nerve injury by gadofluorine M accumulation, and phagocytic cells in inflamed tissue by very small anionic iron oxide particles (VSOP-C184). MRI was correlated with immunohistological sections. In this study, we discovered very early BBB breakdown of white and grey brain matter in 25 mice; one mouse developed exclusively spinal cord inflammation. Widely disseminated contrast-enhancing lesions preceded the onset of disease in 10 animals. Such lesions were present despite the absence of any clinical disease formation in four mice, and coincided with the first detectable symptoms in others. Cranial nerves, predominantly the optic and trigeminal nerves, showed signal intensity changes in nuclei and fascicles of 14 mice. At all sites of MRI lesions we detected cellular infiltrates on corresponding histological sections. The discrepancy between the disease burden visualized by MRI and the extent of disability indeed mimics the human clinico-radiological paradox. MRI should therefore be implemented into evaluational in vivo routines of future therapeutic EAE studies.
实验性自身免疫性脑脊髓炎（EAE）作为多发性硬化症的动物模型，其在提供新的诊断和治疗依据方面的价值近来备受争议。本研究首次报道，在小鼠过继性转移EAE中，无论临床症状是否出现，在疾病前期或早期阶段，斑块呈播散性分布，包括累及脑神经。我们通过过继性转移蛋白脂蛋白特异性T细胞，在26只雌性SJL/J小鼠中诱导EAE，并纵向应用高场强磁共振成像（MRI）扫描，通过钆喷酸葡胺增强来评估血脑屏障（BBB）破坏情况。我们通过钆弗显积聚观察炎性神经损伤，通过超顺磁性氧化铁纳米颗粒（VSOP-C184）观察炎症组织中的吞噬细胞。将MRI结果与免疫组织学切片进行对比。在本研究中，我们发现25只小鼠的脑白质和灰质出现了非常早期的血脑屏障破坏；1只小鼠仅出现脊髓炎症。10只动物在疾病发作前出现广泛播散的对比增强病变。在4只小鼠中，尽管没有任何临床疾病表现，但仍存在此类病变，而在其他小鼠中，此类病变与首次可检测到的症状同时出现。14只小鼠的脑神经，主要是视神经和三叉神经，在神经核和神经束中出现信号强度变化。在MRI病变的所有部位，我们在相应的组织学切片上检测到细胞浸润。MRI显示的疾病负担与残疾程度之间的差异确实类似于人类临床放射学悖论。因此，MRI应纳入未来治疗性EAE研究的体内评估常规流程。
