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“Immune deviation” with IL-4 could prove beneficial in psoriasis
SCIENCE AND MEDICINE
“Immune deviation” with IL-4 could prove beneficial in psoriasis methotrexate but, says Christopher Griffiths (University of Manchester School of Medicine, UK), “few patients are satisfied with these and
Rights were not granted to include this image in electronic media. Please refer to the printed journal. Bring on the immune deviation
several new systemic, immunotherapies are in development that either target T-cell activation or modulate cytokine production”. The latter type of therapy can be subdivided into therapies that block cytokine action and those that switch the cytokine profile within plaques from a proinflammatory Th1 response to an anti-inflammatory Th2 response. Building on previous preclinical work, Röcken and co-workers tested whether treatment with IL-4, a cytokine produced by Th2 cells,
Science Photo Library
pilot study of recombinant human interleukin 4 (rhuIL-4) therapy may offer new hope to people with psoriasis. Martin Röcken (Eberhard Karls Universität Tübingen, Germany) and colleagues report that 15 out of 20 study patients had an improvement of more than 68% in the psoriasis area and severity index (PASI). “This is the first clinical trial in which rhuIL-4 has been tested for treatment of an inflammatory autoimmune disease”, explains Röcken, “and our results indicate that the human immune response can be therapeutically deviated from a proinflammatory toward an anti-inflammatory response”. These results, he says, provide the basis for the development of a vaccine strategy for psoriasis and other autoimmune inflammatory diseases. Psoriasis is a common autoimmune inflammatory disease affecting the skin and joints. Psoriasis plaques contain oligoclonal pro-inflammatory Th1 cells and several lines of evidence indicate that activated T cells are involved in psoriasis pathogenesis. Current therapies include topical vitamin D derivatives, phototherapy, and
A
could modify the cytokine response of activated T cells within psoriasis plaques. In their dose escalation study, 20 patients with severe psoriasis self-injected rhuIL-4 thrice daily, 5 days a week for 6 weeks. The treatment, which was well tolerated, skewed the original Th1 response in the skin to a Th2 response. Furthermore, after rhuIL-4 therapy the condition of 18 patients remained stable or improved when treated with previously ineffective therapies (Nat Med; published online Dec 2; DOI: 10.1038/nm804). “Although this is a open, pilot study with all the drawbacks that entails, these results are impressive”, says Griffiths. “I think that once you get a greater than 70% reduction in the PASI, then the result has clinical significance.” Röcken is more cautious, particularly about the long-term effects of rhuIL-4 therapy. “Although I am hopeful, the clinical results include some subjective evaluations and a prospective placebo-controlled trial is clearly the next step forward”, he concludes. Jane Bradbury
A pill for secretory diarrhoea on the horizon? ecretory diarrhoea and cystic fibrosis are linked by a protein responsible for chloride ion transport across cell membranes. An international research team has identified a compound that inhibits action of the protein, cystic fibrosis transmembrane conductance regulator (CFTR). The discovery may eventually lead to development of a treatment for secretory diarrhoea as well as development of suitable animal models for cystic fibrosis research. A normal CFTR protein allows secretion of chloride ions into either the intestinal cavity or the mucus secretions lining the respiratory tract. These chloride secretions create an osmotic pressure that draws water from the blood stream. In cystic fibrosis patients, a mutant form of CFTR prevents efficient chloride ion transport. In secretory diarrhoea, increased secretions triggered by the infectious agent lead to severe dehydration. Secretory diarrhoea is the leading cause of death in children less than 5 years of age in developing countries. The research team, led by Alan Verkman (University of California,
S
San Francisco, CA, USA), used a cell-based fluorescence assay to screen 50 000 chemical compounds and selected a thiazolidinone CFTR inhibitor that showed the most promise in inhibiting chloride transport. The team then tested it for antidiarrhoeal properties in a mouse model of cholera-induced secretory diarrhoea and found it to be effective (J Clin Invest 2002; 110: 1651–58). “It is a superb achievement that involves technical ingenuity at many levels, in the development of the screening assay, in the development of the measurement of the effect and in the comprehensiveness of the way they have investigated the effect of their drug on the process of secretion”, says Qais Al-Awqati (Columbia University College of Physicians and Surgeons, New York, NY, USA), who wrote an accompanying commentary (J Clin Invest 2002; 110: 1599–01). Cystic fibrosis research has been hindered by the lack of a suitable animal model. Mouse models do not develop respiratory symptoms. No large-animal models are available. But Verkman says that the CFTR
THE LANCET • Vol 360 • December 7, 2002 • www.thelancet.com
inhibitor discovery may make it easier for researchers to develop one in the near future. He feels, however, that the demonstration of the CFTR inhibitor’s effect on secretory diarrhoea is more significant. Terrence Barrett (Northwestern University Medical School, Chicago, IL, USA), who led an unrelated study of immune-mediated diarrhoea also published in the same issue (J Clin Invest 2002; 110: 1739–47) agrees. “The idea that CFTR inhibitors can block secretory diarrhoea has wide ranging implications for human disease and mortality in third world countries due to vibrio cholera”, Barrett says. While Al-Awqati says that oral rehydration is still the treatment of choice for dehydration caused by secretory diarrhoea, Verkman says there is a clear niche for a drug based upon a CFTR inhibitor. “In children, when they lose massive amounts of fluid rapidly, and in the field, where you don’t have large supplies of fresh water available for rehydration, a pill would be beneficial”, says Verkman. David M Lawrence
1845
For personal use. Only reproduce with permission from The Lancet Publishing Group.
“Immune deviation” with IL-4 could prove beneficial in psoriasis methotrexate but, says Christopher Griffiths (University of Manchester School of Medicine, UK), “few patients are satisfied with these and
Rights were not granted to include this image in electronic media. Please refer to the printed journal. Bring on the immune deviation
several new systemic, immunotherapies are in development that either target T-cell activation or modulate cytokine production”. The latter type of therapy can be subdivided into therapies that block cytokine action and those that switch the cytokine profile within plaques from a proinflammatory Th1 response to an anti-inflammatory Th2 response. Building on previous preclinical work, Röcken and co-workers tested whether treatment with IL-4, a cytokine produced by Th2 cells,
Science Photo Library
pilot study of recombinant human interleukin 4 (rhuIL-4) therapy may offer new hope to people with psoriasis. Martin Röcken (Eberhard Karls Universität Tübingen, Germany) and colleagues report that 15 out of 20 study patients had an improvement of more than 68% in the psoriasis area and severity index (PASI). “This is the first clinical trial in which rhuIL-4 has been tested for treatment of an inflammatory autoimmune disease”, explains Röcken, “and our results indicate that the human immune response can be therapeutically deviated from a proinflammatory toward an anti-inflammatory response”. These results, he says, provide the basis for the development of a vaccine strategy for psoriasis and other autoimmune inflammatory diseases. Psoriasis is a common autoimmune inflammatory disease affecting the skin and joints. Psoriasis plaques contain oligoclonal pro-inflammatory Th1 cells and several lines of evidence indicate that activated T cells are involved in psoriasis pathogenesis. Current therapies include topical vitamin D derivatives, phototherapy, and
A
could modify the cytokine response of activated T cells within psoriasis plaques. In their dose escalation study, 20 patients with severe psoriasis self-injected rhuIL-4 thrice daily, 5 days a week for 6 weeks. The treatment, which was well tolerated, skewed the original Th1 response in the skin to a Th2 response. Furthermore, after rhuIL-4 therapy the condition of 18 patients remained stable or improved when treated with previously ineffective therapies (Nat Med; published online Dec 2; DOI: 10.1038/nm804). “Although this is a open, pilot study with all the drawbacks that entails, these results are impressive”, says Griffiths. “I think that once you get a greater than 70% reduction in the PASI, then the result has clinical significance.” Röcken is more cautious, particularly about the long-term effects of rhuIL-4 therapy. “Although I am hopeful, the clinical results include some subjective evaluations and a prospective placebo-controlled trial is clearly the next step forward”, he concludes. Jane Bradbury
A pill for secretory diarrhoea on the horizon? ecretory diarrhoea and cystic fibrosis are linked by a protein responsible for chloride ion transport across cell membranes. An international research team has identified a compound that inhibits action of the protein, cystic fibrosis transmembrane conductance regulator (CFTR). The discovery may eventually lead to development of a treatment for secretory diarrhoea as well as development of suitable animal models for cystic fibrosis research. A normal CFTR protein allows secretion of chloride ions into either the intestinal cavity or the mucus secretions lining the respiratory tract. These chloride secretions create an osmotic pressure that draws water from the blood stream. In cystic fibrosis patients, a mutant form of CFTR prevents efficient chloride ion transport. In secretory diarrhoea, increased secretions triggered by the infectious agent lead to severe dehydration. Secretory diarrhoea is the leading cause of death in children less than 5 years of age in developing countries. The research team, led by Alan Verkman (University of California,
S
San Francisco, CA, USA), used a cell-based fluorescence assay to screen 50 000 chemical compounds and selected a thiazolidinone CFTR inhibitor that showed the most promise in inhibiting chloride transport. The team then tested it for antidiarrhoeal properties in a mouse model of cholera-induced secretory diarrhoea and found it to be effective (J Clin Invest 2002; 110: 1651–58). “It is a superb achievement that involves technical ingenuity at many levels, in the development of the screening assay, in the development of the measurement of the effect and in the comprehensiveness of the way they have investigated the effect of their drug on the process of secretion”, says Qais Al-Awqati (Columbia University College of Physicians and Surgeons, New York, NY, USA), who wrote an accompanying commentary (J Clin Invest 2002; 110: 1599–01). Cystic fibrosis research has been hindered by the lack of a suitable animal model. Mouse models do not develop respiratory symptoms. No large-animal models are available. But Verkman says that the CFTR
THE LANCET • Vol 360 • December 7, 2002 • www.thelancet.com
inhibitor discovery may make it easier for researchers to develop one in the near future. He feels, however, that the demonstration of the CFTR inhibitor’s effect on secretory diarrhoea is more significant. Terrence Barrett (Northwestern University Medical School, Chicago, IL, USA), who led an unrelated study of immune-mediated diarrhoea also published in the same issue (J Clin Invest 2002; 110: 1739–47) agrees. “The idea that CFTR inhibitors can block secretory diarrhoea has wide ranging implications for human disease and mortality in third world countries due to vibrio cholera”, Barrett says. While Al-Awqati says that oral rehydration is still the treatment of choice for dehydration caused by secretory diarrhoea, Verkman says there is a clear niche for a drug based upon a CFTR inhibitor. “In children, when they lose massive amounts of fluid rapidly, and in the field, where you don’t have large supplies of fresh water available for rehydration, a pill would be beneficial”, says Verkman. David M Lawrence
1845
For personal use. Only reproduce with permission from The Lancet Publishing Group.