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Voltage-gated potassium channels (Kv channels) are ion channels, openings of which provide an outward flow of potassium ions repolarising the cell. In neurons, Kv channels play a crucial role in action potential repolarisation and in shaping neuronal excitability. In non-excitable cells, such as T lymphocytes, Kv channels and calcium-activated K+ channels (KCa channels) determine the driving force for Ca2+ entry. During T cell activation the calcium entry depolarises the cell and increases the cytosolic calcium concentration, which in return activates Kv and KCa channels. K+ channel opening repolarises the cell and drives the membrane potential to a negative voltage. The roles of Kv channels in nervous and immune systems have been investigated here by means of a rat experimental autoimmune disease of the central nervous system, the experimental autoimmune encephalomyelitis (EAE). EAE is characterised clinically by paralysis, and pathologically by inflammatory cell infiltrations into the brain and the spinal cord. Among the inflammatory cells, T lymphocytes play a major role. Hence, EAE can be adoptively transferred into syngenic animals by the injection of T cells reactive to myelin antigens. During adoptive-EAE, somato-sensory evoked potentials recorded along the spinal tracts decrease in amplitude and axonal propagation is disrupted. We have analysed the consequences of Kv channels blockade by peptidyl toxins on central nerve conduction, on T cell activation and on the time course of EAE. In rat optic nerves, Kv channels have been identified up from postnatal day 1. Their blockade by kaliotoxin (a scorpion toxin) or by dendrotoxin-I (a snake toxin) enlarges the compound action potentials, demonstrating the participation of Kv channels to spike repolarisation. This effect disappears at adult age due to the sequestration of Kv channels under the myelin, in the paranodal regions. During acute demyelination by lysophosphatidyl-choline, the surface area of compound action potential decreased probably because conduction block occurred. Demyelination unmasked Kv channels, which are again accessible to toxins. Their blockade by dendrotoxin-I or kaliotoxin favoured a slow delayed conduction suggesting that those Kv channel blockers exert a neurological benefit during demyelinating diseases. In a T-cell line reactive to myelin basic protein antigen, which is used to adoptively transfer experimental autoimmune encephalomyelitis, Kv1.3 channels are constitutively expressed. Their blockade leads to a pronounced reduction of the T cell proliferative response, cytokine production and Ca2+ influx. In the rat, blockade of Kv1.3 inhibits the delayed type hypersensitivity response to myelin basic protein prevents and treats adoptive experimental autoimmune encephalomyelitis. Blockade of Kv channels alone or in combination with KCa channels improves the symptoms of the disease. These results demonstrate that K+ channel blockers displaying high selectivity are potent immunosuppressive agents with beneficial symptomatic effects in experimental autoimmune encephalomyelitis.

Experimental autoimmune encephalomyelitis is an induced inflammatory and demyelinating disease of the central nervous system widely used as an animal model for multiple sclerosis. New insights into its pathophysiology have been possible due to recent immunological concepts. New therapeutical approaches have been designed and tested in experimental autoimmune encephalomyelitis and are now entering the clinical setting.

Nuclear magnetic resonance imaging (MRI) proved to be, from the first, a very sensitive method, allowing the visualisation of multiple sclerosis lesions, yet which never permitted to establish a non equivocal relationship between the semeiology of such lesions and the clinical signs. The multifocal aspect of disseminated multiple sclerosis lesions is probably one of several factors accounting for this discrepancy. The study of an autoimmune disease, experimental allergic encephalomyelitis (EAE), regarded as a suitable model for multiple sclerosis in humans, has been performed using MRI in order to unravel the pathogenesis of the disease and apprehend the mechanisms responsible for the formation of multiple sclerosis lesions. The study focused on the part played by the blood-brain barrier (BBB) in the induction process of an autoimmune disease, since the central nervous system is normally screened from immunological supervision, by this barrier. Models both of acute EAE, induced by active or passive transfer of the antigen (myelin basic protein-MBP)--and chronic EAE, induced by passive transfer of MBP-specific T cells and myelin glycoproteins or MOG-specific monoclonal antibodies, have been reproduced, and their evolution followed up using high field MRI. Every time, the crucial role of the BBB was evidenced by the synchronism existing between the clinical signs, the appearance of lesions, preferentially in the most sensitive or permeable areas, and the BBB breakdown encouraged by the action of adjuvants. The physiopathological study of EAE using MRI is suggestive of the concept of systemic disease for multiple sclerosis, according to a two-step process, involving, in a first stage some primary viral or bacterial infection, causing T-cells to be sensitized to the host's own proteins by molecular mimicry, and in a second stage some bacterial infection or accidental circumstances which, resulting in a BBB breakdown, would provide immunocompetent cells with an opportunity to reach their target.