Scientific Abstract

Proposal No. IBD-0263R
Principal Investigator: Ingrid Olsen, DVM, Ph.D.
Applicant Organization:  Rikshospitalet University Hospital, Oslo University Hospital (Norway)
Project Title:  Isolation of Mycobacterium avium subsp. paratuberculosis antigen reactive T-lymphocytes from intestinal biopsies from Crohn's patients
Period of Award:  May 1, 2009 – April 30, 2011

The etiology of Crohn’s disease (CD) is still unknown, but several studies have shown a clear genetic component. Genes showed to be specifically associated with CD is NOD2, an intracellular pathogen recognition receptor, and ATG16L and IRGM involved in the authophagy pathway which also is important for handling of intracellular bacteria. Thus, these recent studies suggest that CD is a caused by a defect in the innate immune system rendering the patient more susceptible to intracellular bacteria rather than an overreaction to the normal intestinal bacteria as previously was the most prevailing hypothesis. The intracellular pathogen most often associated with CD is Mycobacterium avium subspecies paratuberculosis (MAP). MAP causes a chronic granulomatous inflammation of the intestine in ruminants with similarities to paratuberculosis in animals. MAP was first isolated from CD patients in 1984 and over the last decades several studies have looked at the presence of MAP by cultivation, PCR and in situ hybridization. The data are somewhat conflicting, however, meta-analyses have concluded that MAP is more often present in CD patients than patients with ulcerative colitis (UC) and healthy controls.

Nevertheless, the question remains unanswered whether MAP can trigger CD or is involved in the pathogenesis of CD. To answer this question we will look at the intestinal T lymphocytes that are present in a CD lesion.  Our hypothesis is that if MAP causes CD the CD4+ T-cells in CD granulomas should respond to MAP derived antigens. To address the potential contribution of MAP to the inflammatory lesions seen in CD, we will isolate intestinal T-cells from CD, UC and non-IBD patients and test for response to MAP antigens. Attempts will then be made to identify which MAP antigens the response is directed to and to see if the responding T cells produce inflammatory cytokines like IFN-γ and IL-17.