Session Information
Session Title: Rheumatoid Arthritis - Animal Models
Session Type: Abstract Submissions (ACR)
Background/Purpose
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.
Methods
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.
Results
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).
Conclusion
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.
Disclosure:
M. R. Hillen,
None;
S. A. Y. Hartgring,
None;
T. R. D. J. Radstake,
None;
C. E. Hack,
None;
F. P. J. G. Lafeber,
None;
J. A. G. van Roon,
None.
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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/