Involvement of CCR5 signaling in macrophage recruitment to porcine islet xenografts.
BACKGROUND
Porcine antigen primed and CD4+ T-cell-activated macrophages are capable of both recognition and rejection of porcine xenografts. However, the specific signaling mechanisms involved remains to be addressed. The aim of this study was to examine the role of chemokine receptor and CD40 signaling in macrophage recruitment and graft destruction.


METHODS
Macrophages were isolated from rejecting CCR2, CCR5, CD40 and control C57BL/6 mice that were recipients of neonatal porcine pancreatic cell cluster (NPCC) xenografts and were transferred to NPCC recipient NOD-SCID mice.


RESULTS
Macrophages isolated from rejecting NPCC xenografts in CD40 and wildtype C57BL/6 mice demonstrated upregulated expression of macrophage activation markers as well as CCR5 and CCR2 genes, and caused pig islet xenograft destruction 8 days after transfer to NOD-SCID recipients. Graft infiltrating macrophages from rejecting CCR2 mice showed a similar activation phenotype and destroyed NPCC xenografts 10 days after transfer to NOD-SCID mice. Blockade of MCP-1 by anti-MCP-1 mAb did not prolong graft survival in CD4+ T cell reconstituted NPCC recipient NOD-SCID mice. By contrast, the graft infiltrating macrophages from rejecting CCR5 recipients showed impaired macrophage activation when compared to control C57BL/6 recipients, and transfer of these macrophages did not result in xenograft destruction in NOD-SCID recipients until day 16 after transfer. Analysis of graft infiltrating macrophages from these rejecting NOD-SCID mice showed an impaired activation phenotype.


CONCLUSIONS
These results demonstrate that CCR5 is involved in both the activation and recruitment of macrophages to rejecting islet xenografts but other pathways are involved.
Yi
Shounan
S
Center for Transplant and Renal Research, Westmead Millennium Institute, Westmead Hospital, New South Wales, Australia.
Ouyang
Li
L
Ha
Hong
H
O'Hara
Jennifer M
JM
Chandra
Abhilash P
AP
Akima
Satoshi
S
Hawthorne
Wayne
W
Patel
Anita T
AT
Stokes
Rebecca
R
O'Connell
Philip J
PJ
D019264:Adoptive Transfer; D000818:Animals; D015496:CD4-Positive T-Lymphocytes / Q000502:physiology; D019013:CD40 Antigens / Q000502:physiology; D018932:Chemokine CCL2 / Q000502:physiology; D005260:Female; D006084:Graft Rejection / Q000276:immunology*; D016381:Islets of Langerhans Transplantation / Q000473:pathology / Q000502:physiology*; D008262:Macrophage Activation / Q000502:physiology*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D054390:Receptors, CCR2; D019713:Receptors, CCR5 / Q000502:physiology*; D019707:Receptors, Chemokine / Q000502:physiology; D015398:Signal Transduction / Q000502:physiology*; D013552:Swine; D014183:Transplantation, Heterologous / Q000276:immunology
D019013:CD40 Antigens; C515335:Ccr2 protein, mouse; D018932:Chemokine CCL2; D054390:Receptors, CCR2; D019713:Receptors, CCR5; D019707:Receptors, Chemokine