Active immunisation of human interferon alpha transgenic mice with a human interferon alpha Kinoid induces antibodies that neutralise interferon alpha in sera from patients with systemic lupus erythematosus.

摘要

OBJECTIVES: Interferon alpha (IFNalpha) plays a central role in the pathogenesis of systemic lupus erythematosus (SLE) and is considered a target for its treatment. In the current study, the ability of active immunisation with a human (hu) IFNalpha2b Kinoid (IFN-K) to break B cell tolerance to IFNalpha and to induce huIFNalpha-neutralising antibodies in mice immunotolerant to huIFNalpha2b was assessed. METHODS: IFN-K was manufactured by crosslinking huIFNalpha2b to keyhole limpet haemocyanin (KLH). Transgenic mice expressing huIFNalpha2b received by intramuscular injection either saline or polymerised huIFNalpha2b as controls, or IFN-K, emulsified in ISA51vg adjuvant. RESULTS: All of the huIFNalpha2b-expressing mice immunised with IFN-K generated neutralising antibodies against huIFNalpha2b. In addition, these antibodies neutralised all 13 subtypes of huIFNalpha. They also neutralised IFNalpha activity in sera collected from 10 different patients with active SLE. However, the antibodies did not bind to huIFNgamma or huIFNbeta. Finally, cellular activation assays showed that immunisation with IFN-K did not induce memory T cells reactive to native huIFNalpha2b, whereas it did induce memory cells reactive to KLH. CONCLUSION: These results show that active immunisation with IFN-K induces polyclonal antibodies that neutralise all subtypes of huIFNalpha as well as IFNalpha in sera from patients with SLE by breaking humoral but not cellular tolerance to IFNalpha. This suggests that immunisation with IFN-K is a promising new therapeutic strategy for the treatment of SLE.