title: The Additive Inflammatory In Vivo and In Vitro Effects of IL-7 and TSLP in Arthritis Underscore the Therapeutic Rationale for Dual Blockade.
abstract: BACKGROUND
  The cytokines interleukin (IL)-7 and thymic stromal lymphopoietin (TSLP) signal through the IL-7R subunit and play proinflammatory roles in experimental arthritis and rheumatoid arthritis (RA). We evaluated the effect of inhibition of IL-7R- and TSLPR-signalling as well as simultaneous inhibition of IL-7R- and TSLPR-signalling in murine experimental arthritis. In addition, the effects of IL-7 and TSLP in human RA dendritic cell (DC)/T-cell co-cultures were studied.
  
  
  METHODS
  Arthritis was induced with proteoglycan in wildtype mice (WT) and in mice deficient for the TSLP receptor subunit (TSLPR-/-). Both mice genotypes were treated with anti-IL-7R or phosphate buffered saline. Arthritis severity was assessed and local and circulating cytokines were measured. Autologous CD1c-positive DCs and CD4 T-cells were isolated from peripheral blood of RA patients and were co-cultured in the presence of IL-7, TSLP or both and proliferation and cytokine production were assessed.
  
  
  RESULTS
  Arthritis severity and immunopathology were decreased in WT mice treated with anti-IL-7R, in TSLPR-/- mice, and the most robustly in TSLPR-/- mice treated with anti-IL-7R. This was associated with strongly decreased levels of IL-17, IL-6 and CD40L. In human DC/T-cell co-cultures, TSLP and IL-7 additively increased T-cell proliferation and production of Th17-associated cytokines, chemokines and tissue destruction factors.
  
  
  CONCLUSIONS
  TSLP and IL-7 have an additive effect on the production of Th17-cytokines in a human in vitro model, and enhance arthritis in mice linked with enhanced inflammation and immunopathology. As both cytokines signal via the IL-7R, these data urge for IL-7R-targeting to prevent the activity of both cytokines in RA.
authors.affiliation: Department of Rheumatology & Clinical Immunology, University Medical Center Utrecht, Utrecht, The Netherlands; Laboratory of Translational Immunology, University Medical Center Utrecht, Utrecht, The Netherlands.
authors.forename: Maarten R
authors.initials: MR
authors.lastname: Hillen
authors.affiliation: Department of Rheumatology & Clinical Immunology, University Medical Center Utrecht, Utrecht, The Netherlands; Laboratory of Translational Immunology, University Medical Center Utrecht, Utrecht, The Netherlands.
authors.forename: Sarita A Y
authors.initials: SA
authors.lastname: Hartgring
authors.affiliation: Inflammation Lab, Amgen Inc., Seattle, Washington, United States of America.
authors.forename: Cynthia R
authors.initials: CR
authors.lastname: Willis
authors.affiliation: Department of Rheumatology & Clinical Immunology, University Medical Center Utrecht, Utrecht, The Netherlands; Laboratory of Translational Immunology, University Medical Center Utrecht, Utrecht, The Netherlands.
authors.forename: Timothy R D J
authors.initials: TR
authors.lastname: Radstake
authors.affiliation: Department of Rheumatology & Clinical Immunology, University Medical Center Utrecht, Utrecht, The Netherlands; Laboratory of Translational Immunology, University Medical Center Utrecht, Utrecht, The Netherlands.
authors.forename: Cornelis E
authors.initials: CE
authors.lastname: Hack
authors.affiliation: Department of Rheumatology & Clinical Immunology, University Medical Center Utrecht, Utrecht, The Netherlands.
authors.forename: Floris P J G
authors.initials: FP
authors.lastname: Lafeber
authors.affiliation: Department of Rheumatology & Clinical Immunology, University Medical Center Utrecht, Utrecht, The Netherlands; Laboratory of Translational Immunology, University Medical Center Utrecht, Utrecht, The Netherlands.
authors.forename: Joel A G
authors.initials: JA
authors.lastname: van Roon
mesh_terms: D000818:Animals; D000911:Antibodies, Monoclonal / Q000494:pharmacology; D001169:Arthritis, Experimental / Q000235:genetics / Q000276:immunology / Q000378:metabolism*; D001172:Arthritis, Rheumatoid / Q000276:immunology / Q000378:metabolism*; D016207:Cytokines / Q000235:genetics / Q000378:metabolism*; D006801:Humans; D007249:Inflammation / Q000235:genetics / Q000276:immunology / Q000378:metabolism*; D015851:Interleukin-7 / Q000378:metabolism*; D051379:Mice; D018345:Mice, Knockout; D020395:Receptors, Interleukin-7 / Q000276:immunology*; D015398:Signal Transduction / Q000187:drug effects*; D000094632:Thymic Stromal Lymphopoietin
chemical_list: D000911:Antibodies, Monoclonal; D016207:Cytokines; D015851:Interleukin-7; D020395:Receptors, Interleukin-7; D000094632:Thymic Stromal Lymphopoietin