Final Progress Report

Proposal No.   IBD-0035
Principal Investigator: Stanford Peng, M.D., Ph.D.
Applicant Organization:  Washington University (St. Louis, Missouri, U.S.A.)
Project Title:  The roles of NFATs and innate immunity in intestinal inflammation
Period of Award:  October 1, 2002 - September 30, 2003

A.  Summary of project aims.

We proposed three aims that concerned an inflammatory bowel disease-like syndrome that we had observed in NFATc2 -/- NFATc1 +/- Rag -/- mice:

   1. Fully characterize the clinical disease in NFAT-mutant, Rag-deficient mice.
   2. Define the requirement for specific NFAT isoforms in disease pathogenesis.
   3. Define the cell populations responsible for intestinal autoimmunity in NFAT-mutant, Rag-deficient mice.

B.  Accomplishments towards meeting those aims.

We are pleased to report that all three aims have been largely accomplished.  Our findings are detailed in the next section.

C.  List of significant results (positive or negative).

Aim 1.  Characterization of clinical disease.

We found that the IBD syndrome of NFAT animals were highly reminiscent of ulcerative colitis, being primarily confined to the distal colon and rectum.  Disease onset was relatively late, at around 20-24 weeks of median age.

Aim 2.  Requirement for specific NFAT isoforms.

We found that NFATc1 heterozygosity was dispensable for the IBD phenotype; i.e., NFATc2-deficient Rag-deficient animals demonstrated disease nearly indistinguishable from the original cohort.

Aim 3.  Cell populations responsible for IBD.

We found that granulocytes/macrophages were the only detectable cells in the intestinal inflammatory infiltrate.  The disease could be suppressed by B cells, but not T cells.

D.  Lay summary of this report.

The cause of inflammatory bowel diseases (IBD), which include Crohn’s disease and ulcerative colitis, remains largely unknown.  Recent studies have drawn attention to the role of the innate immune system, which includes cells like neutrophils and macrophages, in disease pathogenesis.  We have recently discovered a fascinating role in IBD and innate immunity for the nuclear factor of the activated T cells (NFAT) protein family.  These proteins are transcription factors that regulate the expression of many immune genes.  Animals that bear mutant forms of the NFAT proteins spontaneously develop IBD due to innate immunity, demonstrating that the NFAT proteins are critical in regulating inflammation in the intestine.  Interestingly, we find that B lymphocytes – immune cells that secrete antibodies – are responsible for suppressing the inflammation.  We are particularly excited about these studies since the NFAT proteins have historically been highly amenable to pharmacological manipulation, such as with drugs like cyclosporin A and FK506.  Our studies indicate that at least some components of the immune system that are affected by these drugs may actually play protective, rather than pathogenic, roles in intestinal autoimmunity.  Continued study with this IBD model will likely allow us to better discern the context and importance of the NFAT proteins in intestinal inflammation.