Chronic granulomatous disease

Failing phagocytes become fighters

For the first three years of Brian Simpkins' life, masses of inflamed tissue called granulomas filled his esophagus, causing him to vomit whenever he ate solid foods. Doctors at Children's Hospital in Boston recently began treating Brian -- the victim of a genetic disorder called chronic granulomatous disease (CGD) -- with an experimental drug called gamma interferon. The granulomas disappeared within five weeks.

Brian's treatment was prompted by two studies, reported this month, showing that gamma interferon can remedy defective immune activity in CGD patients. Although CGD is rare, the findings may also benefit victims of other immunodeficiencies and inflammatory diseases, says John Gallin of the National Institute of Allergy and Infectious Diseases (NIAID), a coauthor of one of the articles.

CGD patients cannot produce superoxide anions, molecular fragments responsible for killing bacteria, fungi and other intruders. About two-thirds of CGD patients have a defect in a gene lying on the X chromosome and appear to lack cytochrome b, a membrane protein necessary for superoxide production. Others have a defect on a non-sex-linked, or autosomal, chromosome.

Normally, when a microorganism infects a person, white blood cells called phagocytes engulf it, destroying it with a toxic soup of enzymes, chlorine and superoxides. The phagocytes of CGD patients, lacking superoxides, can engulf but cannot destroy. Infections occur fequently and inflammation persists. Scientists reported last year that they used a genetically engineered gamma interferon to activate abnormal phagocytes in culture to make superoxide. Gamma interferon is normally produced by immune cells called T-lymphocytes.

Researchers then moved from the test tube to the human body. Alan Ezekowtiz, Stuart Orkin and their co-workers at Children's Hospital in Boston gave low doses of gamma interferon to four patients with X-linked CGD on two consecutive days, they report in the July 21 NEW ENGLAND JOURNAL OF MEDICINE. In all four patients the phagocytes' ability to produce superoxides and to kill bacteria increased, reaching normal levels in two patients, and remained raised for more than two weeks. The scientists also observed an increase in cytochrome b levels, which implies the interferon somehow boosted the genes coding for this critical protein.

In the July PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES (Vol. 85, No. 13), Gallin, Harry Malech and their colleagues at NIAID report they administered gamma interferon to 30 patients representing both forms of CGD. About one-third of the X-linked patients and almost all of the autosomal patients improved. Curiously, they found the improvement in bacterial killing was greater than the superoxide improvement. they speculate that gamma interferon enhances cytochrome b and additional genes.

Both research teams plan to participate in a test of gamma interferon involving 100 CGD patients worldwide. They say the treatment looks promising, with no serious side effects. "In research, it's so seldom that you do anything with direct utility for people," says Ezekowitz. Brian, he reports, can now eat a hearty meal of hamburgers and french fries.

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