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Addition of Salbutamol Enhances Oral Tolerance in Rats With Established Arthritis

Dec 18, 2002
By Faith Reidenbach
Reuters Health

The beta-agonist salbutamol (albuterol), when administered along with immunizing therapy, results in arthritis-suppressive tolerance induction in rats that have an ongoing inflammatory response, a Dutch research team reports.

In a previous animal study the group conducted, "tolerance could only be achieved when the tolerizing antigen was administered before disease induction," senior researcher Dr. Cobi J. Heijnen said in an interview with Reuters Health. "Now we can induce effective tolerance during the disease process."

In the November 1 issue of The Journal of Immunology, Dr. Heijnen and colleagues at Utrecht University note that the addition of salbutamol to an antigen-stimulated culture has been shown to inhibit the proinflammatory cytokine interferon-gamma and upregulate the anti-inflammatory cytokine interleukin-4. They speculated that, in vivo, such a shift in cytokine balance in the gut might enhance oral tolerance induction.

In eight rats exhibiting early symptoms of induced arthritis, the researchers orally administered salbutamol plus mycobacterial 65-kDa heat shock protein (HSP65), salbutamol alone, HSP65 alone, or salbutamol with or without superoxide dismutase (SOD), which was used as an irrelevant antigen. The animals were treated every other day for a total of five doses.

At the end of the treatment period, the cumulative arthritis score was significantly lower in rats that received salbutamol/HSP65 than in those that received HSP65 alone or SOD. Salbutamol alone and salbutamol/SOD had no effect on disease severity.

"The use of adrenergic drugs will really make a step forward in the therapy for autoimmune diseases using tolerance induction," Dr. Heijnen told Reuters Health. "We know that the studies have not been successful so far. But the use of this drug really opens up a new possibility to help patients with arthritis and, very likely, multiple sclerosis."

To investigate the modulating effect of salbutamol over the long term, the researchers studied a murine model of ovalbumin (OVA)-induced delayed-type hypersensitivity. They observed that oral coadministration of OVA and salbutamol induced tolerance, and with booster doses the effects persisted throughout 12 weeks of observation.

Yet by the end of 12 weeks, cytokine patterns in the gut were the same as in saline-treated animals, according to the report. In contrast, splenocyte production of OVA-induced IFN-gamma remained elevated.

"We suggest that long-lasting tolerance induction is not simply mediated by a decrease in the balance between pro- and anti-inflammatory cytokines," the authors write, "but will involve immediate upregulation of anti-inflammatory cytokines during oral antigen administration as well as long-lasting upregulation of some proinflammatory mediators, i.e., INF-gamma, to control the ongoing immune or disease process."

J Immunol 2002;169:5028-5035.

© 2002 Reuters Ltd