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Biomedical subjects

T Sorsa

Publications and source records attributed to T Sorsa.

At least 19 recordsLinked to original sources
PubMed2006

Gelatinase B [matrix metalloproteinase (MMP)-9] and collagenases (MMP-8/-13) are upregulated in cerebrospinal fluid during aseptic and bacterial meningitis in children.

We investigated the protein expression of gelatinases [matrix metalloproteinase (MMP)-2 and -9] and collagenases (MMP-8 and -13) in cerebrospinal fluid (CSF) from patients with bacterial (BM, n = 17) and aseptic (AM, n = 14) meningitis. In both, MMP-8 and -9 were increased in 100% of patients, whereas MMP-13 was detectable in 53% and 82% respectively. Three patients with clinical signs of meningitis, without CSF pleocytosis, scored positive for all three MMPs. MMP-8 appeared in two isoforms, granulocyte-type [polymorphonuclear cell (PMN)] and fibroblast/macrophage (F/M) MMP-8. Analysis of kinetic changes from serial lumbar punctures showed that these MMPs are independently regulated, and correlate only partly with CSF cytosis or levels of the endogenous inhibitor, tissue inhibitor of matrix metalloproteinase-1. In vitro, T cells, peripheral blood mononuclear cells (PBMCs) and granulocytes (PMN) release MMP-8 and -9, whereas MMP-13 could be found only in the former two cell types. Using models of exogenous (n-formyl-Met-Leu-Phe, T cell receptor cross-linking) and host-derived stimuli (interleukin-2), the kinetics and the release of the MMP-8, -9 and -13 showed strong variation between these immune cells and suggest release from preformed stocks. In addition, MMP-9 is also synthesized de novo in PBMCs and T cells. In conclusion, invading immune cells contribute only partially to MMPs in CSF during meningitis, and parenchymal cells are an equally relevant source. In this context, in patients with clinical signs of meningitis, but without CSF pleocytosis, MMPs seem to be a highly sensitive marker for intrathecal inflammation. The present data support the concept that broad-spectrum enzyme inhibition targeting gelatinases and collagenases is a potential strategy for adjunctive therapy in infectious meningitis.

Adolescent↗
PubMed2006

Capsaicin-induced local elevations in collagenase-2 (matrix metalloproteinase-8) levels in human gingival crevice fluid.

BACKGROUND AND OBJECTIVES: Application of capsaicin on alveolar mucosa provokes pain and neurogenic vasodilatation in the adjacent gingiva. Pain-associated inflammatory reactions may initiate expression of several pro-inflammatory mediators. Collagenase-2 (matrix metalloproteinase-8: MMP-8) is the major destructive protease, especially in the periodontitis-affected gingival crevice fluid (GCF). With this background, we wished to study whether capsaicin stimulation of alveolar mucosa can induce changes in the GCF MMP-8 levels. MATERIAL AND METHODS: For 10 generally and periodontally healthy human volunteers, capsaicin (3%)-moistened filter paper was applied unilaterally to the buccal alveolar mucosa on the anterior maxilla. GCF samples were collected from the tooth at the stimulation site and from several other incisors in the upper jaw. MMP-8 levels and molecular forms in GCF samples were determined by immunofluorometric assay (IFMA) and western immunoblotting, respectively. RESULTS: Capsaicin stimulation of the alveolar mucosa induced significant local elevations in levels and activation of MMP-8 in GCF of the adjacent teeth. Western immunoblot revealed that both neutrophil- and mesenchymal-type MMP-8 isoforms were elevated and activated, together with 110 kDa high-molecular size MMP-8 species. This capsaicin-evoked MMP-8 elevation lasted several minutes after stimulation. During the experiments, no marked changes occurred in MMP-8 levels in the GCF of distantly located teeth. CONCLUSIONS: These results suggest that capsaicin-evoked neurogenic gingival inflammation can trigger the expression and activation of MMP-8 in GCF of the adjacent teeth.

Adult↗
PubMed2006

Monitoring periodontal disease status in smokers and nonsmokers using a gingival crevicular fluid matrix metalloproteinase-8-specific chair-side test.

BACKGROUND AND OBJECTIVE: With current periodontal diagnostic tools it is difficult to identify susceptible individuals or sites at risk. The aim of this study was to evaluate the efficacy of the matrix metalloproteinase (MMP)-8-specific chair-side dip-stick test in longitudinally monitoring the periodontal status of smoking (S) and nonsmoking (NS) patients with chronic periodontitis, using their gingival crevicular fluid (GCF) MMP-8 concentrations. MATERIAL AND METHODS: Clinical parameters, MMP-8 test results and concentrations were monitored in 16 patients after initial treatment and in 15 patients after scaling and root planing (SRP), every other month, over a 12-mo time period. Progressing and stable sites, and sites with exceptionally high MMP-8 concentrations, were analysed in smokers and nonsmokers. RESULTS: SRP reduced the mean GCF MMP-8 levels, test scores, probing depth (PD), attachment loss (AL) and bleeding on probing (BOP). In sites of periodontal disease progression, the distribution of MMP-8 concentrations was broader than in stable sites, indicating a tendency for elevated concentrations in patients with periodontal disease. The mean MMP-8 concentrations in smokers were lower than in nonsmokers, but in smokers' and nonsmokers' sites with progressive disease, MMP-8 concentrations were similar. Sites with exceptionally elevated MMP-8 concentrations were clustered in smokers who also showed a poor response to SRP. In these sites, the MMP-8 concentration did not decrease with SRP and these sites were easily identified by the MMP-8 test. CONCLUSION: Persistently elevated GCF MMP-8 concentrations may indicate sites at risk, as well as patients with poor response to conventional periodontal treatment (e.g. SRP). MMP-8 testing may be useful as an adjunct to traditional periodontal diagnostic methods during the maintenance phase.

Biomarkers↗
PubMed2006

Salivary matrix metalloproteinase-8 in patients with and without coronary heart disease may indicate an increased susceptibility to periodontal disease.

BACKGROUND AND OBJECTIVE: Tissue destruction caused by periodontitis may increase the number of cytokines implicated in the pathogenesis of cardiovascular diseases. We measured the concentration of the leukocyte-derived proteolytic enzyme, salivary neutrophil collagenase-2 [matrix metalloproteinase-8 (MMP-8)], as a marker of periodontal disease and assessed its relationship to coronary heart disease (CHD). Our aim was to study whether salivary MMP-8 levels were different among patients with and without CHD. The hypothesis was that patients with heart disease might present higher salivary MMP-8 levels than cardiologically healthy controls. MATERIAL AND METHODS: Saliva samples were taken from 256 patients with CHD and from 250 matched controls with known oral and general health status. The MMP-8 levels in saliva were analyzed by immunofluorometric assay, salivary albumin was assessed by enzyme-linked immunosorbent assay (ELISA) and total protein was determined using the colorimetric method. We further investigated the molecular forms and isoform distribution of salivary MMP-8 by western immunoblotting. The MMP-8 results were adjusted for the number of teeth and salivary protein concentrations. RESULTS: The adjusted logarithmic MMP-8 values were 0.145 +/- 0.245 microg/l in patients with CHD and 0.088 +/- 0.115 microg/l in controls (p < 0.01). The respective MMP-8 : total protein and MMP-8 : albumin ratios were also significantly higher in CHD patients than in non-CHD subjects. CONCLUSION: Elevated salivary MMP-8 levels seemed to associate with CHD, suggesting more tissue breakdown as a result of periodontitis among the patients with heart disease.

Analysis of Variance↗
PubMed2006

Collagen degradation by interleukin-1beta-stimulated gingival fibroblasts is accompanied by release and activation of multiple matrix metalloproteinases and cysteine proteinases.

OBJECTIVE: Several collagenolytic matrix metalloproteinases (MMPs) have recently been identified in gingival fibroblasts, while secreted cysteine proteinases could also participate in connective tissue destruction in periodontitis. To clarify their involvement, we examined enzyme release during collagen breakdown by cultured cytokine-stimulated fibroblasts. MATERIALS AND METHODS: Gingival fibroblasts were derived from four chronic periodontitis patients and cultured on collagen gels in serum-free medium for 1-4 days. Collagenolysis was measured by hydroxyproline release into the medium. Proteinases were assessed by electrophoresis and immunoblotting. RESULTS: Adding interleukin-1beta resulted in progressive gel breakdown. This was associated particularly with a shift in MMP-1 band position from proenzyme to active enzyme and the appearance of active as well as proenzyme forms of cathepsin B. There was also partial processing of pro-MMP-13 and increased immunoreactivity for active cathepsin L. In addition, both pro-forms and active forms of MMP-8, membrane-type-1-MMP and MMP-2 were present in control and treated cultures. CONCLUSIONS: Fibroblast MMP-1 was most likely responsible for collagen dissolution in the culture model, while cathepsin B may have been part of an activation pathway. All studied proteinases contribute to extracellular matrix destruction in inflamed gingival tissue, where they probably activate each other in proteolytic cascades.

Adult↗
PubMed2006

Effects of alendronate and hormone replacement therapy, alone and in combination, on saliva, periodontal conditions and gingival crevicular fluid matrix metalloproteinase-8 levels in women with osteoporosis.

OBJECTIVE: To compare the effects of hormone replacement therapy (HRT), alendronate and their combination on oral health of elderly postmenopausal women with osteoporosis. MATERIALS AND METHODS: Sixty patients, aged 65-80 years (mean 71 years), with a T-score of bone mineral density of -2.5 s.d. or less at either the lumbar spine or the femoral neck, were randomized to receive 2 mg of estradiol plus 1 mg norethisterone acetate (HRT) (n = 20), 10 mg of alendronate (n = 18), or their combination (n = 22) for 2 years. Periodontal and oral status and mouth symptoms were recorded, and salivary analyses made at the beginning and at the end of the study. Gingival crevicular fluid (GCF) matrix metalloproteinase (MMP-8) levels were determined to address destructive events in periodontal tissue. RESULTS: Resting salivary flow rate decreased by 19% (P < 0.05), and GCF MMP-8 tended to increase in the alendronate group. None of the regimens affected subjective feelings of dry or burning mouth. There were no significant changes in dental or periodontal status, stimulated flow rate or composition of saliva during the study. CONCLUSIONS: Alendronate decreased resting salivary flow rate but otherwise HRT or alendronate separately or in combination had no effect on oral health in elderly women with osteoporosis.

Aged↗
PubMed2006

Specificity of the monoclonal antibody 3H8 in the immunohistochemical identification of Candida species.

Candida albicans has been shown to be involved in the pathogenesis of adult periodontitis (AP). The diagnosis of Candida-associated AP depends largely on the identification of yeast and pseudomycelial forms in gingival tissue samples by using periodic acid-Schiff and Gomori methenamine silver stains. However, these stains are non-specific and also reveal confusing artifacts seemingly rather difficult to distinguish from yeasts. With the recent development and availability of monoclonal antibodies (Mabs) to various epitopes of C. albicans, for example Mab 3H8 which recognizes a mannoprotein, it is now possible to identify Candida in human tissue biopsies. To explore further the usefulness of this Mab in detecting Candida in periodontal disease the antibody was tested against a wide range of yeast species and strains and various morphological forms, grown in agar blocks at various temperatures and for various time periods. Furthermore, considering the location of the 3H8 epitope on the external cell wall of certain C. albicans strains, it seemed reasonable to determine whether the epitope could be expressed into the surrounding environment, further aiding the recognition of the organism in tissue. The 3H8 epitope appeared to be located at the external surface and on the septum between the mother cell and germ tube of some C. albicans strains but it was partially cryptic in the cell wall of other strains. Both yeast blastoconidia and pseudohyphae were labeled by the 3H8 antibody. Candida lusitaniae, C. glabrata, C. krusei, C. parapsilosis and C. tropicalis did not posses the epitope. The epitope was expressed extracellularly by both blastoconidia and pseudohyphae of C. albicans. This Mab appears to be suitable for the identification of C. albicans in periodontal tissue and may provide further insight into the role of C. albicans in the pathogenesis and diagnosis of periodontal diseases.

Animals↗
PubMed2006

Gingival crevicular fluid matrix metalloproteinase-13 levels and molecular forms in various types of periodontal diseases.

BACKGROUND: The purpose of this study was to evaluate the levels, molecular forms and activation degree of matrix metalloproteinase-13 (MMP-13) in the gingival crevicular fluid (GCF) of patients with periodontal diseases and to correlate these findings with periodontal clinical parameters. METHODS: Sixty one subjects participated in this study as healthy (n = 18), gingivitis (n = 17), aggressive periodontitis (AgP; n = 15) and chronic periodontitis (CP; n = 11) groups. Clinical measurements and GCF samples were obtained from each subject. The molecular forms of MMP-13 in GCF samples were analyzed by Western immunoblotting method. Differences among the groups were assessed using non-parametric statistical analysis. RESULTS: In the CP group, levels of 29-30 kDa fragment of MMP-13, total MMP-13, and activated form of MMP-13 were significantly higher than in the healthy, gingivitis and AgP groups. GCF levels of all molecular forms of MMP-13 in AgP group were similar to those of healthy and gingivitis groups. Total and activated MMP-13 levels were positively correlated with all clinical parameters. 29-30 kDa fragment levels of MMP-13 were also positively correlated with papillary bleeding index and plaque index. CONCLUSION: These results indicate that elevated GCF MMP-13 levels may play an important role in the pathogenesis of CP. These data demonstrate, for the first time, pathologically activated and elevated MMP-13 in GCF.

Acute Disease↗
PubMed2006

Gingival tissue and crevicular fluid co-operation in adult periodontitis.

Activated matrix metalloproteinase-3 (MMP-3) can contribute to periodontal ligament destruction in adult periodontitis. Since MMP-3 has been reported to activate proMMP-8 and -9, it was speculated that gingival tissue fibroblast-derived MMP-3 might, in periodontitis, be responsible for activation of gingival crevicular fluid (GCF) neutrophil-derived proMMP-8 and -9. Immunohistochemistry disclosed MMP-3 in gingival fibroblasts in periodontitis. Cultured gingival fibroblasts released only pro-MMP-3 when stimulated with tumor necrosis factor-alpha. However, Western blot revealed partially activated MMP-3, MMP-8, and MMP-9 in periodontitis GCF. Active MMP-8 (p < 0.05) and MMP-9 (p < 0.05) correlated with the presence of active MMP-3. It seems that resident gingival fibroblasts produce pro-MMP-3 in GCF, where it becomes activated, probably by cathepsin G or elastase released by neutrophils. Active MMP-3 then activates neutrophil-derived pro-MMP-8 and -9. Different tissue compartments/cells exert co-operative actions in mutual local MMP activation cascades.

Adult↗
PubMed2005

Alpha v beta 6 integrin down-regulates the MMP-13 expression in oral squamous cell carcinoma cells.

The integrin alphavbeta6, a receptor for fibronectin, vitronectin, tenascin and TGF-beta latency-associated peptide (LAP), is not detectable on normal oral epithelium but is neo-expressed in oral squamous cell carcinomas (OSCC) and epithelial dysplasia. Previously it has been shown that alphavbeta6 integrin can up-regulate MMP-3 and -9 expression in OSCC cells. Using beta6-transfected and control OSCC cells we demonstrate that alphavbeta6 integrin down-regulates MMP-13 expression at both mRNA and protein level. Although expressing less MMP-13, beta6-transfected cells were found to have similar collagenolytic activity as control cells and invade at similar levels through type I collagen. Growth of the tumour cells in organotypic culture and confocal microscopy confirmed low levels of MMP-13 in cells with high alphavbeta6 expression. Furthermore, human squamous cell carcinomas of the tongue with high expression of alphavbeta6 showed lower MMP-13 levels than carcinomas with low levels of alphavbeta6. Our results suggest that alphavbeta6 down-regulates MMP-13 expression in OSCC cells and that MMP-13 is not essential for the degradation of type I collagen by OSCC cells.

Antigens, Neoplasm↗
PubMed2005

Chemically modified tetracycline (CMT)-3 inhibits histamine release and cytokine production in mast cells: possible involvement of protein kinase C.

OBJECTIVE: To find novel inhibitors of mast cell function we have studied the effect of a potent, non-antimicrobial, chemically modified tetracycline, CMT-3 or COL-3, on key functions of mast cells. METHODS AND RESULTS: In the presence of 25 microM CMT-3, the 48/80-induced histamine release from rat serosal mast cells was inhibited significantly, to 43.0 +/- 7.3% of control. Similarly, the activation-induced secretion of TNF-alpha and IL-8 by HMC-1 cells were decreased in the presence of 25 microM CMT-3 to 13.5 +/- 4.1% and 9.7 +/- 1.1% of control, respectively. CMT-3 did not cause intracellular accumulation of TNF-alpha but instead it reduced the expression of TNF-alpha mRNA in HMC-1 cells. Moreover, CMT-3 was found to significantly inhibit the protein kinase C (PKC) activity with IC(50) value of 31 microM. CMT-3 inhibited effectively both human recombinant PKCalpha and PKCdelta isoforms. In comparison to doxycycline, CMT-3 was more effective as an inhibitor of both cytokine production and PKC activity. CONCLUSIONS: Considering the central role of PKC in mast cell activation, PKC inhibition could, at least partially, explain the observed inhibitory effects of CMT-3. The inhibition of the key proinflammatory functions of mast cells by CMT-3 suggests its potential clinical usefulness in the treatment of allergic and inflammatory disorders.

Animals↗
PubMed2005

Effect of E. faecalis on the release of serine proteases elastase and cathepsin G, and collagenase-2 (MMP-8) by human polymorphonuclear leukocytes (PMNs).

AIM: To measure the release of hydrolytic enzymes [elastase, cathepsin G and collagenase-2 (MMP-8)] from human polymorphonuclear leukocytes (PMNs) during interaction with strains of Enterococcus faecalis isolated from endodontic infections. METHODOLOGY: Six E. faecalis strains isolated from treatment resistant cases of apical periodontitis were included in the study. Overnight cultures of the microbes were used for the experiments. PMNs were isolated using the Ficoll Paque technique, and their vitality was assessed throughout the experiments by the Trypan Blue exclusion test. A known amount of microbes and PMNs were mixed in PBS at +37 degrees C in air, and the release of elastase, cathepsin G and MMP-8 was measured at 0, 20, 60 and 120 min after initiation of incubation. The activities of elastase and cathepsin G were analysed by spectrophotometer assays using specific synthetic peptide substrates, and MMP-8 by western immunoblotting quantitated by computer densitometry. PMNs incubated in buffer without any added microbes served as negative controls, cells incubated with 5 ng mL(-1) phorbol myristic acetate (PMA) served as a positive control. The 95% confidence interval was used to compare the relative amount of elastase and cathepsin G released from the samples. RESULTS: One E. faecalis strain induced a similar or higher elastase, cathepsin G and MMP-8 release than the positive control, whereas the other five strains induced only moderate or no release of the three enzymes examined as compared with the negative and positive controls. Western immunoblot revealed that released MMP-8 had molecular sizes of 60 and 75 kDa representing active and latent forms of MMP-8. In addition, >110 kDa high molecular size and a fragmented 20-30 kDa MMP-8 species could be observed. CONCLUSIONS: The majority of the E. faecalis strains induced little or no release of hydrolytic enzymes from the PMN cells. The finding may partly explain the clinical observation that root canal infections dominated by E. faecalis are usually symptom free.

Blotting, Western↗
PubMed2005

In vivo relationship between collagenase-2 and interleukin-8 but not tumour necrosis factor-alpha in chronic rhinosinusitis with nasal polyposis.

BACKGROUND: The characteristic feature of chronic rhinosinusitis with nasal polyposis (CRSwNP) is eosinophilic inflammation of the sinus mucosa; a type of inflammation also seen in asthmatic airways. Similar histopathologic findings of airway remodelling are present in both diseases. Remodelling is tightly controlled by matrix metalloproteinases (MMP). Increase of collagenase-2 (MMP-8) expression in the bronchial epithelial cells has been described in asthmatic patients, but it has not been studied in CRSwNP. METHODS: The concentrations and degree of activation of MMP-8 were analysed by immunofluorometric assay and Western blotting, respectively, in sinus mucus samples from CRSwNP patients and in nasal lavages from healthy controls in relation to inductive cytokines interleukin-8 (IL-8) and tumour necrosis factor-alpha (TNF-alpha). RESULTS: Significantly elevated levels of MMP-8 and IL-8 but not TNF-alpha were found in CRSwNP patients relative to controls. In particular, the activation of mesenchymal-type MMP-8 but not polymorphonuclear-type MMP-8 was associated with elevated IL-8 levels. CONCLUSIONS: The IL-8 and MMP-8 seemingly form an inductive cytokine-proteinase cascade in CRSwNP pathogenesis. Together they provide a target for novel therapies and a diagnostic tool for monitoring CRSwNP treatment.

Aged↗
PubMed2005

Painful tooth stimulation elevates matrix metalloproteinase-8 levels locally in human gingival crevicular fluid.

Recent studies have demonstrated that pulpal pain can induce neurogenic inflammatory reactions in gingiva and the expression of pro-inflammatory neuropeptides in gingival crevicular fluid (GCF). Neuropeptides co-ordinate the activity of immuno-effector cells and may influence the secretion of matrix metalloproteinase (MMP)-8, the major tissue-destructive protease in GCF. With this background, we studied whether experimental pulpal pain can trigger changes in GCF MMP-8 levels. The molecular forms of MMP-8 in the GCF of stimulated and non-stimulated teeth were analyzed by Western immunoblot, and MMP-8 levels by quantitative immunofluorometric assay. Painful stimulation of the upper incisor provoked significant elevations in GCF MMP-8 levels of the stimulated tooth. Western immunoblot revealed elevations in both neutrophil- and mesenchymal-type MMP-8 isoforms. At the same time, the GCF MMP-8 levels of the non-stimulated teeth were not changed. Analysis of these data indicated that pulpal pain can induce local elevations in MMP-8 levels in GCF.

Adult↗
PubMed2004

Candida yeasts in chronic periodontitis tissues and subgingival microbial biofilms in vivo.

The frequency of Candida infection in periodontal tissues of chronic periodontitis (CP) patients and the extent of candidal penetration into gingival tissues was studied. Tissue specimens collected from 25 CP patients during periodontal flap operations of initial periodontal therapy were examined by immunohistochemistry using Candida albicans-specific antibodies. Sections were also stained with periodic acid-Schiff (PAS) and subgingival plaque samples from 17 patients were cultured. Immunoreactivity for Candida was present in four of the 25 CP specimens (16%). Only one yeast-positive specimen was found when PAS-staining was used (4%) and two yeast-positive specimens were found with plaque culture (8%). Hyphal formation seemed essential and candidal hyphae were found to extend into the periodontal connective tissue. The degree and type of inflammation adjacent to the hyphae varied from a site and a patient to another. The sensitivity of specific antibodies was superior to PAS-stain or plaque culture in detection of Candida in tissues.

Biofilms↗
PubMed2004

Chlamydia pneumoniae together with collagenase-2 (MMP-8) in periodontal lesions.

OBJECTIVE: Dental infections may be associated with subsequent atherosclerosis. In this regard we wanted to study if traces of Chlamydia pneumoniae can be found from deep periodontal pockets characterized with elevated collagenase-2 [matrix metalloproteinase (MMP)-8] levels in gingival crevicular fluid (GCF). Chlamydia pneumoniae has not previously been found to infect the oral cavity. SUBJECTS AND METHODS: Subgingival samples of dental plaque were collected from 31 teeth in 12 adult periodontitis patients by means of sterile curettes and examined for C. pneumoniae using a quantitative PCR technique. GCF samples were also collected and assayed by an immunofluorometric assay (IFMA) for MMP-8. RESULTS: Chlamydia pneumoniae RNA was demonstrated in a sample from one of the patients studied. Periodontal treatment eliminated the C. pneumoniae from the patient's subgingival dental plaque as well as reduced GCF MMP-8 level. CONCLUSIONS: Our findings suggest that C. pneumoniae, which is not normally thought to be involved in periodontitis, can be found in dental plaque.

Adult↗
PubMed2004

Treatment of experimental autoimmune encephalomyelitis with a neurotropic alphavirus vector expressing tissue inhibitor of metalloproteinase-2.

Prompted by our recent observations of increased MMP-8 and MMP-9 with simultaneous downregulation of tissue inhibitor of metalloproteinase-2 (TIMP-2) and TIMP-3 mRNA levels in the central nervous system (CNS) of mice with severe experimental autoimmune encephalomyelitis (EAE), we used Semliki Forest virus (SFV) to transfer and express recombinant murine TIMP-1-3 genes in the CNS. TIMP-1, TIMP-2 and TIMP-3 expression was confirmed in cultured cells and in the CNS of infected mice. Following intraperitoneal infection with 10(6) plaque-forming units (PFU) of SFV-TIMP, focal TIMP protein expression was achieved throughout the brain. Although already treatment with empty vector inhibited development of EAE to some extent, the expression of TIMP-2 by the virus significantly enhanced the inhibition. TIMP-3-administered mice also had lower disease grade, but the inhibition was not statistically significant. In contrast, SFV-TIMP-1 had no effect, similar to co-infection with TIMP-2 and TIMP-3. We found TIMP-2 expression also by non-infected CNS-resident cells surrounding the virus-positive areas, suggesting a bystander TIMP-2 induction. These data strengthen the view that matrix metalloproteinases are involved in the pathogenesis of EAE and provide clear evidence that virus-mediated delivery of their protein inhibitors can be effective in preventing the clinical disease. TIMPs might be candidates for novel treatment regimens in CNS autoimmune disorders, such as multiple sclerosis.

Animals↗