Intraarticular interferon-beta gene therapy ameliorates adjuvant arthritis in rats.

Interferon (IFN)-beta has significant immunomodulatory properties and has received much interest as a potentially therapeutic agent for rheumatoid arthritis (RA). Systemic IFN-beta treatment of patients with RA was not effective, probably because of pharmacokinetic issues. Therefore, we studied the effect of local IFN-beta production by adenovirus-mediated gene transfer to the ankle joints of arthritic rats. Adjuvant arthritis (AA) in rats was used as a model to study intraarticular gene therapy with an adenoviral vector encoding the rat IFN-beta gene (Ad.IFN-beta). The effect on paw swelling was measured by water displacement plethysmometry. Synovial tissue of the hind paws was examined by immunohistochemistry. Bone destruction was analyzed on the basis of radiographs. In addition, quantitative real-time polymerase chain reaction was used to assess IFN-beta expression. Levels of IFN-beta mRNA and protein peaked 2 days after intraarticular injection and declined thereafter. Local delivery of Ad.IFN-beta after the onset of disease reduced paw swelling significantly. This was accompanied by a reduction in synovial inflammation. The clinical effects in rat AA lasted up to 9 days. Strikingly, Ad.IFN-beta treatment protected bone from erosion, reduced levels of c-Cbl and Cbl-b (both signaling molecules essential for osteoclast activity), and reduced the matrix metalloproteinase-3:tissue inhibitor of metalloproteinase-1 ratio in the joint. Immunohistochemical analysis of the synovial tissue revealed a clear shift toward a more antiinflammatory cytokine profile. Local overexpression of IFN-beta inhibits arthritis progression and protects against bone destruction in rat AA. These findings validate IFN-beta as a therapeutic molecule for intraarticular gene therapy of arthritis.

Expression of interferon beta in synovial tissue from patients with rheumatoid arthritis: comparison with patients with osteoarthritis and reactive arthritis.

BACKGROUND: IFNbeta may have immunomodulatory effects in rheumatoid arthritis (RA) and its increased production in RA synovium may be a reactive attempt to inhibit inflammation. OBJECTIVE: To determine the expression of IFNbeta in the synovial tissue of patients with RA, osteoarthritis, and reactive arthritis. METHODS: Synovial biopsy specimens were obtained by arthroscopy from patients with RA and disease controls for immunohistological analysis using a monoclonal antibody specific for IFNbeta. Bound antibody was detected by an immunoperoxidase method. Stained sections were evaluated by computer assisted image analysis. Double stainings were performed with antibodies to detect CD55 positive fibroblast-like synoviocytes (FLS), CD68 positive macrophages, and CD83 positive dendritic cells (DCs) co-expressing IFNbeta. RESULTS: IFNbeta protein was abundantly expressed in the synovium of patients with RA. Digital image analysis showed a significant increase in the mean integrated optical density for IFNbeta expression in RA synovial tissue compared with disease controls. Specific up regulation of IFNbeta expression was also seen when the results were controlled for cell numbers. Phenotypic analysis showed that FLS, especially, but also macrophages and DCs may express IFNbeta in RA synovial tissue. CONCLUSIONS: The increased expression of IFNbeta in RA synovium suggests activation of an immunomodulatory mechanism that could inhibit synovial inflammation.

A multicentre, randomised, double blind, placebo controlled phase II study of subcutaneous interferon beta-1a in the treatment of patients with active rheumatoid arthritis.

OBJECTIVE: To assess the efficacy of interferon beta (IFN beta) in combination with methotrexate in treatment of patients with rheumatoid arthritis. METHODS: 209 patients with active rheumatoid arthritis, who had been on methotrexate for at least six months and at a stable dose for four weeks before study entry, were randomised in double blind fashion to receive placebo (0.05 ml or 0.5 ml), IFN beta 2.2 microg (0.05 ml), or IFN beta 44 microg (0.5 ml), given subcutaneously three times weekly for 24 weeks. The primary efficacy measure was a change in radiological scores at week 24. The secondary endpoint was the proportion of patients who met the ACR 20% improvement criteria at the end of the study. Synovial biopsy specimens were obtained before and after treatment from a subset of patients. Immunohistochemistry was used to detect the presence of inflammatory cells and the results were measured by digital image analysis. Collagen crosslinks were measured in urine at different times throughout the study. RESULTS: Analysis of radiological scores and clinical variable showed no changes in any of the groups, and there were no differences between the groups. On microscopic analysis of synovial tissue there was no significant change in the scores for infiltration by inflammatory cells after IFN beta treatment. Urinary levels of collagen crosslinks were unchanged between the treatment groups. CONCLUSIONS: At the doses tested, treatment with IFN beta three times weekly in combination with methotrexate did not have a clinical or radiological effect in patients with rheumatoid arthritis.

Cosmological Higgs fields.

We present a time-dependent solution to the coupled Einstein-Higgs equations for general Higgs-type potentials in the context of flat Friedmann-Robertson-Walker cosmological models. Possible implications are discussed.

A precious metal alloy for construction of MR imaging-compatible balloon-expandable vascular stents.

The authors developed ABI alloy, which mechanically resembles stainless steel 316. The main elements of ABI alloy are palladium and silver. Magnetic resonance (MR) images and radiographs of ABI alloy and stainless steel 316 stent models and of nitinol, tantalum, and Elgiloy stents were compared. ABI alloy showed the least MR imaging artifacts and was more radiopaque than stainless steel 316. ABI alloy has the potential to replace stainless steel 316 for construction of balloon-expandable MR imaging-compatible stents.

Orally administered Lactobacillus strains differentially affect the direction and efficacy of the immune response.

In mice, strain dependent cytokine production profiles are induced after oral administration of Lactobacillus. Such a cytokine profile seems to determine the direction and efficacy of the humoral response. In SJL mice lactobacilli are able to enhance or inhibit the development of disease after induction of experimental autoimmune encephalomyelitis (EAE). Immuno-histochemical analysis of cytokine profiles showed that differential modulation is obtained dependent on the Lactobacillus strain applied. Serum antibody responses to i.p. immunisation with chicken gamma globulin in BALB/c mice are also modulated by oral application of Lactobacillus. Lactobacilli are now being developed as safe live antigen carriers for application in vaccine technology, but also for the excretion of autoantigens in order to induce tolerance. The findings of this study imply that by proper strain selection the direction of the response can be influenced by the induction of a specific cytokine profile.

Tick-borne relapsing fever and pregnancy outcome in rural Tanzania.

OBJECTIVE: To assess the impact of tick-borne relapsing fever (TBRF) on the outcome of pregnancy. DESIGN: Case control study of 137 pregnant women (cases) and 120 non-pregnant women (controls) with TBRF between 1985 and 1995. SETTING: A rural hospital in Tabora Region, Tanzania. RESULTS: Risk of birth during the attack of TBRF was 58.0%, with an extremely high perinatal mortality of 436 per 1000 births. The total loss of pregnancies including abortions was 475. per 1000. Case-fatality rate in pregnant women was 1.5%, compared to 1.7% in the non-pregnant women. A Jarisch-Herxheimer reaction was seen in 1.5% of the cases and in 1.7% of controls. Relapse rate was 3.6%, compared to 1.7% in non-pregnant women. Pregnant women with TBRF show higher densities of spirochetes than non-pregnant women (p < 0.001). The risk of delivery during the attack was positively correlated to increasing density of the spirochetemia (p < 0.001) and to gestational age (p < 0.001). Perinatal death was related to low birthweight (p < 0.001) and low gestational age (p < 0.001) and not to degree of spirochetemia. CONCLUSIONS: The extremely high perinatal mortality rate during an attack asks for prevention and early effective management of TBRF. This is a challenge where access to health services in rural areas of developing countries is hampered by many factors.

PIP: The impact of tick-borne relapsing fever (TBRF) on pregnancy outcome was investigated in a case-control study of 137 pregnant women and 120 non-pregnant women infected with this condition and treated at a rural hospital in Tanzania's Tabora region during 1985-95. The risk of premature delivery during TBRF was 58%, with a perinatal mortality of 436 per 1000 births. Total pregnancy loss, including abortions, was 475 per 1000. The case-fatality rate was 1.5% in pregnant women compared with 1.7% in non-pregnant controls. The relapse rate was 3.6% in pregnant women and 1.7% in controls. Pregnant women with TBRF had higher densities of spirochetes than controls, and the risk of delivery during an attack was significantly correlated with increasing spirochete density and gestational age. Perinatal mortality was associated with low birth weight and low gestational age, but not with the degree of spirochetemia. The increased spirochete densities in cases are presumed to reflect decreasing immunity during pregnancy. In view of the very high perinatal mortality associated with preterm delivery in TBRF-infected women, prevention and early management are crucial. Although house spraying with benzene hexachloride will temporarily prevent TBRF, permanent results can be achieved only through improved housing construction.