Targeting IL-15 receptor-bearing cells with an antagonist mutant IL-15/Fc protein prevents disease development and progression in murine collagen-induced arthritis

Sylvie Ferrari-Lacraz, Eric Zanelli, Manfred Neuberg, Elina Donskoy, Yon Su Kim, Xin Xiao Zheng, Wayne W. Hancock, Wlodzimierz Maslinski, Xian Chang Li, Terry B. Strom, Thomas Moll

Research output: Contribution to journalArticlepeer-review

105 Scopus citations

Abstract

It has been suggested that the inflammatory cytokine IL-15 plays an important role in the development of several autoimmune diseases, including rheumatoid arthritis. We have generated a unique lytic and antagonistic IL-15 mutant/Fcγ2a fusion protein (CRB-15) that targets the IL-15R. In the present study we examined the effects of targeting the IL-15R on the prevention and treatment of collagen-induced arthritis (CIA) in mice and probed the possible mechanisms of action of this IL-15 mutant/Fcγ2a protein. Upon immunization with type II collagen, DBA/1 mice develop severe articular inflammation and destruction. Treatment of DBA/1 mice with a brief course of CRB-15 at the time of type II collagen challenge markedly inhibited the incidence and severity of arthritis. Moreover, in animals with ongoing established arthritis, treatment with CRB-15 effectively blocked disease progression compared with that in control-treated animals. The therapeutic effect of CRB-15 on either disease development or disease progression is remarkably stable, because withdrawal of treatment did not lead to disease relapse. A detailed analysis revealed that treatment with CRB-15 decreased synovitis in the joints; reduced bone erosion and cartilage destruction; reduced in situ production of the proinflammatory cytokines TNF-α, IL-1β, IL-6, and IL-17; and decreased the responder frequency of autoreactive T cells. Our study suggests that the effective targeting of IL-15R-triggered events with CRB-15 can be of therapeutic importance in the treatment of rheumatoid arthritis.

Original languageEnglish (US)
Pages (from-to)5818-5826
Number of pages9
JournalJournal of Immunology
Volume173
Issue number9
DOIs
StatePublished - Nov 1 2004

ASJC Scopus subject areas

  • Immunology and Allergy
  • Immunology

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