CCFC STUDENT PRIZE. THERAPEUTIC EFFICACY OF RECOMBINANT SOLUBLE IL-1RII (SIL-1RII) IN EXPERIMENTAL...

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CCFC STUDENT PRIZE. THERAPEUTIC EFFICACY OF RECOMBINANT SOLUBLE IL-1RII (sIL-1RII) IN EXPERIMENTAL CROHN’S DISEASE: A PRECLINICAL STUDY

G Fortin, C Collette, A Bitton, C Villani, T Gustot, A Van Gossum, J Deviere, E Louis, A Cohen, E Seidman, G Wild, D Franchimont
Department of Experimental Medicine, McGill University, Montreal, Quebec

Autoinflammation is the fundamental underlying process of chronic relapsing inflammatory diseases, such as Crohn’s disease (CD) and familial fever syndromes, and results from an impairment in IL-1b processing. NOD2 Knock-in mice for CD mutations demonstrate an altered processing of interleukin-1b (IL-1b) leading to an overwhelming mucosal production of IL-1b. We have recently identified sIL1-RII (an inhibitor of IL-1b processing) as a top corticosteroid-inducible gene with potent anti-inflammatory actions. In this study, we examined the regulation of sIL-1RII in CD, and the therapeutic efficacy of a recombinant sIL-1RII Fc chimera in trinitrobenzene sulfonic acid (TNBS) colitis.
METHODS: sIL-1RII levels were quantified by ELISA on serum samples taken from CD patients (cohort 1, n=50 and cohort 2, n=74) and healthy subjects (HS, n=15). Balb/c mice were given from 2.5 mg of TNBS/50% ethanol IR and treated with either 2 mg/kg of the recombinant sIL-1RII Fc fusion protein (n=12) or the Fc fragment alone (control) (n=9). Drug efficacy was determined by mortality, the Wallace criteria, myeloperoxidase (MPO) activity and by measuring cytokine production.
RESULTS: Phase 1: Circulating levels of sIL-1RII were significantly decreased in CD patients in remission (rCD) as compared with those of healthy subjects (HS) (16007 [9855-25507] vs 20073 [14537-28505] pg/mL; P<0.05). This decrease was even more pronounced in active CD (12516 [6270-23996] pg/mL) as compared with rCD (P<0.05) and HS (P<0.01). These results were confirmed in a cohort of patients who were followed prospectively. For those patients who relapsed, baseline sIL-1RII levels (median 15,216 [285-35,725] pg/mL) differed significantly (P<0.0001) from levels measured upon relapse (median 592 [115-2757] pg/mL). Phase 2: At the end of the five day experiment, sIL-1RII-treated mice displayed significant (P<0.05) improvements in all criteria, including: a greater percent body weight than control mice (87.4±4.4 vs 78.5±2.5), fewer mortalities (8% vs 34%), a lower Wallace score (6.3±4.1 vs 12.2±1.4), MPO activity (1.2±0.6 vs 2.7±0.5), serum levels of IL-1b (54.2±44.5 vs 122.5±82.3 pg/mL) and IL-6 (43.9±15.3 vs 123.3±63.5), and expression of IL-1b (3.6-fold, P<0.1) and IL-6 (8.4-fold, P<0.05).
CONCLUSION: The fusion protein Fc/sIL-1RII appears to be an effective therapy in experimental CD that could compensate for the relative deficiency of endogenous sIL-1RII in CD patients.

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