Evidence for a genetic defect in oral tolerance induction in inflammatory bowel disease.
BACKGROUND
Previous studies have suggested that there may be a defect in the control of immune responses locally in the intestines of patients with inflammatory bowel disease (IBD). Recently, we documented a failure to induce oral tolerance to a fed soluble protein antigen, keyhole limpet hemocyanin (KLH), in IBD patients. Both Crohn's disease (CD) and ulcerative colitis (UC) appear to be multigenic disorders with evidence of familial segregation. In this study, we analyzed multiplex IBD families to determine whether the defect in oral tolerance induction is genetically regulated.


METHODS
Patients and first-degree relatives from 6 multiplex families were fed KLH 50 mg on days 0 to 5 and 10 to 15, followed by subcutaneous immunizations on days 26 and 35. Blood was obtained and analyzed for KLH-specific T cell proliferative responses and cytokine production. Intestinal permeability was also assessed.


RESULTS
In contrast to normal controls, all IBD patients, save 1 (10 patients out of 11 tested P<.0001 versus normal controls), failed to develop oral tolerance to KLH. Furthermore, in 3 of the 4 CD families, at least 1 unaffected family member (total of 5/14 unaffected individuals, P=.002 versus normal controls) also failed to tolerize. This is in sharp contrast to unaffected individuals with no family history of IBD (1/31 tested to date).


CONCLUSIONS
This failure of tolerance induction could not be attributed to increased intestinal permeability. In the UC families, the defect in tolerance segregated with disease. These data support a genetic defect in tolerance induction in CD.
Kraus
Thomas A
TA
Mount Sinai School of Medicine Immunobiology Center, New York, New York 10029, USA, and the Gastrointestinal Research Group, University of Calgary Health Sciences Centre, Calgary, Alberta, Canada.
Cheifetz
Adam
A
Toy
Lisa
L
Meddings
Jonathan B
JB
Mayer
Lloyd
L
D000284:Administration, Oral; D000328:Adult; D016022:Case-Control Studies; D004361:Drug Tolerance; D005260:Female; D005500:Follow-Up Studies; D020022:Genetic Predisposition to Disease; D006433:Hemocyanins / Q000008:administration & dosage*; D006801:Humans; D015212:Inflammatory Bowel Diseases / Q000188:drug therapy* / Q000235:genetics*; D007408:Intestinal Absorption / Q000187:drug effects* / Q000235:genetics*; D007413:Intestinal Mucosa / Q000187:drug effects; D008297:Male; D008875:Middle Aged; D010375:Pedigree; D011336:Probability; D012016:Reference Values; D012307:Risk Factors; D012720:Severity of Illness Index
D006433:Hemocyanins; C032808:keyhole-limpet hemocyanin