The National Institute of Allergy and Infectious Diseases (NIAID) has renewed support, with major funding, for an ambitious seven-year-old international research consortium that is pioneering novel strategies for studying and testing new drugs and therapies against autoimmune diseases, organ transplant rejection, asthma and allergic diseases.
The Immune Tolerance Network (ITN), headquartered at UCSF, was established to accelerate development of new therapies to halt diseases caused by inappropriate and harmful responses by the body's immune system. The Network has launched more than 20 clinical trials at some 70 institutions in 10 countries.
The focus of the INT is on new drugs that can be given for a short time and promote immune tolerance -- a redirection of the immune system away from harmful responses to provide long-term acceptance of a patient's own tissues or organ transplants. A key goal of network researchers is to develop biological "markers" that could quickly and easily identify certain illnesses as well as patients likely to respond to specific therapies.
"The strength of the ITN lies in its strong international leadership and the shared assumption that a multi-disease therapeutic focus will result in new insights to mechanisms of disease," says Jeffrey Bluestone PhD, director of the Immune Tolerance Network, the A. W. and Mary Margaret Clausen Distinguished Professorship in Metabolism and Endocrinology at UCSF and Director of the UCSF Diabetes Center.
"On the surface, the various immunologic diseases targeted in ITN trials look very different, but when you delve deep into the immune system, you find that there are many more similarities than there are differences. By studying what happens in one disease, we can learn how to treat all of them much more effectively.
"The NIAID has shown a remarkable amount of foresight in supporting programs such as the ITN," Bluestone says. "There is no doubt in my mind that this model will lead to faster and more efficient means of developing newer, more effective therapies for immune-based diseases. And the bottom line is to help people with these diseases get better."
The NIAID, part of the National Institutes of Health, began its support of the Immune Tolerance Network in 1999, and this month renews its commitment with a contract of more than $220 million over the next seven years. The ITN's current research network includes more than 200 scientists at 70 institutions worldwide.
In auto-immune diseases, the body's own immune system assaults the body, mistaking ones' own tissues for foreign invaders. In organ transplant rejection, the body rejects transplanted organs, also seeing them as foreign, and thus dangerous. In asthma and allergic diseases, the body's immune system overreacts to allergens or other environmental triggers.
The ITN has gained attention for its strategy of combining advanced laboratory and clinical research, for focusing on long-term safety and efficacy of treatments, and studying the molecular and immunological effects of new therapies as an integral part of its clinical trials. Through systematic laboratory studies, ITN researchers and clinicians try to learn not only if certain therapies help patients, but how and why they do or do not work at the cellular and molecular level. They consider such information essential to developing more individually targeted therapies and guiding the development of next-generation therapeutics in these diseases.
In the past year, the ITN has published several reports on clinical trials, including a multicenter study of the Edmonton Protocol of islet transplantation in type 1 diabetes, published in the "New England Journal of Medicine." This study showed for the first time that islet transplantation confers benefits even in those patients who still require insulin following the procedure, since it increases their ability to control blood glucose levels. Another ITN study published in the journal showed that a novel DNA-based ragweed allergy therapy could achieve long-lasting symptom reduction after only six weeks of therapy, compared to current methods that require years of biweekly injections.
ITN studies currently under way examine a diverse range of therapies and conditions, from simple dietary modifications to high tech protein-based therapeutics, in diseases ranging from peanut allergy to multiple sclerosis.
In an example of a possible common strategy against seemingly disparate diseases, Bluestone cites CTLA4Ig, a novel antibody that selectively blocks unwanted immune responses and prevents further tissue damage. ITN researchers are currently testing for its ability to induce immune tolerance in multiple sclerosis, systemic lupus erythematosus and kidney transplantation, three very different conditions, but ones that are rooted in the same problem - an inappropriate immune response that is causing harm to the patient.
In the effort to identify biological markers of diseases, clinicians draw blood from patients, examine tissue and urine samples and analyze what is happening in response to drugs at the molecular and cellular level. The hope is to use these biological indicators to understand how the drugs work and how immune tolerance is created or lost in the body. Currently, Bluestone says, scientists know very little about how these drugs work in people.
"Right now, almost all of our knowledge about how these therapies work comes from animal laboratory studies," he says. "Clinical trials of these therapies are exquisite opportunities to understand how they work in humans -- opportunities we can't afford to pass up. In type 1 diabetes, for instance, we are not only testing new therapies, but we're also looking for an immunologic profile that will help us diagnose the disease before the clinical symptoms start; in kidney and liver transplantation, while we're examining the efficacy of a new drug, we're also looking for a genetic signature that tells us a person may be more likely to successfully reduce their dose of existing anti-rejection drugs."
In organ transplantation, one of the ITN's key goals is to get patients off anti-rejection drugs known as immunosuppressants, which must be taken for a lifetime and which have significant side effects, including a greatly increased risk of serious infections and even cancer. There are now eight kidney and liver transplant recipients in ITN-sponsored studies who are completely off all immunosuppressive medications, and the number is growing. A number of these patients are children, for whom reducing immunosuppression is particularly important since they begin taking these drugs so early in life.
"It may sound strange that solving a major problem in liver transplantation could lead directly to progress against type 1 diabetes, but it highlights that these diseases can't be studied in isolation - they are all related through the immune system," Bluestone says.
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