Oral administration of 1,4-aryl-2-mercaptoimidazole inhibits T-cell proliferation and reduces clinical severity in the murine experimental autoimmune encephalomyelitis model.

Abstract

T cells play a pivotal role in the initiation and progression of multiple sclerosis. We have found that 1,4-aryl-2-mercaptoimidazole (KRM-III) inhibited T-cell antigen receptor- and phorbol myristate acetate/ionomycin-induced activation of nuclear factor of activated T cells (NFAT) and T-cell proliferation with an IC(50) of 5 microM. The KRM-III-mediated inhibitory effect was specific for NFAT activation but not for nuclear factor kappaB. Oral administration of 90 mg/kg KRM-III resulted in complete abrogation of anti-CD3 antibody-induced T-cell activation and a 45.8% reduction in footpad swelling in bovine serum albumin-induced delayed-type hypersensitivity. In the murine experimental autoimmune encephalomyelitis (EAE) model, oral administration of KRM-III significantly attenuated the severity of disease when given before or after disease onset. Draining lymph node cells from KRM-III-treated mice showed markedly reduced proliferation in response to myelin oligodendrocyte glycoprotein peptide. Histological analysis indicated that KRM-III reduced the infiltration of inflammatory cells to the white matter of spinal lumbar cords. These results demonstrate that KRM-III efficiently inhibits T-cell activation and inflammatory responses and lessens EAE clinical signs, which suggest KRM-III as a potential lead compound for the treatment of T-cell-driven autoimmune diseases.

• Authors: Eun Joo Jung, Minkyu Hur, Young Lim Kim, Ge Hyeong Lee, Jeongmin Kim, Ikyon Kim, Minwoo Lee, Ho-Kyun Han, Mi-Soon Kim, Sejin Hwang, Sungjoo Kim, A Mi Woo, Yeup Yoon, Heon Jin Park, Jonghwa Won
• Journal: The Journal of pharmacology and experimental therapeutics (J Pharmacol Exp Ther) Vol. 331 Issue 3 Pg. 1005-13 (Dec 2009) ISSN: 1521-0103 [Electronic] United States
• PMID: 19741152 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• 1,4-diphenyl-2-mercaptoimidazole
• Imidazoles
• Immunologic Factors
• Interleukin-2
• NFATC Transcription Factors
• Receptors, Antigen, T-Cell
• Thiones

Topics

• Administration, Oral
• Animals
• Cell Proliferation (drug effects)
• Encephalomyelitis, Autoimmune, Experimental (diagnosis, drug therapy, immunology)
• Female
• Humans
• Hypersensitivity, Delayed (diagnosis, drug therapy, immunology)
• Imidazoles (administration & dosage, chemistry, pharmacokinetics, therapeutic use)
• Immunologic Factors (administration & dosage, chemistry, pharmacokinetics, therapeutic use)
• Interleukin-2 (immunology)
• Jurkat Cells
• Lymph Nodes (immunology)
• Lymphocyte Activation (drug effects, immunology)
• Mice
• Mice, Inbred BALB C
• Mice, Inbred C57BL
• Molecular Structure
• Multiple Sclerosis (immunology, prevention & control)
• NFATC Transcription Factors (immunology)
• Receptors, Antigen, T-Cell (immunology)
• Severity of Illness Index
• Spinal Cord (immunology)
• T-Lymphocytes (drug effects, immunology)
• Thiones (administration & dosage, chemistry, pharmacokinetics, therapeutic use)