3rd Annual BMRP Investigator Meeting - Abstract

CTLA-4 Immunoglobulin Fusion Protein Increases Indoleamine-2,3-Dioxygenase Expression and Diminishes the Severity of TNBS Colitis

William F. Stenson

Division of Gastroenterology, Washington University School of Medicine (St. Louis, Missouri, U.S.A.)

Background: CTLA-4 immunoglobulin fusion protein (CTLA-4-Ig) is a biological agent consisting of the extracellular domain of Cytotoxic T cell Late Antigen – 4 (CTLA-4) fused to the Fc region of IgG.  CTLA-4-Ig potentially promotes tolerance both via costimulatory blockade as well as through the induction of indoleamine 2,3-dioxygenase (IDO) in professional antigen presenting cells (APCs) like dendritic cells.  The expression of IDO is increase in human IBD. IDO expression is induced in trinitrobenzene sulfonic acid (TNBS) colitis and inhibition of IDO worsens the severity of TNBS colitis.

Objectives: We sought to determine if CTLA-4-Ig administration could abrogate TNBS colitis and, if so, to determine if IDO played a role in this process.

Methods:  Intra-rectal TNBS and intra-peritoneal CTLA-4-Ig were administered to SJL/J mice along with a specific IDO inhibitor.  Clinical and histological criteria were assessed to determine colitis severity.  IDO protein and mRNA expression were assessed by Western blotting and real-time PCR respectively.

Results: CTLA-4-Ig induced IDO in cultured LPMNCs as well as in the murine colon after systemic administration.  Administration of CTLA-4-Ig resulted in a 13-fold increase in colonic IDO mRNA with a parallel increase in IDO protein.  Intra-peritoneal CTLA-4-Ig administration prior to TNBS administration significantly abrogated colitis both clinically and by histological criteria.  Mice treated with CTLA-4-Ig and TNBS had significantly less weight loss (5% vs. 22%) and a significantly improved survival rate compared with mice receiving TNBS alone.  IDO inhibition with 1-methyl-tryptophan (1mT) prevented colitis abrogation by CTLA-4-Ig both clinically and by histological criteria.  Mice treated with CTLA-4-Ig plus 1-mT and TNBS had weight loss and survival that was similar to those receiving TNBS alone.
 
Conclusion: This study demonstrates that treatment of mice with CTLA-4-Ig results in the induction of IDO expression and an improved clinical response in the TNBS colitis.  The beneficial effects of CTLA-4-Ig are reversed by co-administration of an IDO inhibitor suggesting that the effects of CTLA-4-Ig in the TNBS model are mediated through the induction of IDO.  These results suggest a potential therapeutic role for CTLA-4-Ig or other agents that induce IDO in the treatment of IBD.