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

Abstract

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.

• Authors: K Komura, M Fujimoto, K Yanaba, T Matsushita, Y Matsushita, M Horikawa, F Ogawa, K Shimizu, M Hasegawa, K Takehara, S Sato
• Journal: Annals of the rheumatic diseases (Ann Rheum Dis) Vol. 67 Issue 6 Pg. 867-72 (Jun 2008) ISSN: 1468-2060 [Electronic] England
• PMID: 17823201 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Antibodies, Blocking
• Antibodies, Monoclonal
• Autoantibodies
• CD40 Ligand
• DNA Topoisomerases, Type I

Topics

• Animals
• Antibodies, Blocking (therapeutic use)
• Antibodies, Monoclonal (therapeutic use)
• Autoantibodies (blood)
• Autoimmunity
• B-Lymphocytes (immunology)
• CD4-Positive T-Lymphocytes (immunology)
• CD40 Ligand (antagonists & inhibitors, blood, immunology)
• Cell Proliferation
• DNA Topoisomerases, Type I (immunology)
• Disease Models, Animal
• Female
• Fibrosis
• Lymphocyte Activation
• Mice
• Mice, Inbred C57BL
• Mice, Mutant Strains
• Scleroderma, Systemic (immunology, pathology, therapy)
• Skin (pathology)
• Up-Regulation