PMID- 14662900
OWN - NLM
STAT- MEDLINE
DCOM- 20040315
LR  - 20190516
IS  - 0022-1767 (Print)
IS  - 0022-1767 (Linking)
VI  - 171
IP  - 12
DP  - 2003 Dec 15
TI  - Blocking the monocyte chemoattractant protein-1/CCR2 chemokine pathway induces 
      permanent survival of islet allografts through a programmed death-1 
      ligand-1-dependent mechanism.
PG  - 6929-35
AB  - 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.
FAU - Lee, Iris
AU  - Lee I
AD  - 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.
FAU - Wang, Liqing
AU  - Wang L
FAU - Wells, Andrew D
AU  - Wells AD
FAU - Ye, Qunrui
AU  - Ye Q
FAU - Han, Rongxiang
AU  - Han R
FAU - Dorf, Martin E
AU  - Dorf ME
FAU - Kuziel, William A
AU  - Kuziel WA
FAU - Rollins, Barrett J
AU  - Rollins BJ
FAU - Chen, Lieping
AU  - Chen L
FAU - Hancock, Wayne W
AU  - Hancock WW
LA  - eng
GR  - AI40152/AI/NIAID NIH HHS/United States
GR  - DK063591/DK/NIDDK NIH HHS/United States
PT  - Journal Article
PT  - Research Support, U.S. Gov't, P.H.S.
PL  - United States
TA  - J Immunol
JT  - Journal of immunology (Baltimore, Md. : 1950)
JID - 2985117R
RN  - 0 (Antibodies, Monoclonal)
RN  - 0 (Antigens, Surface)
RN  - 0 (Apoptosis Regulatory Proteins)
RN  - 0 (B7-1 Antigen)
RN  - 0 (B7-H1 Antigen)
RN  - 0 (Blood Proteins)
RN  - 0 (Ccr2 protein, mouse)
RN  - 0 (Cd274 protein, mouse)
RN  - 0 (Chemokine CCL2)
RN  - 0 (Ligands)
RN  - 0 (Membrane Glycoproteins)
RN  - 0 (Pdcd1 protein, mouse)
RN  - 0 (Peptides)
RN  - 0 (Programmed Cell Death 1 Receptor)
RN  - 0 (Proteins)
RN  - 0 (Receptors, CCR2)
RN  - 0 (Receptors, Chemokine)
RN  - W36ZG6FT64 (Sirolimus)
SB  - IM
MH  - Animals
MH  - Antibodies, Monoclonal/administration & dosage
MH  - Antigens, Surface/*physiology
MH  - Apoptosis Regulatory Proteins
MH  - *B7-1 Antigen
MH  - B7-H1 Antigen
MH  - Blood Proteins/antagonists & inhibitors/immunology/metabolism/*physiology
MH  - Cell Differentiation/genetics/immunology
MH  - Cell Division/genetics/immunology
MH  - Chemokine CCL2/*antagonists & inhibitors/biosynthesis/physiology
MH  - Clone Cells
MH  - Dose-Response Relationship, Immunologic
MH  - Female
MH  - Graft Enhancement, Immunologic/methods
MH  - Graft Rejection/immunology
MH  - Graft Survival/drug effects/genetics/*immunology
MH  - Islets of Langerhans Transplantation/*immunology/pathology
MH  - Ligands
MH  - Membrane Glycoproteins
MH  - Mice
MH  - Mice, Inbred BALB C
MH  - Mice, Inbred C57BL
MH  - Mice, Knockout
MH  - Organ Culture Techniques
MH  - Peptides/antagonists & inhibitors/immunology/metabolism/*physiology
MH  - Programmed Cell Death 1 Receptor
MH  - Proteins/metabolism/*physiology
MH  - Receptors, CCR2
MH  - Receptors, Chemokine/*antagonists & inhibitors/physiology
MH  - Signal Transduction/drug effects/genetics/immunology
MH  - Sirolimus/administration & dosage/therapeutic use
MH  - T-Lymphocyte Subsets/cytology/immunology
MH  - Up-Regulation/drug effects/genetics/immunology
EDAT- 2003/12/10 05:00
MHDA- 2004/03/17 05:00
CRDT- 2003/12/10 05:00
PHST- 2003/12/10 05:00 [pubmed]
PHST- 2004/03/17 05:00 [medline]
PHST- 2003/12/10 05:00 [entrez]
AID - 10.4049/jimmunol.171.12.6929 [doi]
PST - ppublish
SO  - J Immunol. 2003 Dec 15;171(12):6929-35. doi: 10.4049/jimmunol.171.12.6929.