Role of CXCR3 and CCR5 in allograft rejection.
Chemokines are known to participate in allograft rejection by mediating leukocyte trafficking. Despite redundancy in chemokine family, several chemokine-chemokine receptor interactions have proven critical in alloimmune responses. We sought to determine the effect of combined blockade of CXCR3 and CCR5, two critical chemokine receptors, in acute rejection.


METHODS
Heterotopic heart transplantation was performed using BALB/c to B6/129 mice deficient in CCR5. Following transplantation these mice were treated with goat anti-CXCR3 serum every other day. In the control group, BALB/c hearts were transplanted in wild type B6/129 recipients and treated with goat serum alone. No immunosuppression was given to either group. Recipient mice were then assessed daily for allograft function by abdominal palpation, and graft survival was confirmed by laparotomy.


RESULTS
The donor hearts in the control group were rejected at 6 +/- 1 days posttransplantation. Combined blockade of CXCR3 and CCR5 prolonged allograft survival versus control; all allografts survived to 24 days. In addition, there was a decrease in graft infiltrating CD4 and CD8 lymphocytes in the experimental group at 24 days.


CONCLUSIONS
Combined CXCR3 and CCR5 blockade is effective in prolonging allograft survival in a fully MHC mismatched murine model. Combined chemokine blockade holds promise in control of acute rejection in organ transplantation.
Schnickel
G T
GT
Division of Cardiac Surgery, Department of Surgery, David Geffen School of Medicine at the University of California Los Angeles, Los Angeles, California 90095, USA.
Hsieh
G R
GR
Garcia
C
C
Shefizadeh
A
A
Fishbein
M C
MC
Ardehali
A
A
D000818:Animals; D065100:CCR5 Receptor Antagonists; D006084:Graft Rejection / Q000276:immunology*; D006085:Graft Survival / Q000276:immunology*; D016027:Heart Transplantation / Q000276:immunology*; D051379:Mice; D008807:Mice, Inbred BALB C; D018345:Mice, Knockout; D019713:Receptors, CCR5 / Q000172:deficiency / Q000276:immunology; D054367:Receptors, CXCR3; D019707:Receptors, Chemokine / Q000037:antagonists & inhibitors* / Q000276:immunology; D014184:Transplantation, Homologous / Q000276:immunology*
D065100:CCR5 Receptor Antagonists; C515188:Cxcr3 protein, mouse; D019713:Receptors, CCR5; D054367:Receptors, CXCR3; D019707:Receptors, Chemokine