Brain Advance Access originally published online on December 22, 2003
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Brain, Vol. 127, No. 3, 616-627, 2004
© 2004 Guarantors of Brain
doi: 10.1093/brain/awh068
Blood–brain barrier permeability and monocyte infiltration in experimental allergic encephalomyelitis
A quantitative MRI study
1 Department of Molecular Cell Biology, VU Medical Centre, Amsterdam, 2 Department of Experimental In Vivo NMR, Image Sciences Institute, University Medical Centre Utrecht, Utrecht, and 3 Department of Biomedical Engineering, Section of Biomedical NMR, Eindhoven University of Technology, Eindhoven, The Netherlands
Correspondence to: H. E. de Vries, Department of Molecular Cell Biology, VU Medical Center FdG, P.O. Box 7057, 1007 Mbyte Amsterdam, The Netherlands E-mail: he.devries{at}vumc.nl
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.
Key Words: blood–brain barrier; monocytes; multiple sclerosis; lovastatin; MRI
Abbreviations: BBB= blood brain barrier; CFA = complete Freund’s adjuvant; EAE = experimental allergic encephalomyelitis; Gd-DTPA = gadolinium diethylenetriaminepenta-acetate; i.p. = intraperitoneally; i.v. = intravenously; MBP = myelin basic protein; NMR = nuclear magnetic resonance; PBS = phosphate-buffered saline; ROI = region of interest; TCR = T-cell receptor; USPIO = ultra small particles of iron oxide
Received July 24, 2003. Revised October 29, 2003. Accepted October 31, 2003.
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