Slow-release TNF receptor controls inflammatory disease

THE LANCET

SCIENCE AND MEDICINE

Slow-release TNF receptor controls inflammatory disease

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ontrolled release of soluble tumour necrosis factor (TNF) receptor, sp55-R, from biodegradable polymers can prevent lethal wasting and arthritis induced in mice by chronic exposure to TNF. These results, say Israeli researchers, suggest that slow-release, soluble TNF receptor may be therapeutically useful in chronic inflammatory diseases. It has been known for some time that soluble TNF receptor serum concentrations increase in chronic inflammatory diseases. What has not been clear is whether the soluble receptor lessens the pathological effect of circulating inflammatory TNF by competitively binding TNF away from cell-surface TNF-receptor sites, or whether the soluble receptor increases the duration of TNF action by binding to it and stabilising it. To answer this question, Joseph Kost and Rom Eliaz (Ben-Gurion University, Beer-Sheva, Israel) and David Wallach (Weizmann Institute of Science, Rehovot, Israel) incorporated sp55-R into biodegradable copolymer microspheres and injected the microspheres subcutaneously (Cytokine 1996; 8: 482–87) into mice which had raised amounts of TNF. The copolymer-treated mice were protected from TNF-induced wasting and arthritis. “These microspheres carry and protect the natural soluble peptide receptors. As the copolymer degrades a fairly constant stream of the receptor is released into the blood stream by diffusion, mimicking the process of continuous release of the receptors from sites of local inflammation”, says Wallach. Previous experimental approaches for treating chronic inflammatory diseases with soluble TNF receptors have been based on making the receptors bulkier to reduce their rate of clearance from the blood, but these modifications may mark the receptors as foreign bodies and stimulate an immune response against them. “Our copolymer delivery method allows microgram quantities (far less than needed for injection) of the natural form of the soluble receptors to maintain significant elevation of their concentration in the serum over months, in a way that no injection system could ever accomplish”, says Kost. Rachelle H B Fishman

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Vitamins alter oxidation product excretion

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esearchers at the University of Pennsylvania, USA, report that antioxidant therapy may lead to reduced urinary excretion of 8-epiprostaglandin F2a (8-epi-PGF2a ), a product of lipid peroxidation (Circulation 1996; 94: 19–25). It is thought that smoking induces vascular damage by oxidant injury. One of the products of freeradical attack on blood vessel-bound arachidonic acid is 8-epi-PGF2a (figure). When researchers measured urinary 8-epi-PGF2a in chronic smokers and nonsmokers, they found higher urinary concentrations in smokers than in non-smokers. The increased levels correlated positively with number of cigarettes smoked daily. Urinary excretion of 8-epi-PGF2a dropped if subjects stopped smoking but were not affected by 325 mg/day of aspirin. In the study, subjects were given different doses of vitamins: 100 mg/day vitamin E to moderate smokers; 800 mg/day vitamin E to

heavy smokers; 2 g/day vitamin C; or a combination of the two vitamins. Significant reductions of urinary 8-epi-PGF2a were found only in the latter two groups. The authors allow that although vitamin therapy has not been demon-

strated to be beneficial for the prevention or treatment of atherosclerosis, the 8-epi-PGF2a urine assay, as a quantitative measure of “oxidant stress”, may yield new insights into dose-response relations and efficacy. David H Frankel

HIV-1 group O infection identified in USA

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he US Centers for Disease Control and Prevention (CDC) has reported the first known case of HIV-1 group O infection in the US (MMWR 1996, 45: 561–65). The patient arrived in Los Angeles County, California, from West Central Africa in 1994, and presented with generalised lymphadenopathy later that year. In 1995 a combined ELISA test for HIV-1 and HIV-2 gave negative results, but later tests gave a mixture of negative and weak positive results. Western blots were indeterminate; PCR was negative. Sequence analysis of virus cultured from the patient’s peripheral blood mononuclear cells showed it to be related to ANT70 and MVP5180, the prototypical group O strains. PCR with group O primers was positive, and the serum contained antibodies to group O peptides, but not group M peptides. Like all but one of the European group O cases, this case is thought to have been acquired in Africa;

authorities are currently seeking the one man with whom the patient reported sexual contact in the USA. The US Food and Drug Administration is working with manufacturers to add more reliable group O reactivity to the existing HIV-1 tests. Current tests designed to detect the commoner group M viruses fail to detect group O viruses 20% of the time (Lancet 1994; 343: 1393-94 and 344: 1333-34). Any new HIV-1 test kits submitted for FDA approval will now be expected to reliably detect group O virus. The challenge is to increase sensitivity for group O viruses without reducing the sensitivity to the common group M strains. For patients with HIV symptoms whose laboratory results are negative or equivocal, the CDC recommends that physicians seek help from state and local health departments in testing for group O and other rare strains of the virus. Paul M Rowe

Vol 348 • July 13, 1996