Antibody blockade of ICAM-1 and VCAM-1 ameliorates inflammation in the SAMP-1/Yit adoptive transfer model of Crohn's disease in mice.
OBJECTIVE
Integrins (alpha(4) and beta(2)) and their endothelial ligands vascular cell adhesion molecule-1 (VCAM-1) and intercellular adhesion molecule-1 (ICAM-1) play key roles in leukocyte recruitment to areas of inflammation. ICAM-1 and VCAM-1 are expressed in inflamed intestinal tissues. This study investigates a possible causative role of adhesion molecules ICAM-1, VCAM-1, and alpha(4) integrins in mediating the inflammatory response in a murine model of Crohn's disease (CD).


METHODS
CD4+ mesenteric lymph node cells from SAMP-1/Yit donor mice were adoptively transferred into major histocompatibility complex-matched severe combined immunodeficiency disease mice. Six weeks later, these mice were left untreated or treated for 3 days with monoclonal antibodies (mAbs) to ICAM-1, VCAM-1, or both, and alpha(4), or both ICAM-1 and alpha(4), dexamethasone, or nonblocking isotype control antibodies. On day 4 after treatment, tissues were investigated for expression of ICAM-1, VCAM-1, and for severity of inflammation using a semiquantitative inflammatory score. Dexamethasone treatment resolved all measures of intestinal inflammation.


RESULTS
Blocking either ICAM-1, VCAM-1, or alpha(4) integrins had no significant beneficial effect. However, blocking ICAM-1 and alpha(4), or blocking ICAM-1 and VCAM-1, showed a 70% resolution of the active inflammation, but not chronic inflammation.


CONCLUSIONS
These findings suggest that blocking ICAM-1 and VCAM-1 may have therapeutic benefit for the acute inflammatory component of Crohn's disease.
Burns
R C
RC
Department of Surgery, University of Virginia Health System, P.O. Box 800709, Charlottesville, VA 22906, USA. rcb5y@virginia.edu
Rivera-Nieves
J
J
Moskaluk
C A
CA
Matsumoto
S
S
Cominelli
F
F
Ley
K
K
D019264:Adoptive Transfer; D000818:Animals; D000911:Antibodies, Monoclonal / Q000276:immunology*; D015703:Antigens, CD / Q000276:immunology; D003092:Colitis / Q000276:immunology / Q000378:metabolism / Q000473:pathology; D003106:Colon / Q000378:metabolism* / Q000473:pathology*; D003424:Crohn Disease / Q000276:immunology / Q000378:metabolism* / Q000473:pathology*; D050759:Cyclin-Dependent Kinase Inhibitor p21; D016213:Cyclins / Q000276:immunology; D039441:Integrin alpha4; D018799:Intercellular Adhesion Molecule-1 / Q000276:immunology* / Q000378:metabolism; D051379:Mice; D008815:Mice, Inbred Strains; D016513:Mice, SCID; D008871:Microvilli / Q000473:pathology; D019010:Vascular Cell Adhesion Molecule-1 / Q000276:immunology* / Q000378:metabolism
D000911:Antibodies, Monoclonal; D015703:Antigens, CD; C493957:Cdkn1a protein, mouse; D050759:Cyclin-Dependent Kinase Inhibitor p21; D016213:Cyclins; D019010:Vascular Cell Adhesion Molecule-1; D018799:Intercellular Adhesion Molecule-1; D039441:Integrin alpha4