Blockade of LTB(4) /BLT(1) pathway improves CD8(+) T-cell-mediated colitis.
BACKGROUND
Leukotriene B4 (LTB(4) ) has chemotactic properties for activated T cells expressing the high-affinity receptor BLT(1) . This study investigated whether the LTB(4) antagonist (CP-105,693), selective for BLT(1) receptor, could protect mice from colitis mediated by specific cytotoxic CD8(+) T lymphocytes (CTL).


METHODS
Virus-specific colitis was induced in C57Bl/6 mice transferred with lymphoid cells from P14 TcR Tg mice which are specific to class I GP33 peptide of LCMV. Mice were immunized with GP33-pulsed dendritic cells and colitis was elicited by intrarectal administration of the peptide. Colitis was evaluated by body weight loss and macroscopic and histological analysis of colon. In vivo priming of specific CD8(+) CTL was determined using interferon (IFN)-γ ELISPOT and in vivo CTL assays. In some experiments mice were treated with a selective LTB(4) receptor antagonist.


RESULTS
Immunization with GP33-pulsed dendritic cells (DCs) induced priming of specific CD8(+) CTL, as shown by the presence of IFN-γ-producing CD8(+) T cells in colon draining lymph nodes and in vivo CTL assays. Intrarectal challenge with GP33 induced severe colitis and recruitment of granzyme B(+) P14 CD8(+) cells in colon. Treatment with the specific LTB(4) receptor antagonist before elicitation of colitis reduced the severity of colitis and decreased the frequency of specific effectors.


CONCLUSIONS
Colitis can be induced by IFN-γ-producing cytotoxic CD8(+) CTL specific for viral antigen. Blockade of the LTB(4) /BLT(1) pathway by a selective BLT(1) receptor antagonist attenuates colitis by inhibiting CD8(+) effectors recruitment in colon. These data illustrate the therapeutic potential of LTB(4) receptor selective antagonists in protection from CD8(+) T-cell-mediated intestinal inflammation.
Nancey
Stephane
S
INSERM U 851 Immunité et Vaccination, IFR 128, Lyon, France. stephane.nancey@inserm.fr
Boschetti
Gilles
G
Hacini
Feriel
F
Sardi
Fatima
F
Durand
Pierre-Yves
PY
Le Borgne
Maylis
M
Furhmann
Lydie
L
Flourie
Bernard
B
Kaiserlian
Dominique
D
D000818:Animals; D000956:Antigens, Viral / Q000276:immunology*; D018414:CD8-Positive T-Lymphocytes / Q000276:immunology*; D002462:Cell Membrane / Q000378:metabolism; D002633:Chemotaxis; D003092:Colitis / Q000209:etiology* / Q000378:metabolism / Q000473:pathology; D003106:Colon / Q000276:immunology / Q000378:metabolism / Q000473:pathology; D003713:Dendritic Cells / Q000276:immunology / Q000378:metabolism; D005434:Flow Cytometry; D006023:Glycoproteins / Q000276:immunology*; D007975:Leukotriene B4 / Q000037:antagonists & inhibitors* / Q000378:metabolism; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D010446:Peptide Fragments / Q000276:immunology* / Q000494:pharmacology; D018102:Receptors, Leukotriene B4 / Q000037:antagonists & inhibitors* / Q000378:metabolism; D015398:Signal Transduction; D014764:Viral Proteins / Q000276:immunology*
D000956:Antigens, Viral; D006023:Glycoproteins; C503704:Ltb4r1 protein, mouse; D010446:Peptide Fragments; D018102:Receptors, Leukotriene B4; D014764:Viral Proteins; C094244:glycoprotein peptide 33-41, Lymphocytic choriomeningitis virus; D007975:Leukotriene B4