Monoclonal antibodies specific for beta 7 integrin and mucosal addressin cell adhesion molecule-1 (MAdCAM-1) reduce inflammation in the colon of scid mice reconstituted with CD45RBhigh CD4+ T cells.
Mucosal addressin cell adhesion molecule-1 (MAdCAM-1) is an adhesion protein expressed on endothelium in mucosal tissues that has been shown to play an important role in the selective homing of lymphocytes to intestinal mucosa and associated lymphoid tissue. To determine whether MAdCAM-1 or its ligand alpha 4 beta 7 would be appropriate targets for therapeutic intervention in gut-associated inflammation, we tested the ability of rat mAbs specific for beta 7 integrin and MAdCAM-1 to inhibit chronic colonic inflammation in scid mice reconstituted with CD4+ T cells enriched for the CD45RBhigh subpopulation. Abs specific for beta 7 and MAdCAM-1 blocked recruitment of lymphocytes to the colitic colon, and more importantly, these Abs significantly reduced the severity of colonic inflammatory disease in this animal model. Therefore, the adhesive interactions mediated by alpha 4 beta 7 and MAdCAM are intimately involved in leukocyte recruitment to gut in chronic inflammatory disease and may be relevant therapeutic targets for patients with inflammatory bowel disease.
Picarella
D
D
LeukoSite, Inc., Cambridge, MA 02142, USA.
Hurlbut
P
P
Rottman
J
J
Shi
X
X
Butcher
E
E
Ringler
D J
DJ
D000818:Animals; D019138:Antibodies, Blocking / Q000494:pharmacology / Q000627:therapeutic use; D000911:Antibodies, Monoclonal / Q000494:pharmacology* / Q000627:therapeutic use; D000918:Antibody Specificity; D015496:CD4-Positive T-Lymphocytes / Q000145:classification / Q000276:immunology*; D015815:Cell Adhesion Molecules; D002465:Cell Movement / Q000276:immunology; D002908:Chronic Disease; D003092:Colitis / Q000209:etiology / Q000276:immunology* / Q000473:pathology*; D005260:Female; D007136:Immunoglobulins / Q000096:biosynthesis / Q000276:immunology*; D016130:Immunophenotyping; D039641:Integrin beta Chains; D016023:Integrins / Q000276:immunology* / Q000502:physiology; D007413:Intestinal Mucosa / Q000276:immunology / Q000473:pathology; D017493:Leukocyte Common Antigens / Q000276:immunology* / Q000502:physiology; D051379:Mice; D008807:Mice, Inbred BALB C; D016513:Mice, SCID; D009088:Mucoproteins / Q000096:biosynthesis / Q000276:immunology*; D016201:Receptors, Lymphocyte Homing / Q000276:immunology*
D019138:Antibodies, Blocking; D000911:Antibodies, Monoclonal; D015815:Cell Adhesion Molecules; D007136:Immunoglobulins; D039641:Integrin beta Chains; D016023:Integrins; C489082:Madcam1 protein, mouse; C504268:Madcam1 protein, rat; D009088:Mucoproteins; D016201:Receptors, Lymphocyte Homing; C091368:integrin beta7; D017493:Leukocyte Common Antigens