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The role of T cell Immunoglobulin Mucin domain in Herpes Simplex Virus-induced Behçet’s Disease mouse model

단순포진 바이러스로 유도한 베체트병 마우스 모델에서 T cell immunoglobulin mucin domain(Tim) 의 역할

초록/요약

The T cell immunoglobulin mucin (TIM) proteins regulate T cell activation and tolerance. Individual TIM family members may serve as susceptibility markers for asthma, allergies and autoimmune diseases, as well as potential cell surface markers for T helper type (Th)1 and Th2 T cells. TIM-1 plays an important role in the regulation of immune responses and the development of autoimmune diseases. TIM-4 is a natural ligand of TIM-1, and interaction of TIM-1 and TIM-4 is involved in the regulation of Th cell responses and the modulation of the Th1/Th2 cytokines balance. TIM-4 expression was increased in patients with systemic lupus erythematosus (SLE). It has been also reported that TIM-3 expression was higher in patients with rheumatoid arthritis compared to controls. Further, Galectin-9 (Gal-9) has been identified as a TIM-3 ligand (L) and the TIM-3-TIM-3L interaction serves as a specific down-regulator of the Th1 immune response. Behçet’s disease (BD) is a chronic, multisystemic inflammatory disorder with arthritic, gastrointestinal, mucocutaneous, ocular, vascular, and central nervous system involvement. In herpes simplex virus induced BD mouse model, the expression of Tim-1 and Gal-9 was lower levels compared to asymptomatic BD normal (BDN) mice. The expression of Tim-3 and Tim-4 was higher in BD mice than BDN mice. In addition, Tim-1 vector injected BD mice showed changes of BD-like symptoms and decreased the severity score. Again, treatment with Tim-4 siRNA also improved the BD-like symptoms and decreased the severity score accompanied with up-regulation of regulatory T cells (Treg). Furthermore, administration of Gal-9 improved the BD-like symptoms, decreased the severity score, and increased Treg cells. In addition, Gal-9 induced improvement was associated with down-regulation of pro-inflammatory cytokines and induction of apoptosis. In the present study, we showed that the regulation of Tim-1 or Tim-4 affected the BD-like symptoms and Tim-3-Tim-3L interaction improved the inflammatory symptoms in BD mice.

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TABLE OF CONTENTS

ABSTRACT ⅰ
TABLE OF CONTENTS ⅲ
LIST OF FIGURES ⅴ
LIST OF TABLES ⅶ
Ⅰ. INTRODUCTION 1
Ⅱ. MATERIALS AND METHODS 4
A. Antibodies and reagents 4
B. Animal experiments 4
C. BD-like symptoms 5
D. Tim-1 DNA constructs 5
E. Preparation of Tim-4 small interfering RNA (siRNA) 6
F. Tim-1 vector and Tim-4 siRNA administration to BD mice 6
G. Gal-9 administration to BD mice 6
H. Flow cytometry 6
I. Enzyme-linked immunosorbent assay (ELISA) 7
J. Transmission electron microscopy (TEM) 7
K. Statistical analysis 8
Ⅲ. RESULTS 9
A. The frequencies of Tim-1 and Tim-4 expressing cells in normal healthy, BDN and BD mice 9
B. The expression of Tim-3 and Gal-9 in BD mice 14
C. Administration of Tim-1 vector up-regulates the frequency of Tim-1(+) cells in vivo lymph nodes 16
D. Administration of Tim-1 vector affected the BD-like symptoms 18
E. Tim-1 vector administration affected the regulatory cellular phenotypes 24
F. Pro-inflammatory cytokines were down-regulated by Tim-1 vector administration in BD mice 26
G. Tim-4 siRNA treatment down-regulated the expression of Tim-4 in normal healthy mice 28
H. Administration of siTim-4 changed BD-like symptoms 30
I. Treg cells were up-regulated in siTim-4 treated BD mice 35
J. Treatment with siTim-4 decreased the serum level of IL-17 in BD mice 37
K. Gal-9 treatment up-regulated the expression of Gal-9 in vitro and in vivo 39
L. Gal-9 administration improved BD-like symptoms 41
M. Gal-9 induced the expression of cell death-related molecules in BD mice 43
N. Gal-9 modulated the cell population in BD mice 47
O. Gal-9 regulated cytokine expression in BD mice 49
Ⅳ. DISCUSSION 51
Ⅴ. CONCLUSION 57
REFERENCES 58
국문요약 70

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