Arthritis & Rheumatism, Volume 62,
November 2010 Abstract Supplement

Abstracts of the American College of
Rheumatology/Association of Rheumatology Health Professionals
Annual Scientific Meeting
Atlanta, Georgia November 6-11, 2010.


Tyrosin Kinases Are Essential Mediators in the Development of Antigen Induced Arthritis Regulating Formation of Dendritic Cells and Antigen Presentation.

Dehlin1,  Mats I., Andersson2,  Sofia, Erlandsson2,  Malin, Bokarewa2,  Maria

Department of Rheumatology and Inflammation Research, Sahlgrenska University Hospital, University of Göteborg, Gothenburg, Sweden
Department of Rheumatology and Inflammation Research, Sahlgrenska University Hospital, University of Göteborg, Sweden

Background:

Tyrosine kinases (TKs) are a family of intracellular signaling molecules participating in cell proliferation, development and apoptosis. Inhibition of TKs is effective in the treatment of various malignancies as well as diabetes mellitus. Several families of TKs are implicated in the pathogenesis of rheumatoid arthritis regulating processes in disease onset as well as progression. In previous work we demonstrated that a ligand to TK Flt3 is accumulated in the joints of RA patients and has proarthritic and erosive properties. Here we evaluate the role of TKs and Flt3-signaling in the antigen-induced model of arthritis.

Methods:

Mice (n=75) were immunized with mBSA followed by an i.a. injection of mBSA on day 21. Treatment with TK inhibitor sunitinib (10 an 40 mg/kg/day) was started on day 7 (n=30) and on day 21 (n=30) and continued until day 28. Controls (n=15) received citrate buffer. The mBSA-injected joints were evaluated morphologically and compared to circulating levels of bone (CTX-I) and cartilage (CTX-II) degradation marker and to anti-mBSA antibodies measured by ELISA. The effect of sunitinib on the levels of TK ligands Flt3-L, RANKL and VEGF were measured by ELISA. Expression of Flt3 and development of dendritic cells (DC) was evaluated in the bone marrow and spleen by flow cytometry.

Results:

Sunitinib treatment alleviated mBSA-induced arthritis, reducing intensity of synovitis and frequency of bone erosions. This was accompanied by a reduction of mBSA antibodies and marker for bone degradation, CTX-I.

Sunitinib induced a pronounced increase in Flt3-ligand levels, while levels of VEGF and RANKL were changed only slightly, indicating relative specificity on Flt3-signaling. Following sunitinib treatment, the expression of Flt3 was selectively decreased on CD3+ population in bone marrow.

In spleen, sunitinib induced a significant decrease of pDCs as well as cDCs affecting all cDC subsets. However, sunitinib increased CD8+ population in spleen while the populations of B-cells and CD4+ T-cells were unchanged.

Conclusion:

Sunitinib blocks TKs through Flt3 pathway alleviating synovial inflammation and bone resorption in antigen induced arthritis. This effect is potentially mediated through downregulation of DCs and decreased antigen presentation.

To cite this abstract, please use the following information:
Dehlin, Mats I., Andersson, Sofia, Erlandsson, Malin, Bokarewa, Maria; Tyrosin Kinases Are Essential Mediators in the Development of Antigen Induced Arthritis Regulating Formation of Dendritic Cells and Antigen Presentation. [abstract]. Arthritis Rheum 2010;62 Suppl 10 :293
DOI: 10.1002/art.28062

Abstract Supplement

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2010 ACR/ARHP