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2a Protein Blocks Delayed-Type Hypersensitivity1
*
Department of Medicine, Harvard Medical School, Divisions of
Immunology and
Gastroenterology, Beth Israel Deaconess Medical Center and
§
Renal Division, Brigham and Women’s Hospital, Boston, MA 02215
Owing to shared receptor components, the biologic activities of
IL-15 are similar to those of IL-2. However, the patterns of tissue
expression of IL-2/IL-2R
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 residues within the C terminus of IL-15 to aspartic acid and
genetically linked this mutant IL-15 to murine Fc
2a. These
mutant IL-15 proteins specifically bind to the IL-15R, competitively
inhibit IL-15-triggered cell proliferation, and do not activate the
STAT-signaling pathway. Because the receptor site-specific antagonist
IL-15 mutant/Fc2a fusion proteins had a prolonged
t1/2 in vivo and the potential for
destruction of IL-15R+ leukocytes, we examined the
immunosuppressive activity of this agent. An IL-15 mutant/Fc2a
fusion protein markedly attenuated Ag-specific delayed-type
hypersensitivity responses and decreased leukocyte infiltration within
the delayed-type hypersensitivity sites. These findings suggest that 1)
IL-15/IL-15R+ cells are crucial to these T cell-dependent
immune responses, and 2) treatment with IL-15 mutant/Fc2a protein
may ameliorate T cell-dependent immune/inflammatory diseases.
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