Arthritis & Rheumatism, Volume 60,
October 2009 Abstract Supplement
The 2009 ACR/ARHP Annual Scientific Meeting
Philadelphia October 16-21, 2009.
Receptors for TSLP and IL-7 Strongly Promote Proteoglycan-Induced Arthritis
Hartgring1, Sarita A.Y., Willis2, Cynthia R., Bijlsma1, Johannes W. J., Broere3, Femke, Lafeber1, Floris P.J.G., van Roon1, Joel A.G.
IL-7 is a potent T cell activating cytokine that can lead to T-cell-dependent activation of monocytes, B cells, and osteoclasts. IL-7 effects are mediated through the high affinity IL-7 receptor-alpha chain (IL-7Ra) in conjunction with the common-gamma chain. Another cytokine, thymic stromal lymphopoietin (TSLP), shares the IL-7Ra for signaling, but has a distinctive receptor subunit, the TSLP receptor. TSLP acts on dendritic cells, mast cells, and CD4 T cells and plays a key role in Th2-type inflammatory responses. We used the proteoglycan-induced arthritis (PGIA) model to determine whether there are distinct roles for IL-7Ra and TSLPR in the immunopathology of arthritis.
PGIA was initiated by immunizing aged female wild type BALB/c (WT) or TSLPR knockout BALB/c (TSLPR-/-) mice with human PG. Mice were treated with PBS as a control, or with an anti-IL-7Ra antibody. Clinical arthritis was determined by visual examination of swelling and redness of the paws. Joint destruction on day 33 was assessed on basis of radiographs and histological examinations of the ankle joints. Cellularity of thymus and spleen and numbers of T-cell subsets, and B cells were assessed. Proinflammatory mediators were assessed by multi-analyte profiling in serum and paw protein lysates.
Anti-IL-7Ra treatment in WT mice significantly reduced arthritis, compared with PBS WT (mean inhibition 55%, p=0.007). The TSLPR-/- mice also showed decreased arthritis severity compared with PBS WT (56%, p=0.019). Ablation of the TSLPR toghether with IL-7Ra blockade showed an even stronger reduction of arhritis (70%, p=0.002). Total numbers of thymocytes or splenocytes in TSLPR-/- mice were not different compared with the PBS WT mice. Splenic CD4 and CD8 T cells were modestly decreased by treatment with anti-IL-7Ra as compared with the non treated mice (PBS WT vs anti-IL-7Ra treated WT 22% decrease; PBS TSLPR-/- vs TSLPR-/- anti-IL-7Ra treated 26% decrease, both p<0.01 for CD4 T cells). The additive effect of blocking both IL-7 and TSLP signaling was clearly shown by radiological scoring of joint damage (PBS WT vs anti-IL-7Ra treated WT 59% decrease, PBS WT vs PBS TSLPR-/- vs 75%, and PBS WT vs anti-IL-7Ra treated TSLPR-/- 94%, all p<0.01). This was consistent with the histological joint damage, showing additive (p<0.05) reduction of cell infiltrates, bone and cartilage erosions. Furthermore, multi-analyte profiling of serum and paw lysates showed decreased (at least p<0.05) concentrations of cytokines, chemokines, acute phase reactants, and factors associated with tissue destruction.
Our data show that both IL-7Ra and TSLPR signaling promote arthritis and joint destruction. Blocking both pathways results in additive disease suppression indicating the distinct contributions of TSLPR and IL-7Ra in arthritis and the potential of targeting these receptors in arthritic conditions, including RA.
To cite this abstract, please use the following information:
Hartgring, Sarita A.Y., Willis, Cynthia R., Bijlsma, Johannes W. J., Broere, Femke, Lafeber, Floris P.J.G., van Roon, Joel A.G.; Receptors for TSLP and IL-7 Strongly Promote Proteoglycan-Induced Arthritis [abstract]. Arthritis Rheum 2009;60 Suppl 10 :1240