CD8 T cell-mediated rejection of intestinal allografts is resistant to inhibition of the CD40/CD154 costimulatory pathway.
BACKGROUND
Disruption of the CD40/CD154 pathway inhibits rejection in numerous models. The importance of this pathway on intestinal allograft rejection was examined in this study.


METHODS
Intestinal grafts from B6C3F1 mice transplanted into C57BL/6 recipients were assessed histologically for rejection.


RESULTS
The monoclonal antibody to CD154, MR1, failed to inhibit rejection in wild-type mice. Similarly, CD154-/- recipient mice rejected intestinal allografts. MR1 did inhibit early rejection in CD8-/- mice, but had no effect in CD4-/- recipients. All MR1-treated CD8-/- recipients eventually developed rejection. No benefit was observed when blockade of the CD40/CD154 pathway by MR1 was combined with blockade of the CD28/B7 pathway by mCTLA4Ig.


CONCLUSIONS
These data suggest that CD4+ T cells mediating intestinal allograft rejection may be more dependent upon the CD40/CD154 pathway than CD8+ T cells. This finding highlights the importance of identifying agents that suppress CD8+ T cell-mediated rejection.
Guo
Z
Z
Department of Surgery, University of Chicago, Illinois 60637, USA.
Meng
L
L
Kim
O
O
Wang
J
J
Hart
J
J
He
G
G
Alegre
M L
ML
Thistlethwaite
J R
JR
Pearson
T C
TC
Larsen
C P
CP
Newell
K A
KA
D000818:Animals; D000911:Antibodies, Monoclonal / Q000627:therapeutic use; D015496:CD4-Positive T-Lymphocytes / Q000502:physiology; D019013:CD40 Antigens / Q000276:immunology / Q000502:physiology*; D023201:CD40 Ligand / Q000276:immunology / Q000502:physiology*; D018414:CD8-Positive T-Lymphocytes / Q000502:physiology; D006084:Graft Rejection / Q000517:prevention & control; D006085:Graft Survival / Q000502:physiology; D007421:Intestine, Small / Q000637:transplantation*; D007583:Jejunum / Q000637:transplantation; D051379:Mice; D008810:Mice, Inbred C57BL; D012333:RNA, Messenger / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects / Q000502:physiology; D014184:Transplantation, Homologous / Q000276:immunology / Q000473:pathology
D000911:Antibodies, Monoclonal; D019013:CD40 Antigens; D012333:RNA, Messenger; D023201:CD40 Ligand