Document Detail

Targeting lymphatic vessel activation and CCL21 production by vascular endothelial growth factor receptor-3 inhibition has novel immunomodulatory and antiarteriosclerotic effects in cardiac allografts.
MedLine Citation:
PMID:  20231530     Owner:  NLM     Status:  MEDLINE    
BACKGROUND: Lymphatic network and chemokine-mediated signals are essential for leukocyte traffic during the proximal steps of alloimmune response. We aimed to determine the role of lymphatic vessels and their principal growth signaling pathway, vascular endothelial growth factor (VEGF)-C/D/VEGFR-3, during acute and chronic rejection in cardiac allografts. METHODS AND RESULTS: Analysis of heterotopically transplanted rat cardiac allografts showed that chronic rejection increased VEGF-C(+) inflammatory cell and hyaluronan receptor-1 (LYVE-1)(+) lymphatic vessel density. Allograft lymphatic vessels were VEGFR-3(+), contained antigen-presenting cells, and produced dendritic cell chemokine CCL21. Experiments with VEGFR-3/LacZ mice or mice with green fluorescent protein-positive bone marrow cells as cardiac allograft recipients showed that allograft lymphatic vessels originated almost exclusively from donor cells. Intraportal adenoviral VEGFR-3-Ig (Ad.VEGFR-3-Ig/VEGF-C/D-Trap) perfusion was used to inhibit VEGF-C/D/VEGFR-3 signaling. Recipient treatment with Ad.VEGFR-3-Ig prolonged rat cardiac allograft survival. Ad.VEGFR-3-Ig did not affect allograft lymphangiogenesis but was linked to reduced CCL21 production and CD8(+) effector cell entry in the allograft. Concomitantly, Ad.VEGFR-3-Ig reduced OX62(+) dendritic cell recruitment and increased transcription factor Foxp3 expression in the spleen. In separate experiments, treatment with a neutralizing monoclonal VEGFR-3 antibody reduced arteriosclerosis, the number of activated lymphatic vessels expressing VEGFR-3 and CCL21, and graft-infiltrating CD4(+) T cells in chronically rejecting mouse cardiac allografts. CONCLUSIONS: These results show that VEGFR-3 participates in immune cell traffic from peripheral tissues to secondary lymphoid organs by regulating allograft lymphatic vessel CCL21 production and suggest VEGFR-3 inhibition as a novel lymphatic vessel-targeted immunomodulatory therapy for cardiac allograft rejection and arteriosclerosis.
Antti I Nyk?nen; Henrik Sandelin; Rainer Krebs; Mikko A I Ker?nen; Raimo Tuuminen; Terhi K?rp?nen; Yan Wu; Bronislaw Pytowski; Petri K Koskinen; Seppo Yl?-Herttuala; Kari Alitalo; Karl B Lemstr?m
Publication Detail:
Type:  Journal Article; Research Support, Non-U.S. Gov't     Date:  2010-03-15
Journal Detail:
Title:  Circulation     Volume:  121     ISSN:  1524-4539     ISO Abbreviation:  Circulation     Publication Date:  2010 Mar 
Date Detail:
Created Date:  2010-03-30     Completed Date:  2010-05-24     Revised Date:  -    
Medline Journal Info:
Nlm Unique ID:  0147763     Medline TA:  Circulation     Country:  United States    
Other Details:
Languages:  eng     Pagination:  1413-22     Citation Subset:  AIM; IM    
Cardiopulmonary Research Group, Transplantation Laboratory, Haartman Institute, FI-00014 University of Helsinki and Helsinki University Central Hospital, Helsinki, Finland. Antti.Nykanen@Helsinki.Fi
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MeSH Terms
Antibodies, Monoclonal / pharmacology,  therapeutic use
Antigen-Presenting Cells
Arteriosclerosis / drug therapy,  prevention & control*
Cell Movement / immunology
Chemokine CCL21 / biosynthesis*
Graft Rejection / immunology
Heart Transplantation / immunology*
Immunomodulation / drug effects*
Lymphatic Vessels / metabolism*
Mice, Knockout
Signal Transduction / immunology
Vascular Endothelial Growth Factor Receptor-3 / antagonists & inhibitors*,  immunology
Reg. No./Substance:
0/Antibodies, Monoclonal; 0/CCL21 protein, human; 0/Chemokine CCL21; EC Endothelial Growth Factor Receptor-3

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