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*
Experimental Neuroimmunotherapy Unit, Department of Biotechnology, and
Department of Neurology, San Raffaele Scientific Institute, Milan, Italy;
Roche Milano Ricerche, Milan, Italy;
§
Department of Neurology, Casa Sollievo della Sofferenza Scientific Institute, San Giovanni Rotondo (FG), Italy;
¶
Howard Huges Medical Institute, Yale University School of Medicine, New Haven, CT 06510; and
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Vertex Pharmaceuticals, Inc., Cambridge, MA 02139
T cell-mediated inflammation is considered to play a key role in
the pathogenic mechanisms sustaining multiple sclerosis (MS).
Caspase-1, formerly designated IL-1ß-converting enzyme, is crucially
involved in immune-mediated inflammation because of its pivotal role in
regulating the cellular export of IL-1ß and IL-18. We studied the
role of caspase-1 in experimental autoimmune encephalomyelitis (EAE),
the animal model for MS. Caspase-1 is transcriptionally induced during
EAE, and its levels correlate with the clinical course and
transcription rate of proinflammatory cytokines such as TNF-
,
IL-1ß, IFN-
, and IL-6. A reduction of EAE incidence and severity
is observed in caspase-1-deficient mice, depending on the
immunogenicity and on the amount of the encephalitogenic myelin
oligodendrocyte glycoprotein (MOG) peptide used. In caspase-1-deficient
mice, reduced EAE incidence correlates with defective development of
anti-MOG IFN--producing Th1 cells. Finally, pharmacological
blockade of caspase-1 in Biozzi AB/H mice, immunized with spinal cord
homogenate or MOG35–55 peptide, by the caspase-1-inhibitor
Z-Val-Ala-DL-Asp-fluoromethylketone,
significantly reduces EAE incidence in a preventive but not in a
therapeutic protocol. These results indicate that caspase-1 plays an
important role in the early stage of the immune-mediated inflammatory
process leading to EAE, thus representing a possible therapeutic target
in the acute phase of relapsing remitting MS.
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