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Blockade of CD40/CD40 ligand interactions attenuates skin fibrosis and autoimmunity in the tight-skin mouse.

Authors: Komura, K  Fujimoto, M  Yanaba, K  Matsushita, T  Matsushita, Y  Horikawa, M  Ogawa, F  Shimizu, K  Hasegawa, M  Takehara, K  Sato, S 
Citation: Komura K, etal., Ann Rheum Dis. 2008 Jun;67(6):867-72. Epub 2007 Sep 6.
Pubmed: (View Article at PubMed) PMID:17823201
DOI: Full-text: DOI:10.1136/ard.2007.073387

OBJECTIVE: To assess the association of CD40/CD40 ligand (CD40L) interactions with the development of skin fibrosis and autoimmunity in tight-skin (TSK/+) mouse, which is a mouse model for human systemic sclerosis. METHODS: Newly born TSK/+ mice were treated with murine anti-CD40L monoclonal antibody (100 microg intraperitoneally weekly). Hypodermal thickness of 8-week-old female mice (defined as the thickness of a subcutaneous loose connective tissue layer beneath the panniculus carnosus) was measured under a light microscope. All skin sections were taken from the para-midline, upper back region. Serum anti-topoisomerase I autoantibody levels, serum immunoglobulin levels and plasma soluble CD40L levels were determined by enzyme-linked immunosorbent assay. For analysis of lymphocyte surface molecules, single cell suspensions of lymphocytes were stained by monoclonal antibodies. Proliferation of TSK/+ B cells and fibroblasts to anti-CD40 antibodies was assessed by the uptake of [3H]-labelled thymidine and bromodeoxyuridine, respectively. RESULTS: The blockade of CD40/CD40L interactions by anti-CD40L monoclonal antibody significantly reduced cutaneous fibrosis (65%) and anti-topoisomerase I autoantibody in TSK/+ mice. Anti-CD40L monoclonal antibody also normalised B lymphocyte abnormal activation in TSK/+ mice, demonstrated by hyper-gamma-globulinaemia. Furthermore, augmented CD40/CD40L interactions in TSK/+ mice were suggested by upregulated expression of CD40L on CD4(+) T cells, elevated plasma soluble CD40L levels. The hyperresponsiveness to CD40 stimulation was also observed in TSK/+ B cells and fibroblasts. CONCLUSIONS: Cutaneous fibrosis and autoimmunity in TSK/+ mice are closely correlated with CD40/CD40L interactions.


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RGD Object Information
RGD ID: 8547759
Created: 2014-02-21
Species: All species
Last Modified: 2014-02-21
Status: ACTIVE


RGD is funded by grant HL64541 from the National Heart, Lung, and Blood Institute on behalf of the NIH.