The Journal of the Korean Society for Transplantation  1998;12(2):173-182

New Immunosuppressive Agent: The Effects of an Antagonist IL-15/IgG Fusion Protein.

Yon Su KIM 1 ; Dong Wan CHAE ; Terry B STROM

Affiliations

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Keywords

Mutant IL-15/IgG fusion protein; Delayed type hypersensitivity; Tolerance induction

Country

Republic of Korea

Language

Korean

Abstract

Owing to shared receptor components, the biological activities of IL-15 are similar to those of IL-2. However the patterns of tissue expression of IL-2/IL-2R alpha and IL-15/IL-15R differ. The development of agents targeting the receptor and signaling elements of IL-15 may provide a new perspective for treatment of diseases associated with expression of IL-15/IL-15R. We designed, genetically constructed and expressed a receptor site specific IL-15 antagonist by mutating glutamine residue within the C-terminus of IL-15 to aspartic acid and linked this mutant IL-15 to murine IgG2a. These IL-15 mutant/IgG fusion proteins specifically bound to the IL-15R, and competitively inhibited IL-15 triggered cell proliferation. We examined the immunosuppressive activity of this agent because of prolonged half-life and the potential for destruction of IL-15R+ leukocytes. The IL-15 mutant/IgG proteins markedly attenuated antigen specific DTH responses in Balb-c mice comparing with the responses in the mice treated with control IgG. Intraperitoneal injection of this mutant protein enhanced the acceptance of crude islet allograft from DBA/2J (H-2(d)) to B6AF1 (H-2(b/d),k) rendered diabetic by injection of streptozotocin (15 vs >65 days; control IgG vs IL-15 mutant/IgG treatment, mean survival time, 8 mice in each group). These findings suggest that i) IL-15/IL-15R+ cells are crucial to these T-cell dependent immune responses, and ii) treatment with IL-15 mutant/IgG protein may ameliorate T-cell dependent immune/inflammatory diseases.