Scientific Abstract

Proposal No.   IBD-0052
Principal Investigator:  Koichi Kobayashi, M.D., Ph.D.
Applicant Organization:  Yale University (New Haven, Connecticut, U.S.A.)
Project Title:  A role of innate immunity in the pathogenesis of inflammatory bowel disease
Period of Award:  January 1, 2003 – February 28, 2005

 Some of the factors involved in the pathogenesis of inflammatory bowel diseases (IBD) include the genetic background of patients, the effect of commensal or pathogenic bacteria in the gut, and abnormal activation of innate or adaptive immune responses.  Activation of the immune system by bacterial flora is a major factor in the pathogenesis.  For example, treatment with antibiotics may relieve the symptoms of IBD patients.  Mouse models of IBD such as IL-10 deficient mice do not develop IBD under germ-free conditions, although they develop severe IBD under normal housing conditions.

Recent studies on the innate immune system indicate that a variety of microorganisms or products of microorganisms are detected by germline-encoded receptors, which are called Toll-like receptors (TLRs).  TLRs are evolutionarily highly conserved proteins that detect specific pathogens or pathogen associated molecular patterns (PAMPs); each TLR recognizes specific products of microorganisms.  We hypothesize that abnormal activation of the innate immune system by the bacterial flora in the intestinal tract via the TLR system plays an important role in the development of IBD.  To test this hypothesis, we will use two genetically engineered strains of mice, MyD88 deficient mice and IRAK-M deficient mice.  MyD88 deficient mice have decreased TLR signaling while IRAK-M deficient mice have increased TLR signaling.

Recent findings have revealed that mutation of the Nod2 gene is connected with Crohn's disease.  Nod2 has been shown to be involved in the innate immune response and it is possible that Nod2 is either a distinct system from TLRs to detect pathogens or is a part of the TLR system.  We will test if TLR signaling and mutation of the Nod2 gene cooperate in the development of Crohn's disease.  We have generated mice that lack the Nod2 gene.  Comparison of the phenotype of the Nod2 null mutants to the Nod2 null mutation combined with MyD88 null mutation will indicate if these systems work independently or dependently to generate Crohn's disease.

A relationship between IBD pathogenesis and innate immunity has been postulated, yet no clear relevance has been shown. Our project is characterized by the usage of gene deficient mice which show increased or decreased TLR signaling. The information obtained by this project could provide new insights into IBD pathogenesis by the innate immune system and could provide the basis for new therapies for IBD through intervention in the TLR and Nod2 signaling system.