Partial inhibition of AT-EAE by an antibody to ICAM-1: clinico-histological and MRI studies.

The role of quantitative proton magnetic resonance imaging (MRI) for the evaluation of immunopathological lesions in the CNS was studied in adoptively transferred experimental allergic encephalomyelitis (AT-EAE). We utilized a recently established treatment model, inhibition of the cell adhesion molecule ICAM-1 by the monoclonal antibody 1A-29. The animals were scanned on days 3, 5 and 7 after injection of encephalitogenic T-cells, before and after bolus injection of Gd-DTPA by performing T1-measurements to assess the integrity of the blood-brain barrier (BBB). On day 7, immunohistochemistry was performed looking for T-cells, activated macrophages, and albumin staining. There was clinical evidence of partial inhibition of AT-EAE in rats treated with antibodies against ICAM-1. This finding was in line with a significantly reduced number of T-cells in the medulla. However, the number of activated macrophages and the distribution of albumin did not differ from untreated AT-EAE animals. The histological findings are in agreement with the MRI data before and after Gd-DTPA injection which were similar in treated and untreated AT-EAE rats on day 3 and 5. On day 7 after Gd-DTPA injection there was evidence of a delayed breakdown of the BBB in the treated rats. The observation of a dissociation of clinical and MRI findings, especially evidence of Gd-enhancement despite clinical improvement, may be important in the context of interpreting MRI studies in MS patients in treatment trials.

In vivo MRI and its histological correlates in acute adoptive transfer experimental allergic encephalomyelitis. Quantification of inflammation and oedema.

In vivo proton MRI was carried out on a 7 Tesla system at 2-3 day intervals over 10 days in rats with adoptive transfer experimental allergic encephalomyelitis (AT-EAE), an animal model of some aspects of multiple sclerosis. In order to assess the integrity of the blood-brain barrier (BBB), MRI was performed by acquiring quantitative MR-relaxation time T1 images of the AT-EAE rat brain before and after i.v. injection gadolinium-diethylene triaminepentaacetic acid (Gd-DTPA) using an ultrafast MRI technique. The MRI findings were compared with the immunohistochemical stain of T cells, macrophages and albumin and, in addition, apoptosis of T cells was assessed using in situ nick translation (ISNT). Prior to injection of Gd-DTPA, an increase of T1 times in the brain of the AT-EAE rats was observed, which paralleled the time course of albumin in histological sections. These were MRI findings observed well before the onset of major cellular infiltration and before the onset of clinical signs. After i.v. injection of Gd-DTPA the observed decrease of T1 times paralleled macrophage activation, and less closely T-cell infiltration. Our results provide evidence that using MRI, it is possible to assess quantitatively the breach of the BBB and to distinguish in vivo between two components of the early phase of the lesion, inflammatory infiltrates and vasogenic oedema.

Magnetic resonance imaging investigation of blood-brain barrier damage in adoptive transfer experimental autoimmune encephalomyelitis.

Recent advances in fast magnetic resonance imaging (MRI) techniques have allowed quantification of parameters such as T1 relaxation time, which can be modified by changes in the water content of a tissue. We have used this new method to study the evolution of blood-brain barrier (BBB) changes after adoptive transfer of MBP-specific (AT-EAE) and ovalbumin-specific T cell lines in Lewis rats. Measurable changes in T1 relaxation time suggesting widespread increase in BBB permeability were found, starting on day 3 post inoculation (p.i.), in the midbrain and brainstem of AT-EAE rats. In addition, we noted a significant decrease in T1 relaxation time before injection of a paramagnetic agent, in the cisternal cerebrospinal fluid (CSF) of diseased animals, starting on day 5 p.i. In vitro measurement of T1 in CSF containing various concentrations of albumin, IgM and glucose showed that, at physiological concentrations, a T1 decrease is mainly associated with an increase in albumin concentration. A moderate increase in BBB and blood-CSF barrier permeability was found as early as 4-8 h p.i., in rats injected with MBP-specific as in animals injected with ovalbumin-specific T cell lines, suggesting a non-specific mechanism. Experimental MRI may become a powerful tool to sequentially analyse changes in barrier dynamics, for example following pharmacological intervention.