Potential IBD (Crohn's Disease and ulcerative colitis) treatments tested in areas of anti-adhesion therapy; platelet recruitment modulated by ICAM-1, P-selectin, PSGL-1; and CTLA-4-Ig abrogating TNBS colitis
Snowmass, Co. (September 9, 2004) Inflammatory Bowel Diseases, comprised of Crohn's Disease and ulcerative colitis, are for the most part incurable and their causes are still unknown. About 1 million Americans suffer from IBD and research around the world on new therapeutic strategies against IBD is being reported at a conference sponsored by the American Physiological Society.
Below are reports on three presentations.
Anti-adhesion therapy in the treatment of IBD Julian Panes and Josep M. Pique of the Gastroenterology Department of the Hospital Clinic Barcelona, Spain, note that the localization for leukocytes to inflammatory areas has key implications in the pathogenesis, diagnosis and treatment of IBD. A major effort has been directed toward identifying and characterizing the adhesion glycoproteins that enable leukocytes to bind to vascular endothelial cells. Drugs that specifically target adhesion molecules involved in leukocyte recruitment are effective in treating intestinal inflammation.
They said that experimental models have shown that blockade of VLA-4, VCAM-1 and P-selectin afford significant amelioration of intestinal inflammation. In experimental models, response to adhesion molecule blockage varies according to the type of inflammatory intestinal condition. In humans VLA-4 immunoneutralization has been effective in inducing remission in Crohn's Disease, but no data is available for ulcerative colitis.
The researchers call for experimental and clinical controlled trials comparing the effectiveness of different strategies of CAM blockade, and suggest that this therapeutic approach be compared with current therapies.
Platelet recruitment in intestinal inflammation modulated by ICAM-1, P-selectin, PSGL-1
Researchers from LSU and the University of Muenster studied the mechanisms responsible for platelet-WBC and platelet-endothelial cell (EC) interactions that occur in experimental colitis. This was prompted by the recognition of cross-talk between platelets and leukocytes in inflammation. Compared with controls, colitis-induced wild type mice showed significantly increased adhesion of platelets, with 2.5% of platelets adhering to ECs directly and 97.5% binding to adherent WBC. ICAM-1 deficient mice with induced colitis had significantly decreased platelet-WBC adhesion.
Wild-type mice made neutropenic with anti-netrophil serum (ANS) exhibited reduced platelet-WBC binding, but significantly increased platelet-EC adhesion. The increase in platelet-EC adhesion in neutropenic animals was presented by both, a single dose of either P-selectin of PSGL-1 blocking monoclonal antibody.
They conclude that in induced colitis, platelet accumulation in venules is dependent on both leukocyte adhesion as well as on mechanisms involving the adhesion molecules P-selectin and PSGL-1. The researchers from the Department of Molecular and Cellular Physiology, Louisiana State University Health Sciences Center, Shreveport, include Thorsten Vowinkel, Mikiji Mori, Katherine Wood, Janice Russel and D. Neil Granger; and Christian F. Krieglstein from the Department of General Surgery, University of Muenster, Germany.
CTLA-4-Ig abrogates TNBS colitis
Researchers at the Division of Gastroenterology of Washington University School of Medicine, St. Louis, Mo., wanted to determine if the biological agent CTLA-4-Ig would abrogate trinitrobenzene sulfonic acid (TNBS) colitis, and if so, to determine if indoleamine 2,3-dioxygenase (IDO) played a role in the process.
The researchers included Gregory J. Gurtner, Thomas M. Ogel, Suzanne R. Schloemann, Keely G. McDonald, Rodney D. Newberry and William F. Stenson.
They found that CTLA-4-Ig induced IDO in the murine colon after systemic administration.
Intraperitonial 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 a 100% survival rate and a significant reduction in colonic TNFámRNA expression regardless of IDO inhibition. IDO inhibition with 1-methyl-tryptophan (1mT), however, prevented colitis abrogation by CTLA-4-Ig both clinically and by histological criteria, and decreased colonic TGFâmRNA expression.
The researchers conclude their study suggests that CTLA-4-Ig promotes tolerance in TNBS colitis both via IDO induction as well as through costimulatory blockade, and suggests a potential therapeutic role for CTLA-4-Ig in treating IBD.
Source: Eurekalert & othersLast reviewed: By John M. Grohol, Psy.D. on 21 Feb 2009
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