Session Title: Rheumatoid Arthritis - Animal Models
Session Type: Abstract Submissions (ACR)
Interleukin (IL)-7 and thymic stromal lymphopoietin (TSLP) are cytokines that signal through the IL-7Ra subunit and play proinflammatory roles in experimental arthritis and rheumatoid arthritis (RA). IL-7R blockade can potentially block signalling of both cytokines. In this study the potential of IL-7R and TSLPR signalling inhibition as well as simultaneous inhibition was investigated in murine experimental arthritis. In addition, the additive effects of IL-7 and TSLP in human RA in vitro dendritic cell (DC)/T-cell co-cultures were studied.
Proteoglycan-induced arthritis was induced in wildtype mice (WT) and mice deficient for the TSLP receptor subunit (TSLPR) and mice of both genotypes were treated with anti-IL-7R or PBS. Arthritis severity was assessed and paw lysate and serum were collected for cytokine analyses. CD1c DCs and CD4 T-cells were isolated from blood of RA patients and were co-cultured in presence of IL-7, TSLP or the combination of both cytokines and proliferation and cytokine production were assessed.
Arthritis severity and synovitis were significantly decreased in TSLPR-/- mice treated with anti-IL-7R compared to control mice (Arthritis severity; mean area under the curve ± SEM: 25 ± 5.9 vs. 50.7 ± 6.9; p<0.01). This was associated with strongly reduced radiographic joint damage and osteoclast activity, which were significantly lower in TSLPR-/- mice treated with anti-IL-7R compared to WT mice treated with anti-IL-7R, PBS treated TSLPR-/- mice or PBS treated WT mice (Radiographic joint damage: Mean score ± SEM: 0.1 ± 0.1, 0.6 ± 0.1, 0.3 ± 0.1, 1.4 ± 0.2 respectively; all p<0.001). This was associated with decreased levels of IL-17, IL-6, IL-1β and CD40L, which were all robustly downregulated by combined blockade of IL-7 and TSLP signalling (all p<0.05). In DC/CD4 T-cell co-cultures from RA patients, TSLP and IL-7 additively increased T-cell proliferation (p<0.01) and production of Th17-associated cytokines (IL-17, IL-22, IL-6; all p<0.05) and T-cell attracting chemokines (all p<0.05).
TSLP and IL-7 additively promote production of Th17-specific and Th17-associated cytokines, linked with enhanced inflammation and immunopathology. As both cytokines signal via the IL-7Ra, these data emphasize the need for drugs that target this subunit to abrogate activity of both ligands and prevent immunopathology in RA.
M. R. Hillen,
S. A. Y. Hartgring,
T. R. D. J. Radstake,
C. E. Hack,
F. P. J. G. Lafeber,
J. A. G. van Roon,
« Back to 2014 ACR/ARHP Annual Meeting
ACR Meeting Abstracts - https://acrabstracts.org/abstract/the-additive-inflammatory-in-vivo-and-in-vitro-effects-of-thymic-stromal-lymphopoietin-tslp-and-il-7-in-arthritis-underscore-the-therapeutic-rationale-for-blockade-of-their-common-receptor-subu/