Blocking the monocyte chemoattractant protein-1/CCR2 chemokine pathway induces permanent survival of islet allografts through a programmed death-1 ligand-1-dependent mechanism.
Islet allografts are subject to rapid rejection through host cellular immune responses involving mononuclear cell recruitment and tissue injury. Interruption of leukocyte recruitment through chemokine receptor targeting is of therapeutic benefit in various experimental models, but little is known about the contribution of chemokine pathways to islet allograft rejection. We found that murine islets produce monocyte chemoattractant protein-1 (MCP-1; CCL2) in vitro and that islet allograft rejection was associated with intragraft expression of MCP-1 and its receptor, CCR2. We therefore investigated whether MCP-1 and CCR2 are required for the rejection of fully MHC-disparate islet allografts. Wild-type mice treated with blocking anti-MCP-1 mAb plus a brief, subtherapeutic course of rapamycin had long-term islet allograft survival, in contrast to the effect of treatment with either mAb or rapamycin alone. CCR2(-/-) mice treated with rapamycin also maintained islet allografts long-term. Both MCP/CCR2- and rapamycin-sensitive signals were required for maximal proliferation of alloreactive T cells, suggesting that MCP-1/CCR2 induce rejection by promoting alloreactive T cell clonal expansion and homing and migration. Prolonged islet allograft survival achieved by blockade of the MCP-1/CCR2 pathway plus rapamycin therapy was accompanied by a mononuclear cell infiltrate expressing the inhibitory receptor, programmed death-1 (PD-1), and its ligand (PD-L1, B7-H1), and prolongation of islet allograft survival was abrogated by anti-PD-L1 mAb therapy. These data show that the blockade of MCP-1 binding to CCR2 in conjunction with subtherapeutic immunosuppression can have profound effects on islet allograft survival and implicate the expression of the PD-1/PD-L1 pathway in the regulation of physiologic responses in vivo.
Lee
Iris
I
Department of Pathology and Laboratory Medicine, Joseph Stokes, Jr., Research Institute and Biesecker Pediatric Liver Center, Children's Hospital of Philadelphia and University of Pennsylvania, Philadelphia, PA 19104, USA.
Wang
Liqing
L
Wells
Andrew D
AD
Ye
Qunrui
Q
Han
Rongxiang
R
Dorf
Martin E
ME
Kuziel
William A
WA
Rollins
Barrett J
BJ
Chen
Lieping
L
Hancock
Wayne W
WW
D000818:Animals; D000911:Antibodies, Monoclonal / Q000008:administration & dosage; D000954:Antigens, Surface / Q000502:physiology*; D051017:Apoptosis Regulatory Proteins; D018122:B7-1 Antigen; D060890:B7-H1 Antigen; D001798:Blood Proteins / Q000037:antagonists & inhibitors / Q000276:immunology / Q000378:metabolism / Q000502:physiology*; D002454:Cell Differentiation / Q000235:genetics / Q000276:immunology; D002455:Cell Division / Q000235:genetics / Q000276:immunology; D018932:Chemokine CCL2 / Q000037:antagonists & inhibitors* / Q000096:biosynthesis / Q000502:physiology; D002999:Clone Cells; D004306:Dose-Response Relationship, Immunologic; D005260:Female; D006082:Graft Enhancement, Immunologic / Q000379:methods; D006084:Graft Rejection / Q000276:immunology; D006085:Graft Survival / Q000187:drug effects / Q000235:genetics / Q000276:immunology*; D016381:Islets of Langerhans Transplantation / Q000276:immunology* / Q000473:pathology; D008024:Ligands; D008562:Membrane Glycoproteins; D051379:Mice; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009924:Organ Culture Techniques; D010455:Peptides / Q000037:antagonists & inhibitors / Q000276:immunology / Q000378:metabolism / Q000502:physiology*; D061026:Programmed Cell Death 1 Receptor; D011506:Proteins / Q000378:metabolism / Q000502:physiology*; D054390:Receptors, CCR2; D019707:Receptors, Chemokine / Q000037:antagonists & inhibitors* / Q000502:physiology; D015398:Signal Transduction / Q000187:drug effects / Q000235:genetics / Q000276:immunology; D020123:Sirolimus / Q000008:administration & dosage / Q000627:therapeutic use; D016176:T-Lymphocyte Subsets / Q000166:cytology / Q000276:immunology; D015854:Up-Regulation / Q000187:drug effects / Q000235:genetics / Q000276:immunology
D000911:Antibodies, Monoclonal; D000954:Antigens, Surface; D051017:Apoptosis Regulatory Proteins; D018122:B7-1 Antigen; D060890:B7-H1 Antigen; D001798:Blood Proteins; C515335:Ccr2 protein, mouse; C498919:Cd274 protein, mouse; D018932:Chemokine CCL2; D008024:Ligands; D008562:Membrane Glycoproteins; C491383:Pdcd1 protein, mouse; D010455:Peptides; D061026:Programmed Cell Death 1 Receptor; D011506:Proteins; D054390:Receptors, CCR2; D019707:Receptors, Chemokine; D020123:Sirolimus