TIM-4 has dual function in the induction and effector phases of murine arthritis.
T cell Ig and mucin domain (TIM)-4 is involved in immune regulation. However, the pathological function of TIM-4 has not been understood and remains to be clarified in various disease models. In this study, DBA/1 mice were treated with anti-TIM-4 mAb during the induction or effector phase of collagen-induced arthritis (CIA). Anti-TIM-4 treatment in the induction phase exacerbated the development of CIA. In vitro experiments suggest that CD4 T cells bind to TIM-4 on APCs, which induces inhibitory effect to CD4 T cells. In contrast, therapeutic treatment with anti-TIM-4 mAb just before or after the onset or even at later stage of CIA significantly suppressed the development and progression by reducing proinflammatory cytokines in the ankle joints without affecting T or B cell responses. Consistently, clinical arthritis scores of collagen Ab-induced arthritis, which is not mediated by T or B cells, were significantly reduced in anti-TIM-4-treated mice with a concomitant decrease of proinflammatory cytokines in the joints. In vitro, macrophages secreted proinflammatory cytokines in response to TIM-4-Ig protein and LPS, which were reduced by the anti-TIM-4 mAb. The anti-TIM-4 mAb also inhibited the differentiation and bone-resorbing activity of osteoclasts. These results indicate that TIM-4 has two distinct functions depending on the stage of arthritis. The therapeutic effect of anti-TIM-4 mAb on arthritis is mediated by the inhibition of proinflammatory cytokine production by inflammatory cells, osteoclast differentiation, and bone resorption, suggesting that TIM-4 might be an appropriate target for the therapeutic treatment of arthritis.
Department of Immunology, Juntendo University School of Medicine, Tokyo 113-8421, Japan;
Yoshiyuki
Y
Abe
Fumitaka
F
Kamachi
Toshio
T
Kawamoto
Fumihiko
F
Makino
Jun
J
Ito
Yuko
Y
Kojima
Alaa El Din Hussein
Ael D
Moustapha
Yoshihiko
Y
Usui
Hideo
H
Yagita
Yoshinari
Y
Takasaki
Ko
K
Okumura
Hisaya
H
Akiba
D000818:Animals; D000911:Antibodies, Monoclonal / Q000276:immunology* / Q000627:therapeutic use; D000938:Antigen-Presenting Cells / Q000276:immunology; D001169:Arthritis, Experimental / Q000276:immunology*; D001402:B-Lymphocytes / Q000276:immunology; D001862:Bone Resorption / Q000276:immunology; D015496:CD4-Positive T-Lymphocytes / Q000276:immunology; D002454:Cell Differentiation / Q000187:drug effects / Q000276:immunology; D003094:Collagen; D016207:Cytokines / Q000096:biosynthesis; D008070:Lipopolysaccharides; D008213:Lymphocyte Activation / Q000187:drug effects / Q000276:immunology; D008264:Macrophages / Q000378:metabolism; D008297:Male; D008565:Membrane Proteins / Q000276:immunology* / Q000378:metabolism*; D051379:Mice; D008807:Mice, Inbred BALB C; D008811:Mice, Inbred DBA; D018345:Mice, Knockout; D010010:Osteoclasts / Q000187:drug effects / Q000276:immunology
D000911:Antibodies, Monoclonal; D016207:Cytokines; D008070:Lipopolysaccharides; D008565:Membrane Proteins; C500399:TIM-4 protein, mouse; D003094:Collagen