bb-1101 and Autoimmune-Diseases

EAU is characterized by breakdown of the blood-retinal barrier and extravasation of leucocytes into retinal tissue leading to destruction of photoreceptor cells. Matrix metalloproteinases (MMP) have been implicated in trafficking of cells into tissues, but their role in inflammatory eye disease is unclear. A synthetic MMP inhibitor, BB-1101, was administered subcutaneously, from either day 0 or day 7, to Lewis rats challenged with bovine S-antigen to induce EAU. When given up to day 14, BB-1101 reduced the incidence of disease and delayed the day of onset of clinical disease. When administered from day 7 until day 21, EAU was completely abrogated. A quantitative polymerase chain reaction (PCR) assay showed an increase of both matrilysin (MMP-7), neutrophil collagenase (MMP-8) and macrophage metalloproteinase (MMP-12) in retinas from EAU animals compared with naive controls. These enzymes are produced by activated leucocytes and act on components of the basement membrane. These results therefore implicate these MMP as integral to the development of pathology in EAU.

Topics: Animals; Arrestin; Autoimmune Diseases; Benzyl Compounds; Dexamethasone; Drug Combinations; Male; Matrix Metalloproteinase Inhibitors; Matrix Metalloproteinases; Pentoxifylline; Protease Inhibitors; Rats; Rats, Inbred Lew; Retina; Retinitis; RNA, Messenger; Succinates; Time Factors; Tumor Necrosis Factor-alpha; Uveitis

The proinflammatory Th1 cytokine, tumor necrosis factor-alpha (TNF alpha), the cell death signaling molecule FasL, and several extracellular matrix degrading metalloproteinases have been implicated in the pathogenesis of multiple sclerosis (MS). The latter enzymes, as well as TNF alpha-converting enzyme and FasL-converting enzyme, can be blocked by matrix metalloproteinase inhibitors (MMPIs). In this study, we show that a potent MMPI was clinically effective in an animal model for MS, experimental autoimmune encephalomyelitis (EAE) in the SJL/J mouse. Efficacy was remarkable, as indicated by blocking and reversal of acute disease and reduced number of relapses and diminished mean cumulative disease score in chronic relapsing animals. Also, demyelination and glial scarring were significantly decreased in MMPI-treated mice with chronic relapsing EAE, as was central nervous system gene expression for TNF alpha and fasL. It is interesting that expression of the beneficial cytokine interleukin-4 (IL-4) was increased, and IL-4 was expressed on glial cells. The relevance of these compounds for MS was underscored by their ability to specifically inhibit TNF alpha shedding and cytotoxicity of myelin-autoreactive human cytotoxic CD4+ T-cell clones. This is the first report to show a positive effect by MMPIs on chronic relapsing EAE, its central nervous system cytokine profile, and on TNF alpha shedding by human myelin-autoreactive T cells.

Topics: Animals; Astrocytes; Autoimmune Diseases; Base Sequence; Benzyl Compounds; Chi-Square Distribution; Clone Cells; Cytokines; Demyelinating Diseases; Dexamethasone; Down-Regulation; Drug Combinations; Encephalitis; Gene Expression Regulation; Glial Fibrillary Acidic Protein; Humans; Hydroxamic Acids; Immunohistochemistry; Metalloendopeptidases; Mice; Microglia; Microscopy, Electron; Multiple Sclerosis; Optic Nerve; Organic Chemicals; Pentoxifylline; Protease Inhibitors; Recurrence; RNA; Spinal Cord; Statistics, Nonparametric; Succinates; Tumor Necrosis Factor-alpha; Up-Regulation