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Objective Transforming growth factor β-inducible gene h3 (βIG-H3), which is abundantly expressed in rheumatoid synovium, and matrix metalloproteinases (MMP) play important roles in the pathogenesis of rheumatoid arthritis (RA). The aim of this study was to determine the therapeutic efficacy of βIG-H3-derived peptides using MMP-1-dependent target tissue delivery in chronic inflammatory arthritis. Methods Peptides developed from βIG-H3 derivatives, including the second and fourth YH peptides, the fourth fas-1 domain, the fourth fas-1 domain truncated for H1 and H2 sequences (dhfas-1), and an MMP-1- cleavable composite peptide (MFK24), were cloned. We confirmed the specificity of MFK24 cleavage by immunoblot analysis after treatment with different proteases. Results The YH18 peptide in the fourth fas-1 domain of βIG-H3 was weakly effective in suppressing arthritis severity in mice with collagen-induced arthritis (CIA). Treatment with higher-dose dhfas-1 (30 mg/kg) showed remarkable efficacy, whereas treatment with a lower dose (10 mg/kg) resulted in only partial improvement. MFK24, a composite peptide consisting of dhfas-1 and RGD peptide linked by MMP-1 substrate, was cleaved specifically by MMP-1. The adhesion and migration of NIH3T3 cells mediated by βIG-H3 were inhibited by MFK24 at a low concentration. MFK24 suppressed the adhesion of NIH3T3 cells more efficiently compared with murine dhfas-1 (MFK00) or RGD, either alone or in combination. The therapeutic efficacy of MFK24 in mice with CIA was remarkably enhanced, with consistently reduced expression of inflammatory mediators within joint tissue. Conclusion This proof-of-concept study showed that an MMP-cleavable composite peptide, based on βIG-H3 derivatives, had markedly improved therapeutic efficacy in chronic inflammatory arthritis, implicating a new expandable strategy for enhancement of the efficacy of 2 different active molecules in RA. [ABSTRACT FROM AUTHOR]

The human polyomavirus JC virus (JCV) is the etiologic agent of the fatal demyelinating central nervous system disease progressive multifocal leukoencephalopathy (PML), which occurs in 4-7% of AIDS patients. Two Korean AIDS patients with PML were assayed for JCV, and the virus was genotyped by polymerase chain reaction, DNA sequencing and phylogenetic analysis. Using immunohistochemical analysis, we also examined the distribution of JCV antigen in the brains of the patients. The JCV genome was detected in peripheral lymphocytes, brain and cerebrospinal fluid from these Korean PML patients. Although type 2 is the most common genotype in Asia, the genotype of the JCV in these two AIDS patients was characterized as type 1, which is of European origin. We found that JCV antigen was selectively detected in oligodendrocytes and astrocytes of the brains from these patients. Compared to the prototype type 1 (Mad-1), two different nucleotides (G-->C) in the KOR-1 strain identified here were found at positions 2488 and 2490 of the major capsid protein VP1 gene. In summary, this is the first report of PML in Korean AIDS patients; it is also the first isolation of JCV type 1 in PML in East Asians., (Copyright 2002 S. Karger AG, Basel)