Clinical application of limitin that has anti-tumor and anti-viral activity

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Limitin is an interferon (IFN)-like cytokine that has sequence homology with previously known type I IFNs and utilizes the IFN-α/β receptor for its biological activities. Using our established the anti-limitin antibody and recombinant limitin protein, we compared biological functions between limitin and IFN-α, and analyzed in vivo expression of limitin protein. (1) Limitin augmented the killer activity of cytotoxic T lymphocytes as well as the surface expression of MHC class I molecules. Limitin inhibited the proliferation of FDCP-1 cells stably transfected with p210bcr/abl. Limitin also induced antiviral state against EMCV, MHV, and HSV. Although the above functions of limitin were similar to those of IFN-α, higher concentration of limitin was required than IFN-α for the inhibition of CFU-IL7 or CFU-Meg colony formation. Limitin could not inhibit CFU-GM or BFU-E colony formation while IFN-α did. These data suggest that limitin may be less toxic than other IFNs, and therefore may have a uniqueclinical niche for treatment of diseases where type I IFNs have proven useful. (2) Immunohistochemical analysis revealed that the limitin protein is produced by mature T lymphocytes in spleen and thymus in healthy mice. This result propose that cDNA from human thymus is a suitable source of cDNA library to screen human homolog of limitin. (3) The disruption of tyrosine kinase Tyk2 completely abrogated IFN-α-induced inhibition of CFU-IL7 and CFU-Meg colony formation as well as up-regulation and translocation of DAXX. These data indicate that Tyk2 plays an important role in IFN-mediated myelosuppression, and we are now analyzing the difference of signaling pathways between limitin and IFN-α.