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In situ-targeting of dendritic cells with donor-derived apoptopic cells restrains indirect allorecognition and ameliorates allograft vasculopathy

Wang, Z and Shufesky, WJ and Montecalvo, A and Divito, SJ and Larregina, AT and Morelli, AE (2009) In situ-targeting of dendritic cells with donor-derived apoptopic cells restrains indirect allorecognition and ameliorates allograft vasculopathy. PLoS ONE, 4 (3).

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Abstract

Chronic allograft vasculopathy (CAV) is an atheromatous-like lesion that affects vessels of transplanted organs. It is a component of chronic rejection that conventional immuno-suppression fails to prevent, and is a major cause of graft loss. Indirect allo-recognition through T cells and allo-Abs are critical during CAV pathogenesis. We tested whether the indirect allo-response and its impact on CAV is down-regulated by in situ-delivery of donor Ags to recipient's dendritic cells (DCs) in lymphoid organs in a pro-tolerogenic fashion, through administration of donor splenocytes undergoing early apoptosis. Following systemic injection, donor apoptotic cells were internalized by splenic CD11chi CD8α+ and CD8- DCs, but not by CD11cint plasmacytoid DCs. Those DCs that phagocytosed apoptotic cells in vivo remained quiescent, resisted ex vivo-maturation, and presented allo-Ag for up to 3 days. Administration of donor apoptotic splenocytes, unlike cells alive, (i) promoted deletion, FoxP3 expression and IL-10 secretion, and decreased IFN-γ-release in indirect pathway CD4 T cells; and (ii) reduced cross-priming of anti-donor CD8 T cells in vivo. Targeting recipient's DCs with donor apoptotic cells reduced significantly CAV in a fully-mismatched aortic allograft model. The effect was donor specific, dependent on the physical characteristics of the apoptotic cells, and was associated to down-regulation of the indirect type-1 T cell allo-response and secretion of allo-Abs, when compared to recipients treated with donor cells alive or necrotic. Down-regulation of indirect allo-recognition through in situ-delivery of donor-Ag to recipient's quiescent DCs constitutes a promising strategy to prevent/ameliorate indirect allorecognition and CAV. © 2009 Wang et al.


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Details

Item Type: Article
Status: Published
Creators/Authors:
CreatorsEmailPitt UsernameORCID
Wang, Z
Shufesky, WJwjs2@pitt.eduWJS2
Montecalvo, A
Divito, SJ
Larregina, ATadrianal@pitt.eduADRIANAL
Morelli, AEmorelli@pitt.eduMORELLI
Contributors:
ContributionContributors NameEmailPitt UsernameORCID
EditorUnutmaz, DeryaUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Centers: Other Centers, Institutes, Offices, or Units > Thomas E. Starzl Transplantation Institute
Date: 31 March 2009
Date Type: Publication
Journal or Publication Title: PLoS ONE
Volume: 4
Number: 3
DOI or Unique Handle: 10.1371/journal.pone.0004940
Refereed: Yes
PubMed Central ID: PMC2660580
PubMed ID: 19333400
Date Deposited: 25 Jul 2012 14:13
Last Modified: 26 Jan 2019 10:55
URI: http://d-scholarship.pitt.edu/id/eprint/13123

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