NDDIC News

Interagency Committees Review Progress in Understanding IBD, PBC; Establish New Research Priorities

The Division of Digestive Diseases and Nutrition (DDN), part of the National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK), manages research programs addressing a wide range of digestive diseases. In addition to evaluating and funding digestive research through grants and clinical trials, DDN staff members work with representatives of other Federal agencies to coordinate all Government efforts in this area and to set research priorities.

In recent months, DDN personnel have led two interagency committees to review progress in inflammatory bowel disease and primary biliary cirrhosis. The June 2003 meeting on PBC was the first of the newly convened Liver Diseases Interagency Coordinating Committee.

Inflammatory Bowel Disease (IBD)

In April 2003, the Digestive Diseases Interagency Coordinating Committee (DDICC) met to review the current state of research on IBD and recommend appropriate directions for new research. Guest speakers included leading researchers, clinicians, academicians, and policymakers in the field of gastroenterology.

Dr. Richard Blumberg of Harvard Medical School reviewed the strategic plan of the Crohn's and Colitis Foundation of America (CCFA). He identified a number of promising areas of research that CCFA is supporting, including genetic and molecular studies and epidemiological studies to identify novel risk factors, and endorsed randomized clinical trials in important human disease models (e.g., postsurgical relapse or pouchitis) and the coupling of these trials with translational studies.

Dr. Charles O. Elson of the University of Alabama at Birmingham reviewed the immunology and microbiology of IBD. He emphasized that researchers need to delineate the function of the genes associated with it and reach a fuller understanding of the relationship of these genes to the microbiota, the epithelium, and the immune system. Recently developed technologies, such as genetically defined microbes, epithelial cell studies, induced mutant mice models, gnotobiotic facilities, and gene expression arrays, enable investigators to examine the mechanism and manipulation of gene interaction and its implications for IBD research.

In talking about the genetics of IBD, Dr. John Rioux of the Whitehead Institute in Cambridge (MA) listed priority areas for future research: identifying IBD genes and causal genetic variation in understudied populations, understanding the role of IBD genes in biology and pathophysiology, and determining the influence of genetic variation on disease.

Dr. Daniel Podolsky of Massachusetts General Hospital in Boston spoke about the epithelial biology of IBD. He stated that a central research objective over the next few years will be to understand more completely how the proteins that form the tight-junction structure of the epithelium are dynamically regulated to sustain the digestive system's barrier and how the epithelial monolayer can be repaired after ulceration has occurred. Dr. Podolsky concluded that understanding the alterations in the epithelial compartment that are associated with or contributing to IBD would enable researchers to design more effective therapies.

Dr. Robert Sandler of the University of North Carolina spoke about the epidemiology of IBD. He pointed out that it is more prevalent in the northern regions of the world and that when individuals move from areas of low incidence to areas of high incidence, their susceptibility increases. These findings indicate that IBD has an environmental as well as a genetic component. According to Dr. Sandler, the best estimates indicate that 1 million people in the United States have IBD. However, even those estimates, based on the only population studies to date, came from an area where IBD rates are suspected to be higher than in most other regions in the country.

Dr. Bruce E. Sands of Massachusetts General Hospital discussed clinical research. He said that identifying surrogate markers is the main goal of current IBD researchers because endoscopies are invasive, expensive, and often imperfect. Dr. Sands stressed that the need for patient-oriented investigators in IBD has reached the crisis point and that, unless this problem is corrected, many questions will go unanswered.

Dr. Warren Strober of the National Institute of Allergy and Infectious Diseases (NIAID) described intramural research at the National Institutes of Health. NIAID's Mucosal Immunity Section (MIS) is studying murine models of mucosal inflammation, such as TNBS-colitis—colitis induced by the introduction of tri-nitrobenzene sulfonic acid into the rectums of mice. Using this model, the MIS has shown that Th-1 colitis is treatable with anti-interleukin (IL)-12. He also described a number of human studies, including studies of the clinical effectiveness and immunological impact of anti-IL-13 therapy, and emphasized the importance of collaborative programs. For example, a consortium organized to study anti-IL-13 therapy or interferon beta therapy could help find a new therapy for ulcerative colitis.

Dr. Frank Hamilton of DDN outlined the success of NIDDK's IBD funding, which has increased from $8.9 million in fiscal year 1992 to over $36 million in fiscal year 2002. Currently, NIDDK-supported IBD research includes the three Digestive Disease Centers, which have four projects representing approximately 20 percent of the product portfolio. In addition, the Institute funds 121 R01 and R03 IBD research grants, among them a multicenter trial on IBD; Career Development awards, which have bolstered the program and contributed to the development of new investigators; and the Small Business Innovation Research program, which has received renewed emphasis.

Dr. Stephen James of NIDDK, DDICC executive secretary, asked Dr. Robert Karp, head of NIDDK's genetics of digestive diseases program, to discuss the IBD Genetics Consortium. Dr. Karp then described the consortium, which is composed of six research centers and one data coordinating center and has annual funding of $2 million. It is primarily trying to identify susceptibility genes for IBD. To that end, it is creating a patient repository, immortalized cell lines, and DNA samples and will ultimately form an extensive database for analysis.

Dr. James thanked the participants for their input and stated that maintaining a continuous dialog between meetings is imperative.

Congress has charged DDICC with coordinating research activities between various institutes and agencies within the Federal Government. The committee, led by NIDDK, includes representatives from the Center for Scientific Review; Food and Drug Administration; Health Resources and Services Administration; National Heart, Lung, and Blood Institute; National Institute of Nursing Research; and National Institute on Alcohol Abuse and Alcoholism.

Primary Biliary Cirrhosis (PBC)

In June 2003, Dr. Jay Hoofnagle, director of NIDDK's new Liver Disease Research Branch, chaired the first meeting of the Liver Disease Interagency Coordinating Committee. The topic under review was translational research in PBC.

After Dr. Hoofnagle's opening remarks on the challenges of translational research, Dr. M. Eric Gershwin of the University of California at Davis reviewed what is known about the pathogenic role of autoreactive B and T cells and outlined questions about the mechanism that turns the immune system against biliary epithelial cells and destroys bile ducts. Dr. Keith D. Lindor of the Mayo Clinic then moderated a discussion on this topic.

Dr. Burton Combes of the University of Texas Southwestern at Dallas reported on a multicenter trial of methotrexate therapy for PBC. The randomized, double-blind trial, designed to compare the efficacy of ursodiol plus methotrexate versus placebo, was terminated early because of the lack of any evidence that methotrexate benefited patients with PBC. Ursodiol plus methotrexate was no more effective than ursodiol alone, and methotrexate can have serious side effects.

Dr. Lindor discussed newer therapies for PBC, including modulation of the body's immune response to pyruvate dehydrogenase, lamivudine, tetracycline, bezafibrate, silymarin (milk thistle), budesonide, and mycophenolate mofetil plus ursodeoxycholic acid (UDCA). Dr. Lindor reported that lamivudine, bezafibrate, and mycophenolate mofetil appear to be the most promising therapies at the moment.

Dr. Henry C. Bodenheimer Jr. of Beth Israel Medical Center in New York City then moderated a discussion on the two preceding presentations.

Finally, Dr. Jeffrey N. Siegel of the Food and Drug Administration spoke about anticytokine therapy in autoimmune disease. Researchers have observed that cytokines play a part in all autoimmune diseases by controlling the mechanisms for inflammation and tissue repair. Agents that block cytokine action show promise in treating several autoimmune diseases. Further testing will be required to determine the long-term effect of these drugs and assess cost-benefit factors.

The meeting closed with a discussion of future research priorities moderated by Dr. Hoofnagle.

[Top]

NIH Publication No. 04–4552
May 2004