Rapid resolution of chronic colitis in the cotton-top tamarin with an antibody to a gut-homing integrin alpha 4 beta 7.
OBJECTIVE
Integrins play diverse roles in cellular actions and signalling in the immune system. In the context of mucosal immune responses, the integrin alpha 4 beta 7 has received particular attention because of its intimate involvement in lymphocyte recruitment to normal gastrointestinal mucosa and associated lymphoid tissue. The aim of this study was to determine the functional relevance of alpha 4 beta 7 in the pathogenesis of colonic inflammatory disease using the colitic cotton-top tamarin, an animal model of human ulcerative colitis.


METHODS
Chronically colitic cotton-top tamarins were given either a cross-reactive monoclonal antibody to human alpha 4 beta 7 or an irrelevant control monoclonal antibody. The animals were then evaluated clinically and mucosal biopsy specimens assessed by histological and quantitative morphometric analysis.


RESULTS
A blocking monoclonal antibody to alpha 4 beta 7 integrin ameliorated inflammatory activity and rapidly improved stool consistency when administered to chronically colitic animals. Furthermore, using morphometric analysis of biopsy specimens, antibody therapy reduced the mucosal density of alpha 4 beta 7+ lymphocytes and alpha 4 beta 7 neutrophils and macrophages.


CONCLUSIONS
These results suggest that the alpha 4 beta 7 integrin represents a novel, potentially organ-specific therapeutic target for the treatment of inflammatory bowel disease.
LeukoSite Inc., Cambridge, Massachusetts, USA.
P E
PE
Hesterberg
D
D
Winsor-Hines
M J
MJ
Briskin
D
D
Soler-Ferran
C
C
Merrill
C R
CR
Mackay
W
W
Newman
D J
DJ
Ringler
D000818:Animals; D000911:Antibodies, Monoclonal / Q000009:adverse effects / Q000627:therapeutic use*; D002908:Chronic Disease; D003092:Colitis / Q000473:pathology / Q000628:therapy*; D006801:Humans; D016023:Integrins / Q000502:physiology*; D012452:Saguinus
D000911:Antibodies, Monoclonal; D016023:Integrins; C071777:integrin alpha4beta7