Aggravation of different types of experimental colitis by depletion or adhesion blockade of neutrophils.
OBJECTIVE
Neutrophils are generally thought to play an important proinflammatory role in the pathogenesis of inflammatory bowel disease. The objective of this study was to evaluate whether blocking the invasion of neutrophils by anti-L-selectin monoclonal antibodies modulates chemically induced colitis and how this modulation is accomplished.


METHODS
Trinitrobenzene sulfonic acid/dinitrobenzene sulfonic acid (TNBS/DNBS)-induced colitis was studied in rats on treatment with anti-L-selectin monoclonal antibodies (mAb) or antineutrophil antiserum. Different anti-L-selectin mAb, either blocking or nonblocking, as well as F(ab)(2) fragments were evaluated. Additionally, leukocyte migration was examined using intravital microscopy. Furthermore, the effect of neutrophil depletion in rat TNBS-induced colitis was studied either prior to or after colitis induction as well as murine CD4(+)CD45RB(high) transfer colitis. Finally, bacterial translocation during DNBS-induced colitis was studied in neutrophil-depleted and control rats.


RESULTS
Anti-L-selectin mAb treatment resulted in increased mortality and bowel inflammation as well as hemorrhagic eye secretion. No clear difference was found between blocking and nonblocking mAb or F(ab)(2) fragments. For all investigated antibodies/fragments, either complete blockade of leukocyte invasion or marked neutrophil depletion was found. Accordingly, neutrophil depletion by antiserum resulted in aggravation of rat DNBS-induced colitis as well as murine transfer colitis.


CONCLUSIONS
Adhesion blockade or neutrophil depletion aggravates rat TNBS/DNBS-induced colitis together with extraintestinal manifestations of the eyes. Therefore, neutrophils appear to have an important role in mucosal repair processes. Importantly, adhesion blockade as a therapeutic concept can be detrimental in inflammatory bowel disease.
Kühl
Anja A
AA
Medizinische Klinik I, Campus Benjamin Franklin, Charité, Berlin, Germany.
Kakirman
Hacer
H
Janotta
Markus
M
Dreher
Stefan
S
Cremer
Philipp
P
Pawlowski
Nina N
NN
Loddenkemper
Christoph
C
Heimesaat
Markus M
MM
Grollich
Katja
K
Zeitz
Martin
M
Farkas
Stefan
S
Hoffmann
Jörg C
JC
D000818:Animals; D000911:Antibodies, Monoclonal / Q000008:administration & dosage; D002448:Cell Adhesion / Q000276:immunology; D002464:Cell Migration Inhibition / Q000276:immunology; D002634:Chemotaxis, Leukocyte / Q000187:drug effects / Q000276:immunology; D003092:Colitis / Q000276:immunology* / Q000503:physiopathology; D004195:Disease Models, Animal; D005260:Female; D007413:Intestinal Mucosa / Q000276:immunology; D009504:Neutrophils / Q000276:immunology*; D051381:Rats; D011917:Rats, Inbred Lew
D000911:Antibodies, Monoclonal