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Establishing a mouse model for ICE Fever, a novel autoinflammatory syndrome associated with procaspase-1 mutations

Final Report Summary - MODEL FOR ICE FEVER (Establishing a mouse model for ICE Fever, a novel autoinflammatory syndrome associated with procaspase-1 mutations)

Background. ICE fever is a rare human disease that is caused by loss of function mutations in the gene encoding pro-caspase 1 (aka ICE, interleukin 1 converting enzyme), the enzyme responsible for activation and release of IL-1beta. Clinically, it is characterized by chronic autoinflammation, manifesting as recurrent fevers, exanthema, increased inflammatory markers, and dysfunction of the musculoskeletal system. It has not been possible to rationally design treatment strategies for ICE fever because of the lack of understanding of its pathogenesis. The aim of the project was to generate a mouse model for ICE fever by establishing transgenic mice expressing pro-caspase 1 variants that recapitulate the effects of the mutations found in patients with ICE fever.

Results. A transgenic mouse line expressing the Casp1C284A allele, which destroys the active center of the enzyme, was generated with ET-cloning. Genetic characterisation confirmed the presence of the transgene in the absence and / or presence of a wild-type Casp1 allele. Preliminary experiments with this Casp1C284A line demonstrate that, while IL-1beta release is impaired as expected, mononuclear cells from these mice clearly possess a hyperinflammatory phenotype, as evidenced by increased release of IL-6 and TNF alpha after stimulation with LPS. A complete immunological characterization of these mice is underway.

Conclusions. A mouse model for ICE fever is being established. Once immunological characterization has been completed, this model will not only improve our understanding of the pathogenesis of ICE fever and related autoinflammatory disorders but also allow testing various hypothesis-based therapeutic interventions, which will likely include inhibition of IL-6 and TNF alpha. Improved treatments will benefit the afflicted individuals by improving their quality of life but also society at large by reducing days of work loss and health care expenses resulting from disease flares.