Targeting IL-15 Receptor-Bearing Cells with an Antagonist Mutant IL-15/Fc Protein Prevents Disease Development and Progression in Murine Collagen-Induced Arthritis

• Published in: The Journal of immunology (1950) 2004-11, Vol.173 (9), p.5818-5826
• Main Authors: Ferrari-Lacraz, Sylvie, Zanelli, Eric, Neuberg, Manfred, Donskoy, Elina, Kim, Yon Su, Zheng, Xin Xiao, Hancock, Wayne W, Maslinski, Wlodzimierz, Li, Xian Chang, Strom, Terry B, Moll, Thomas
• Format: Article
• Language: English
• Subjects: Animals; Arthritis, Experimental - genetics; Arthritis, Experimental - immunology; Arthritis, Experimental - pathology; Arthritis, Experimental - prevention & control; Cell Migration Inhibition; Collagen Type II - immunology; Cytokines - antagonists & inhibitors; Cytokines - biosynthesis; Disease Progression; Gene Targeting - methods; Genetic Vectors; Growth Inhibitors - antagonists & inhibitors; Growth Inhibitors - genetics; Immunoglobulin Fc Fragments - administration & dosage; Immunoglobulin Fc Fragments - genetics; Immunoglobulin G - administration & dosage; Immunoglobulin G - genetics; Incidence; Inflammation Mediators - antagonists & inhibitors; Inflammation Mediators - metabolism; Interleukin-15 - administration & dosage; Interleukin-15 - antagonists & inhibitors; Interleukin-15 - genetics; Interleukin-15 - immunology; Male; Mice; Mice, Inbred DBA; Mutagenesis, Site-Directed; Receptors, Interleukin-15; Receptors, Interleukin-2 - metabolism; Recombinant Fusion Proteins - administration & dosage; Recombinant Fusion Proteins - immunology; Recombinant Fusion Proteins - therapeutic use; Severity of Illness Index; T-Lymphocyte Subsets - immunology; T-Lymphocyte Subsets - metabolism; T-Lymphocyte Subsets - pathology
• ISSN: 0022-1767; 1550-6606
• DOI: 10.4049/jimmunol.173.9.5818

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/Fcgamma2a 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/Fcgamma2a 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-alpha, IL-1beta, 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.