The National Institute of Diabetes & Digestive & Kidney Diseases

Dr. Jay Hoofnagle, Director, Division of Digestive Diseases and Nutrition, NIDDK, opened the meeting at 12:36 p.m. He noted that today's topic, inflammatory bowel disease, related to NIDDK as well as to NIAID, NCI, and NICHD. Before introducing the speakers, Dr. Hoofnagle discussed committee business and asked for the legislative report.

NIDDK has issued a PA for liver diseases in minorities and women; a new RFA has come out on hepatitis C where NIDDK and NIAID worked closely; more than $5 million is available. A meeting on Barrett's esophagus will be held in September in Boston.

Dr. Hoofnagle noted that NIH has created the K-23 (career development for young investigators for patient-oriented research) and K-24 awards (salary awards for early- to mid-career investigators for clinical research plus training).

Genetics are important but not sufficient to cause Crohn's. Genetic anticipation, albeit variable, has been noted (the disease showing up earlier in succeeding generations), and concordance of type and location of disease has been seen in families. Chromosomes 3p (IBD), 7q (IBD), 12 (IBD in two studies), and 16 (Crohn's in four studies) have been implicated. Dr. Podolsky saw future needs for cooperation of groups in genetic research, gene identification, and confirmation of putative genes by disease association. Ninety percent of patients have no family history. We must understand the mechanisms of bowel healing as well as injury.

We should: (a) define the molecular basis of the mucosal barrier and its regulation as well as pathways of transepithelial transport; (b) define the mechanism of mucosal healing; and (c) develop an accurate technique for assessing barrier function in vivo.

The suggestion was made from the floor that NIDDK become more involved in the Human Genome Project and that geneticists need to be on the Institute's peer review panels. It was also noted that genetics are not as strong in ulcerative colitis as in Crohn's disease.

IBD has three etiologic theories: (1) persistent infection with a specific agent -- no strong evidence; (2) a defective mucosal barrier; and (3) an overaggressive immune response. The luminal bacteria provide constant antigenic stimulation; he noted that germ-free rodents don't have chronic intestinal inflammation. Both luminal bacteria and genetic factors are essential for IBD, but neither alone is sufficient for chronic inflammation.

Dr. Sartor also noted that Crohn’s is a systemic disease e.g., when the muscosal barrier is weakened, luminal bacteria and T cells increase causing inflammation in the joints and abnormalities of liver function.

A single antibiotic won't cure IBD; both aerobic and anaerobic bacteria are involved. Dr. Sartor hypothesized that IBD is caused by an overly aggressive immune response to resident bacteria that is mediated by TH1 lymphocytes and macrophages. There is a delicate balance between protective and proinflammatory factors.

Dr. Sartor suggested five future questions for research direction: (1) Which bacteria produce protection and inflammation?; (2) What are the mechanisms of response?; (3) What are the mechanism(s) of host protection?; (4) How can we gain a better understanding of environmental triggers (e.g., antibiotics, diet)?; and (5) What are the mechanisms of genetic susceptibility to chronic inflammation and protection?. Dr. Sartor suggested that there should be shared multi-center studies and that we also need to learn more about antibiotics.

From the floor, Dr. James asked that we encourage research in infection and asked whether the Centers for Disease Control and Prevention's (CDC's) infectious disease resources can be used. It was suggested that CDC be approached through its interest in food safety.

Genetic defects in IBD may involve IL-10, TGF-b IL-12, and IL-4 versus interferon gamma. Dr. Strober asked whether we are ready to do an IL-4 study, and where do we stand with IL-12?

Serum antibodies to _pANCA are markers for ulcerative colitis. In the mucosa, antibodies to tropomyosin/gp185 and to _pANCA are markers. Cell-mediated immunity involves oligoclonality of t-cell receptors alpha, beta, and gamma as well as mechanisms of T-cell apoptosis. Cytokines are a major area of investigation.

Crohn's disease is mediated by TH1 cells; ulcerative colitis by Th-2 cells. In IBD, there is an imbalance in mucosal cytokines (some are pro-inflammatory, others are modulatory). We should also look at the role of Cox2, an oxygen metabolite. Among reactive metabolites, researchers should look at neutrophils and monocytes as well as at elevated ROM. Dr. Fiocchi also mentioned adhesion molecules. In the non-immune system, epithelial cells and mesenchymal cells may play a role.

In IBD, cells are both effectors and targets. A key issue: What would IBD be without physiologic inflammation and enteric flora; would it exist without them? Also, (1) Do pathogenic events in early and chronic IBD differ? (2) Does IBD differ in children and adults? (3) Are etiopathogenic events still present in chronic IBD? (4) Are events perpetuating gut inflammation primarily secondary? (5) Are there immune abnormalities specific for Crohn's disease or ulcerative colitis? (6) Is there a dominant cytokine abnormality in Crohn's disease or ulcerative colitis? (7) Which cell type is central to gut inflammation? (8) Are some cells targeted early and others late? (9) How selective is recruitment of immune cells into the inflamed mucosa? (10) How long do immune cells survive in the mucosa? (11) How is survival or apoptosis controlled? (12) Is any specific tissue mediator responsible?

Acute and chronic IBD seem to be two different diseases. T-cells are more important in the acute disorder than in the chronic versions. In children with ulcerative colitis of recent onset, anti-IL-2 and anti-IL-12 seem to help. In terms of molecular mechanisms, researchers don't know a great deal about upstream and downstream signaling pathways or how messages are sent.

In discussion, it was asserted by one guest that ulcerative colitis is mediated by TH1, not TH2 cells.

For example, ulcerative colitis and Crohn's disease are distinct disorders with possibly a common genetic predisposition. In the intestine, there is a balance of pro- and anti-inflammatory factors; therapy should be directed at altering the immune response. The normal state in the intestine is controlled inflammation, with T-cell mediated suppressive factors at work.

Several overlapping themes emerged in the research agenda: (1) stratification of disease subgroups, (2) immunoregulatory features, (3) genetic associations in human and experimental models, (4) bacteria-host interactions, and (5) triggering events and priming factors. The bottom line is that we must understand the molecular genetic basis of IBD, define disease heterogeneity, elucidate the mechanism of immune responses, and identify the genetic defects.

Resource needs include a DNA/serum database of well-defined clinical subgroups; a gnotobiotic (germ-free animals) facility, which is available at the University of Wisconsin; the Clinical and Pediatric Alliances; and a Website on the Internet. Of proposed workshops, the clinical database workshop has already occurred; systematic gene mapping is planned for the fall; one on phenotype/disease subgroups was also mentioned. Focused meetings would involve animal models, therapeutics/mechanisms, INOS/Cox1/Cox2 (oxygen metabolites), and gene regulation.

The CCFA has not met with NICHD, but this Institute is primarily interested in human development. The NIAID, however, is interested in mucosal immmunology. At the Human Genome Project, Dr. Robbins would be the contact person.

Dr. Hoofnagle noted that automimmune disorders are the big challenge for the upcoming years, even more than viral diseases. Developing a consortium of those interested in autoimmune disorders (e.g., asthma, diabetes, IBD) would be helpful. It was suggested that CCFA involve other Institutes by meeting with representatives; the CDC might be approached on disease clustering. NIDDK will continue its focus on funding, and consider genetics grants and at clinical ideas, including topics in pediatric IBD.

Respectfully submitted,

Thomas Kresina, Ph.D.

Executive Secretary, DDICC