Establishment of a novel IFN therapy with little side effects

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Our identified IFN-ζ/Limitin has similar anti-viral and immunomoduratory activities to IFN-a. However, IFN-ζ/Limitin failed to suppress colony formation of CFU-GM, BFU-E, and CFU-Meg. Although less myelo-suppressive property may suggest wide range of clinical utility of IFN-ζ/Limitin, human homologue of IFN-ζ/Limitin has not been identified yet. There are unique amino acid residues in receptor-binding sites of IFN-ζ/Limitin when compared with IFN-α and IFN-β. To identify responsible amino acid residues for the different biological activities between IFN-t/Lmitin and IFN-α, we constructed several mutated IFN-α (ml-m7-IFN-a) whose amino acid residues were substituted by those of IFN-ζ/Limitin, and compared biological activities of the mutated IFN-as with those of original IFN-α. m3-IFN-α carrying three amino acids substitution in the AB loop has revealed less suppressive effects on colony formation of CFU-GM and BFU-E, while it has similar anti-viral activity to IFN-α. Little myelo-suppr … More essive property of m3-IFN-α was also confirmed by the injection to mice. On the other hand, ml-IFN-α carrying four amino acids substitution in the herix C has revealed higher anti-viral activity than original IFN-α. The other mutated IFN-αs lost both anti-viral and myelo-suppressive activities. These results are useful to construct a novel human IFN, which has IFN-ζ/Limitin-like characters.We have analyzed IFN-signals, which mediate myelo-suppressive activities, and have clarified essential roles of Tyk2 and Daxx. Reduction of protein expression of Tyk2 and/or Daxx by antisense oligonucleotides resulted in lack of myelo-suppressive activities of IFN-α. In addition, a sumoylation-defective Daxx KA mutant (Daxx K630/631A) localized in the cytoplasm, whereas wild-type Daxx localized in the nucleus. Murine pro-B cell line Ba/F3 expressing Daxx KA revealed a resistance to IFN-induced growth suppression, indicating the important role of sumoylation of Daxx in IFN-induced myelo-suppression. These results are useful to design a strategy for the IFN-therapy. Less