Combined blockade of the chemokine receptors CCR1 and CCR5 attenuates chronic rejection.
BACKGROUND
Chemokine-chemokine receptor interaction and the subsequent recruitment of T-lymphocytes to the graft are early events in the development of chronic rejection of transplanted hearts or cardiac allograft vasculopathy (CAV). In this study, we sought to determine whether blockade of chemokine receptors CCR1 and CCR5 with Met-RANTES affects the development of CAV in a murine model.


RESULTS
B6.CH-2(bm12) strain donor hearts were transplanted heterotopically into wild-type C57BL/6 mice (myosin heavy chain II mismatch). Recipients were treated daily with either Met-RANTES or vehicle starting on postoperative day 4 and were euthanized on postoperative days 24 and 56. We found that Met-RANTES significantly reduced intimal thickening in this model of chronic rejection and that Met-RANTES markedly decreased the infiltration of CD4 and CD8 T lymphocytes and MOMA-2+ monocytes/macrophages into transplanted hearts. Met-RANTES also suppressed the ex vivo and in vitro proliferative responses of recipient splenocytes to donor antigens. Finally, Met-RANTES treatment was associated with a marked reduction in RANTES/CCL5 and monocyte chemoattractant protein-1 gene transcript levels in the donor hearts.


CONCLUSIONS
Antagonism of the chemokine receptors CCR1 and CCR5 with Met-RANTES attenuates CAV development in vivo by reducing mononuclear cell recruitment to the transplanted heart, proliferative responses to donor antigens, and intragraft RANTES/CCL5 and monocyte chemoattractant protein-1 gene transcript levels. These findings suggest that chemokine receptors CCR1 and CCR5 play significant roles in the development of chronic rejection and may serve as potential therapeutic targets.
Yun
James J
JJ
Department of Surgery, Division of Cardiothoracic Surgery, University of California at Los Angeles, Los Angeles, Calif, USA.
Whiting
David
D
Fischbein
Michael P
MP
Banerji
Anamika
A
Irie
Yoshihito
Y
Stein
Daniel
D
Fishbein
Michael C
MC
Proudfoot
Amanda E I
AE
Laks
Hillel
H
Berliner
Judith A
JA
Ardehali
Abbas
A
D000818:Animals; D065100:CCR5 Receptor Antagonists; D015496:CD4-Positive T-Lymphocytes / Q000276:immunology; D018414:CD8-Positive T-Lymphocytes / Q000276:immunology; D018932:Chemokine CCL2 / Q000096:biosynthesis / Q000235:genetics; D018946:Chemokine CCL5 / Q000031:analogs & derivatives* / Q000494:pharmacology / Q000627:therapeutic use*; D018925:Chemokines / Q000096:biosynthesis / Q000235:genetics; D002634:Chemotaxis, Leukocyte / Q000187:drug effects; D005260:Female; D006084:Graft Rejection / Q000276:immunology / Q000473:pathology / Q000517:prevention & control*; D016027:Heart Transplantation / Q000276:immunology*; D008213:Lymphocyte Activation / Q000187:drug effects; D007959:Lymphocyte Culture Test, Mixed; D008264:Macrophages / Q000276:immunology; D051379:Mice; D008810:Mice, Inbred C57BL; D009000:Monocytes / Q000276:immunology; D054389:Receptors, CCR1; D019713:Receptors, CCR5 / Q000502:physiology*; D019707:Receptors, Chemokine / Q000037:antagonists & inhibitors / Q000502:physiology*; D013154:Spleen / Q000276:immunology / Q000473:pathology; D019010:Vascular Cell Adhesion Molecule-1 / Q000096:biosynthesis / Q000235:genetics
D065100:CCR5 Receptor Antagonists; C515301:Ccr1 protein, mouse; D018932:Chemokine CCL2; D018946:Chemokine CCL5; D018925:Chemokines; C108335:RANTES, Met-; D054389:Receptors, CCR1; D019713:Receptors, CCR5; D019707:Receptors, Chemokine; D019010:Vascular Cell Adhesion Molecule-1