Blood–brain barrier permeability and monocyte infiltration in experimental allergic encephalomyelitis

Abstract

Enhanced cerebrovascular permeability and cellular infiltration mark the onset of early multiple sclerosis lesions. So far, the precise sequence of these events and their role in lesion formation and disease progression remain unknown. Here we provide quantitative evidence that blood-brain barrier leakage is an early event and precedes massive cellular infiltration in the development of acute experimental allergic encephalomyelitis (EAE), the animal correlate of multiple sclerosis. Cerebrovascular leakage and monocytes infiltrates were separately monitored by quantitative in vivo MRI during the course of the disease. Magnetic resonance enhancement of the contrast agent gadolinium diethylenetriaminepentaacetate (Gd-DTPA), reflecting vascular leakage, occurred concomitantly with the onset of neurological signs and was already at a maximal level at this stage of the disease. Immunohistochemical analysis also confirmed the presence of the serum-derived proteins such as fibrinogen around the brain vessels early in the disease, whereas no cellular infiltrates could be detected. MRI further demonstrated that Gd-DTPA leakage clearly preceded monocyte infiltration as imaged by the contrast agent based on ultra small particles of iron oxide (USPIO), which was maximal only during full-blown EAE. Ultrastructural and immunohistochemical investigation revealed that USPIOs were present in newly infiltrated macrophages within the inflammatory lesions. To validate the use of USPIOs as a non-invasive tool to evaluate therapeutic strategies, EAE animals were treated with the immunomodulator 3-hydroxy-3-methylglutaryl Coenzyme A reductase inhibitor, lovastatin, which ameliorated clinical scores. MRI showed that the USPIO load in the brain was significantly diminished in lovastatin-treated animals. Data indicate that cerebrovascular leakage and monocytic trafficking into the brain are two distinct processes in the development of inflammatory lesions during multiple sclerosis, which can be monitored on-line with MRI using USPIOs and Gd-DTPA as contrast agents. These studies also implicate that USPIOs are a valuable tool to visualize monocyte infiltration in vivo and quantitatively assess the efficacy of new therapeutics like lovastatin.

Quantitative MRI‐pathology correlations of brain white matter lesions developing in a non‐human primate model of multiple sclerosis

“…Accordingly, the macrophage inflammation marker MF I , which reflects whether macrophages in the lesions express markers of active or inactive lesions, showed the highest correlation with MTR. Both in EAE models and MS patients, the presence of inflammatory cells, and particularly macrophages, has been associated with a reduction in MTR (29,(34)(35)(36), but also with an increase in T 1 relaxation time [or decrease in T 1 -weighted intensity, the so called 'black holes' (35,37,38)] and mainly with the presence of Gd-DTPA enhancement (37)(38)(39)(40)(41)(42)(43). However most studies are descriptive and in only a few studies could quantitative MRI data be correlated with (semi-) quantitative histological data.…”

Superparamagnetic Iron Oxide Nanoparticles in Biomedicine: Applications and Developments in Diagnostics and Therapy

“…In small animal models of MS (experimental autoimmune encephalomyelitis (EAE)), SPIO can be used to image macrophage activity [177] and infiltration [178], lymphocyte infiltration (CD3 + cells [179]) and the labeling of T-cells [180]. Also in the case of heart attack, numerous studies show that SPIO can image the accompanying neuroinflammation or the macrophage activity [181] and macrophage migration [182] similarly to the changes in MS.…”

Antioxidants and polyunsaturated fatty acids in multiple sclerosis

“…Several studies revealed statins to ameliorate clinical signs of disease in EAE (Stanislaus et al, 2002;Youssef et al, 2002;Greenwood et al, 2003;Floris et al, 2004). The cholesterollowering effect of statins is regulated through inhibition of b-hydroxy-b-methylglutaryl-CoA (HMG-CoA) reductase.…”

“…Statins may also inhibit T-cell entry into the CNS, inhibit T-cell activation and suppress secretion of numerous inflammatory mediators. Moreover, lovostatin treatment of EAE rats inhibits macrophage infiltration (Floris et al, 2004) and simvastatin treatment is beneficial in relapsing-remitting MS (Vollmer et al, 2004). Statins may be of therapeutic interest since they can be given orally with a very good safety record (Polman & Uitdehaag, 2003).…”