13:40 - 15:10
Workshop 9, “Anti-cytokine therapy for inflammatory human diseases”
Room: ANA Crowne Plaza “Ohtori” Room B
Workshop Session
Chair/s:
John A. Hamilton, Yoshiya Tanaka
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Anti-CX3CL1 monoclonal antibody therapy suppresses the development of bleomycin-induced and growth factors-induced skin fibrosis in mice
Vu Huy Luong1, Takenao Chino1, Noritaka Oyama1, Takashi Obara2, Yoshikazu Kuboi3, Naoto Ishii3, Akihito Machinaga3, Hideaki Ogasawara3, Wataru Ikeda3, Toshio Imai3, Minoru Hasegawa1
1Department of Dermatology, Fukui University, Fukui, Japan, 2Eisai Co..Ltd., Tokyo, Japan, 3KAN Research Institute.Inc., Hyogo, Japan

Objective: Systemic sclerosis (SSc) is a connective tissue disease characterized by inflammation, fibrosis, and vascular injury of the skin and internal organs. We previously reported that expression of CX3CL1　(fractalkine) and its unique receptor, CX3CR1 was augmented in patients with SSc. In this study, we examined the effect of anti-mouse CX3CL1 monoclonal antibody (mAb) therapy for skin fibrosis in two different mouse models of SSc.

Methods: The first SSc model was established on C57BL/6J mice and CX3CR1-deficient mice by daily intradermal injections of bleomycin. In the second model, BALB/c newborn mice received subcutaneous injections of transforming growth factor-β followed by that of connective tissue growth factor. The anti-CX3CL1 mAb originally generated was injected in both models.

Results: The bleomycin injection quickly increased serum levels of CX3CL1. Administration of anti-CX3CL1 mAb or CX3CR1 deficiency significantly suppressed the skin thickness and dermal collagen accumulation induced by bleomycin. In addition, the dermal infiltration of CX3CR1+ cells, macrophages (especially CD11b+Ly6Chi and CD11b+CD206+ subsets), and　CD3+ cells was reduced by anti-CX3CL1 mAb therapy or CX3CR1 deficiency. The mRNA expression levels of fibrogenic molecules such as osteopontin and thymic stromal lymphopoietin were markedly augmented in the skin by bleomycin injection. However, anti-CX3CL1 mAb therapy significantly suppressed them. Anti-CX3CL1 mAb administration resulted in a tendency of protection and/or reorganization of the injured microvasculature in bleomycin-injected skin. In growth factors-induced skin fibrosis model, the mRNA expression of CX3CL1, CX3CR1, and macrophage markers was increased during the fibrotic course. Pre-treatment of anti-CX3CL1 mAb significantly ameliorated the skin fibrosis.

Conclusions: Blockade of the CX3CL1/CX3CR1 pathway can efficiently ameliorate the skin fibrosis in two strategically different SSc mouse models. Anti-CX3CL1 mAb therapy is an ideal candidate for consideration in clinical trials of SSc.

Reference:
Tu-WS9-5
Session:
Workshop 9, “Anti-cytokine therapy for inflammatory human diseases”
Presenter/s:
Vu Huy Luong
Presentation type:
Oral Presentation
Room:
ANA Crowne Plaza “Ohtori” Room B
Chair/s:
John A. Hamilton, Yoshiya Tanaka
Date:
Tuesday, 31 October 2017
Time:
14:40 - 14:55
Session times:
13:40 - 15:10
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