By David N. Leff
Three back-to-back papers in the current issue of Science solve a puzzle ofmolecular immunology related to X-linked severe combined immune deficiency (XSCID)disease. The key to the black box they have opened is the interleukin-2 receptor's gamma (
Twenty-two co-authors contributed to the three cytokine research studies, seven fromtwo universities in Japan, 11 from three National Institutes of Health institutes plusFDA, and four from three biotechnology companies: DNAX Research Institute, a subsidiary ofSchering-Plough Corp.; Immunex Corp.; and R&D Systems Inc.
The first paper, by microbiologist Kazuo Sugamura et al of Tohoku University inSendai, Japan, reveals the sharing of that g chain between theIL-2 and IL-4 mouse receptors. Warren Leonard, chief of pulmonary and molecular immunologyat the NIH's National Heart, Lung and Blood Institute (NHLBI), is principal author of thetwo other papers, reporting the IL-2 g chain's presence androle on IL-4 and IL-7 human receptors.
Defining Molecular Structure
“I think the field in general is at the stage of trying to define the molecularstructure of each of the cytokine receptors -- who's sharing what receptor chains,“said Maureen Howard, director of immunology at DNAX of Palo Alto, Calif. “If you wantto block of activate any specific cytokine, you have to know who else is sharing itschain, who else you're going to either wipe out or turn on at the same time,“ shetold BioWorld.
Nobuyuki Harada, a member of Howard's group at DNAX, contributed assays he haddeveloped for IL-4 receptor binding to Leonard's work. IL-4, also known as B cell growthfactor, stimulates a spectrum of immune responses, notably B cell / T cell interaction.
“Of course, I'm very familiar with the IL-4 because our parent company,Schering-Plough, owns it and is developing it,“ Howard, who is a co-discoverer ofthat cytokine, told BioWorld.
Co-author Steven Ziegler of Immunex of Seattle sent Leonard a cDNA encoding the IL-7receptor and a monoclonal antibody raised against it. And Monica Tsang, executive directorof the cytokine group at R&D Systems, a cytokine reagent company in Minneapolis,provided the NHLBI lab with the IL-7 material for its research.
“Immunex still has an interest in the IL-7 receptor as a potential therapeuticsoluble reagent,“ Ziegler said. “We're doing some animal work but don'tcontemplate any human trials.“
“X-linked SCID occurs probably once in every 100,000 to 200,000 live births andrepresents about half of all SCID types,“ Leonard told BioWorld. (XSCID is notto be confused with the SCID afflicting two small girls who received gene therapy for lackof a functioning adenosine deaminase gene).
“Because it arises from a defective gene on the X chromosome it will manifestitself only in males,“ Leonard explained. XSCID is known as the “bubble-boydisease“ because it came to prominence in the 1970's with “David V,“ apatient who spent all 12 years of his young life in a reverse laminar-flow environment toward off infection. In fact, David V was one of the three XSCID patients whose preservedbiological materials served to carry out Leonard's gene probing.
Leonard and his co-workers discovered the XSCID gene defect about a year ago. He hadobserved that patients with IL-2 deficiency suffered a milder form of SCID, as did mice inwhich the gene for the IL-2 receptor's g chain had been knockedout. “We speculated that the g chain would probablyturn out to be part of more than one interleukin receptor,“ he told BioWorld,“so that knocking out the gamma would knock out not only the IL-2 system butadditional systems as well.“
Leonard and his 14 co-authors confirmed this speculation in their two papers in thecurrent issue of Science, implicating IL-4 and IL-7 in the gamma daisy chainsharing effect with IL-2. So did Japan's Sugamura for the IL-2/IL-4 connection.
Leonard counts three ways in which this finding is important:
• “It helps to explain how IL-7 signaling works because before thisdiscovery, there had been only one known chain for the IL-7 receptor. We showed that thisreceptor was not functional by itself, but if we combined the gamma chain with it, itwas.“
• “In a different fashion, we showed the same thing for the IL-4 receptor.
• “The idea of a common chain among three different cytokine receptors,possessing both overlapping and, at times, opposing functions, helps to explain why theyhave some similar and some competing actions.“
This mutual modulation, Leonard observed, “might be advantageous when you turn onone system to help shut off another. Or maybe you would want them both to synergize orpotentiate some desired effect.“
Leonard's colleagues pinpointed the multipurpose cytokine-receptor gchain gene to the long arm of human chromosome X. “In fact, the gamma chain is thatdefective XSCID gene,“ he said. It has a variety of nonsense mutations, notably somethat switch on stop codons prematurely to interrupt DNA transcription and truncate thegene. Since without successful bone marrow transplantation few if any XSCID victims livebeyond one year, those gene defects must arise de novo to perpetuate the disease.
Pharmaceutical Pay-Offs Real but Remote
Discovery of the g chain's protein presence “has realimplications for prenatal and neonatal diagnosis, female carrier identification and genetherapy,“ Leonard said, “the last, presumably by stem cell-based intervention.People are working on it, but it's not imminent.“
Meanwhile, researchers such as those at Schering Plough are working on the area'sdrug-development potential. “Our parent company, and I imagine other parentcompanies, are just coming to terms with this novel area for new drug discovery,“said DNAX's Howard.
She discerns two likely approaches. “Either modify the cytokine itself so thatit's working outside the cell or, alternatively, target some of those proteins in theintracellular pathways.“ Harada prefers the latter approach, Howard noted.“Cytokine is not the easiest reagent in the world to use in drugs,“ she said.“So those of us who work in this area hope that the next generation of cytokineproducts will be smaller molecules that target the intracellular signals turned on when acytokine binds to its receptor.“
DNAX researchers recently found that IL-4 and IL-13 share a second chain not yetidentified. Leonard and Sugamura both predicted that it will turn out to be the busybodygamma.