Monoclonal antibody against beta7 integrins, but not beta7 deficiency, attenuates intestinal allograft rejection in mice.
BACKGROUND
beta7 integrins mediate homing and retention of lymphocytes to the normal and inflamed small bowel in a tissue-selective fashion. In the present study, we investigated the expression of beta7 integrins after small bowel transplantation (SBT) and tested the effects of blocking beta7-mediated pathways by using monoclonal antibody (mAb) or knockout mice.


METHODS
Heterotopic SBT from BALB/c to C57BL/6 (B6) was used as a surgical model. Expression of beta7 integrins was measured on recipient lymphocytes (CD4 and CD8 ) in spleen, blood, and mesenteric lymph nodes (MLN) using flow cytometry. To analyze the effects of blocking beta7 integrins on graft survival, either beta7-deficient B6 or wild-type B6 mice that were treated with mAb against beta7 were studied.


RESULTS
After allogeneic SBT, there were markedly increased levels of alpha4beta7 recipient CD8 lymphocytes in MLN, blood, and spleen as early as 3 days postoperatively. In contrast, alpha4beta7 integrin levels in isograft recipients were similar to those of normal mice. Mean survival time of intestinal allografts was not affected by beta7 deficiency (7.3+/-1 days) compared with wild-type mice (7.5+/-0.8 days). However, mAb against beta7 integrins significantly prolonged graft survival (12.8+/-1 days) compared with treatment with control mAb (7.3+/-1 days, <0.001). Histologic changes of SBT rejection were significantly attenuated when mice were given mAb against beta7.


CONCLUSIONS
As indicated by the increased levels of alpha4beta7 CD8 lymphocytes, activation of this integrin contributes to the immune response in SBT rejection. Furthermore, blocking beta7 integrins with mAb provides a suitable target for immunosuppressive therapy. The discrepancy in survival data obtained by mAb and beta7 deficiency may be a result of the more rapid activation of compensatory mechanisms in the knockout mice.
Kellersmann
Richard
R
Department of Surgery, University of Würzburg, Würzburg, Germany.
Lazarovits
Andrew
A
Grant
David
D
Garcia
Bertha
B
Chan
Bosco
B
Kellersmann
Anne
A
Wang
Hao
H
Jevnikar
Anthony
A
Wagner
Norbert
N
Müller
Werner
W
Ulrichs
Karin
K
Thiede
Arnulf
A
Zhong
Robert
R
D000818:Animals; D000911:Antibodies, Monoclonal / Q000494:pharmacology; D015815:Cell Adhesion Molecules; D006084:Graft Rejection / Q000503:physiopathology*; D007136:Immunoglobulins / Q000378:metabolism; D039641:Integrin beta Chains / Q000235:genetics / Q000276:immunology / Q000502:physiology*; D016023:Integrins / Q000378:metabolism; D007421:Intestine, Small / Q000637:transplantation*; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout / Q000235:genetics; D009088:Mucoproteins / Q000378:metabolism; D016042:Transplantation, Heterotopic; D014184:Transplantation, Homologous; D019010:Vascular Cell Adhesion Molecule-1 / Q000378:metabolism / Q000502:physiology
D000911:Antibodies, Monoclonal; D015815:Cell Adhesion Molecules; D007136:Immunoglobulins; D039641:Integrin beta Chains; D016023:Integrins; C489082:Madcam1 protein, mouse; D009088:Mucoproteins; D019010:Vascular Cell Adhesion Molecule-1; C091368:integrin beta7