Document Detail


Differential role of CCR2 in islet and heart allograft rejection: tissue specificity of chemokine/chemokine receptor function in vivo.
MedLine Citation:
PMID:  14707046     Owner:  NLM     Status:  MEDLINE    
Abstract/OtherAbstract:
Chemokines have a pivotal role in the mobilization and activation of specific leukocyte subsets in acute allograft rejection. However, the role of specific chemokines and chemokine receptors in islet allograft rejection has not been fully elucidated. We now show that islet allograft rejection is associated with a steady increase in intragraft expression of the chemokines CCL8 (monocyte chemoattractant protein-2), CCL9 (monocyte chemoattractant protein-5), CCL5 (RANTES), CXCL-10 (IFN-gamma-inducible protein-10), and CXCL9 (monokine induced by IFN-gamma) and their corresponding chemokine receptors CCR2, CCR5, CCR1, and CXCR3. Because CCR2 was found to be highly induced, we tested the specific role of CCR2 in islet allograft rejection by transplanting fully MHC mismatched islets from BALB/c mice into C57BL/6 wild-type (WT) and CCR2-deficient mice (CCR2-/-). A significant prolongation of islet allograft survival was noted in CCR2-/- recipients, with median survival time of 24 and 12 days for CCR2-/- and WT recipients, respectively (p < 0.0001). This was associated with reduction in the generation of CD8+, but not CD4+ effector alloreactive T cells (CD62L(low)CD44(high)) in CCR2-/- compared with WT recipients. In addition, CCR2-/- recipients had a reduced Th1 and increased Th2 alloresponse in the periphery (by ELISPOT analysis) as well as in the grafts (by RT-PCR). However, these changes were only transient in CCR2-/- recipients that ultimately rejected their grafts. Furthermore, in contrast to the islet transplants, CCR2 deficiency offered only marginal prolongation of heart allograft survival. This study demonstrates the important role for CCR2 in early islet allograft rejection and highlights the tissue specificity of the chemokine/chemokine receptor system in vivo in regulating allograft rejection.
Authors:
Reza Abdi; Terry K Means; Toshiro Ito; Rex Neal Smith; Nader Najafian; Mollie Jurewicz; Vaja Tchipachvili; Israel Charo; Hugh Auchincloss; Mohamed H Sayegh; Andrew D Luster
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Publication Detail:
Type:  Comparative Study; Journal Article; Research Support, Non-U.S. Gov't; Research Support, U.S. Gov't, P.H.S.    
Journal Detail:
Title:  Journal of immunology (Baltimore, Md. : 1950)     Volume:  172     ISSN:  0022-1767     ISO Abbreviation:  J. Immunol.     Publication Date:  2004 Jan 
Date Detail:
Created Date:  2004-01-06     Completed Date:  2004-04-20     Revised Date:  2007-11-15    
Medline Journal Info:
Nlm Unique ID:  2985117R     Medline TA:  J Immunol     Country:  United States    
Other Details:
Languages:  eng     Pagination:  767-75     Citation Subset:  AIM; IM    
Affiliation:
Laboratory of Immunogenetics and Transplantation, Renal Division, Brigham and Women's Hospital, Harvard Medical School, 75 Francis Street, Boston, MA 02120, USA. rabdi@rics.bwh.harvard.edu
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MeSH Terms
Descriptor/Qualifier:
Animals
Antigens, CD44 / biosynthesis
Cell Differentiation / genetics,  immunology
Chemokines / biosynthesis,  genetics
Cytokines / biosynthesis
Graft Enhancement, Immunologic / methods
Graft Rejection / genetics,  immunology*
Heart Transplantation / immunology*,  pathology*
Islets of Langerhans Transplantation / immunology*,  pathology*
L-Selectin / biosynthesis
Male
Mice
Mice, Inbred BALB C
Mice, Inbred C57BL
Mice, Knockout
Monocyte Chemoattractant Proteins / biosynthesis,  genetics,  physiology*
Organ Specificity / genetics,  immunology
Receptors, CCR2
Receptors, Chemokine / deficiency,  genetics,  physiology*
Signal Transduction / genetics,  immunology
T-Lymphocytes, Regulatory / pathology
Th2 Cells / immunology,  metabolism
Transplantation, Homologous
Grant Support
ID/Acronym/Agency:
HL 52773/HL/NHLBI NIH HHS; P01 AI 41521/AI/NIAID NIH HHS; P01 DK 50305/DK/NIDDK NIH HHS; R01 CA 69212/CA/NCI NIH HHS
Chemical
Reg. No./Substance:
0/Antigens, CD44; 0/Ccl12 protein, mouse; 0/Ccr2 protein, mouse; 0/Chemokines; 0/Cytokines; 0/Monocyte Chemoattractant Proteins; 0/Receptors, CCR2; 0/Receptors, Chemokine; 126880-86-2/L-Selectin

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