title: Targeting IL-15 receptor-bearing cells with an antagonist mutant IL-15/Fc protein prevents disease development and progression in murine collagen-induced arthritis.
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/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.
authors.affiliation: Department of Medicine, Harvard Medical School, Division of Immunology, Beth Israel Deaconess Medical Center, Boston, MA 02215, USA.
authors.forename: Sylvie
authors.initials: S
authors.lastname: Ferrari-Lacraz
authors.forename: Eric
authors.initials: E
authors.lastname: Zanelli
authors.forename: Manfred
authors.initials: M
authors.lastname: Neuberg
authors.forename: Elina
authors.initials: E
authors.lastname: Donskoy
authors.forename: Yon Su
authors.initials: YS
authors.lastname: Kim
authors.forename: Xin Xiao
authors.initials: XX
authors.lastname: Zheng
authors.forename: Wayne W
authors.initials: WW
authors.lastname: Hancock
authors.forename: Wlodzimierz
authors.initials: W
authors.lastname: Maslinski
authors.forename: Xian Chang
authors.initials: XC
authors.lastname: Li
authors.forename: Terry B
authors.initials: TB
authors.lastname: Strom
authors.forename: Thomas
authors.initials: T
authors.lastname: Moll
mesh_terms: D000818:Animals; D001169:Arthritis, Experimental / Q000235:genetics / Q000276:immunology / Q000473:pathology / Q000517:prevention & control*; D002464:Cell Migration Inhibition; D024043:Collagen Type II / Q000276:immunology*; D016207:Cytokines / Q000037:antagonists & inhibitors / Q000096:biosynthesis; D018450:Disease Progression; D018390:Gene Targeting / Q000379:methods*; D005822:Genetic Vectors; D006131:Growth Inhibitors / Q000037:antagonists & inhibitors / Q000235:genetics; D007141:Immunoglobulin Fc Fragments / Q000008:administration & dosage / Q000235:genetics*; D007074:Immunoglobulin G / Q000008:administration & dosage / Q000235:genetics; D015994:Incidence; D018836:Inflammation Mediators / Q000037:antagonists & inhibitors / Q000378:metabolism; D019409:Interleukin-15 / Q000008:administration & dosage / Q000037:antagonists & inhibitors* / Q000235:genetics* / Q000276:immunology; D008297:Male; D051379:Mice; D008811:Mice, Inbred DBA; D016297:Mutagenesis, Site-Directed; D053647:Receptors, Interleukin-15; D015375:Receptors, Interleukin-2 / Q000378:metabolism*; D011993:Recombinant Fusion Proteins / Q000008:administration & dosage / Q000276:immunology / Q000627:therapeutic use; D012720:Severity of Illness Index; D016176:T-Lymphocyte Subsets / Q000276:immunology / Q000378:metabolism / Q000473:pathology
chemical_list: D024043:Collagen Type II; D016207:Cytokines; D006131:Growth Inhibitors; C508025:Il15ra protein, mouse; D007141:Immunoglobulin Fc Fragments; D007074:Immunoglobulin G; D018836:Inflammation Mediators; D019409:Interleukin-15; D053647:Receptors, Interleukin-15; D015375:Receptors, Interleukin-2; D011993:Recombinant Fusion Proteins