Beneficial effects of targeting CCR5 in allograft recipients.
BACKGROUND
The chemokine receptor, CCR5, and its three high-affinity ligands, macrophage inflammatory protein- (MIP) 1alpha, MIP-1beta, and regulated on activation normal T cell expressed and secreted (RANTES), are expressed by infiltrating mononuclear cells during the rejection of clinical and experimental organ allografts, although the significance of these molecules in the pathogenesis of rejection has not been established.


METHODS
We studied intragraft events in four allograft models. First, we studied cardiac transplants in fully MHC-mismatched mice that were deficient in CCR5 or two of its ligands, MIP-1alpha or RANTES. Second we tested the effects of a neutralizing rat anti-mCCR5 monoclonal antibody on allograft survival. Third we assessed whether a subtherapeutic course of cyclosporine would potentiate enhance survival in CCR5-deficient recipients. Finally, we tested the effect of targeting CCR5 in a class II-mismatched model.


RESULTS
Whereas mice deficient in expression of MIP-1alpha or RANTES reject fully MHC-mismatched cardiac allografts normally, CCR5-/- mice, or CCR5+/+ mice treated with a neutralizing mAb to mCCR5, show enhanced allograft survival. MHC class II-disparate mismatched are permanently accepted in CCR5-/- but not CCR5+/+ recipients. Finally, the beneficial effects of targeting of CCR5 are markedly synergistic with the effects of cyclosporine, resulting in permanent engraftment without development of chronic rejection.


CONCLUSIONS
We conclude that CCR5 plays a key role in the mechanisms of host T cell and macrophage recruitment and allograft rejection, such that targeting of CCR5 clinically may be of therapeutic significance.
Gao
W
W
Transplantation, Millennium Pharmaceuticals, Inc., Cambridge, MA 02139, USA.
Faia
K L
KL
Csizmadia
V
V
Smiley
S T
ST
Soler
D
D
King
J A
JA
Danoff
T M
TM
Hancock
W W
WW
D000818:Animals; D000911:Antibodies, Monoclonal / Q000276:immunology / Q000627:therapeutic use; D001787:Blood Group Incompatibility; D065100:CCR5 Receptor Antagonists; D016572:Cyclosporine / Q000627:therapeutic use; D004357:Drug Synergism; D006084:Graft Rejection / Q000503:physiopathology / Q000517:prevention & control*; D006085:Graft Survival; D016027:Heart Transplantation; D000949:Histocompatibility Antigens Class II / Q000032:analysis; D007962:Leukocytes / Q000378:metabolism; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D009000:Monocytes / Q000502:physiology; D051381:Rats; D019713:Receptors, CCR5 / Q000172:deficiency / Q000276:immunology / Q000502:physiology; D013997:Time Factors; D014184:Transplantation, Homologous
D000911:Antibodies, Monoclonal; D065100:CCR5 Receptor Antagonists; D000949:Histocompatibility Antigens Class II; D019713:Receptors, CCR5; D016572:Cyclosporine