In Situ-Targeting of Dendritic Cells with Donor-Derived Apoptotic Cells Restrains Indirect Allorecognition and Ameliorates Allograft Vasculopathy

Derya Unutmaz,Zhiliang Wang,Sherrie J Divito,Adrian E Morelli,Angela Montecalvo,William J Shufesky,Adriana T Larregina

doi:10.1371/journal.pone.0004940

Derya Unutmaz, Zhiliang Wang + Show 5 more

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https://doi.org/10.1371/journal.pone.0004940

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Journal: PloS one	Publication Date: Mar 31, 2009
Citations: 102	License type: CC BY 4.0

Affiliation: University of Pittsburgh Medical Center

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.

Highlights

Chronic rejection (CR) is a major problem in transplantation that immuno-suppressive reagents fail to prevent and that limits long-term allograft survival [1]
We and others have shown in mice that (i) blood-borne leukocytes undergoing apoptosis are captured by splenic CD11chi dendritic cells (DCs) [21,22,23], and (ii) in situ-delivery of allo-Ags to splenic DCs by i.v. injection of donor apoptotic cells down-regulates anti-donor T cell immunity, prolongs cardiac allograft survival [37,38] and facilitates BM engraftment [39,40,41]
We demonstrated that delivery of donor allo-Ags to recipient’s DCs in situ is an efficient approach to control the indirect anti-donor response that contributes to chronic allograft vasculopathy (CAV), Figure 5

Summary

Introduction

Chronic rejection (CR) is a major problem in transplantation that immuno-suppressive reagents fail to prevent and that limits long-term allograft survival [1]. T cell recognize donor allo-peptides presented by recipient’s APCs through the indirect pathway of allorecognition [9], a mechanism that generates indirect pathway CD4 T cells and alloAbs, both critical in the pathogenesis of CAV [10,11,12] and CR [13,14]. By using mice deficient in dendritic cells (DCs), we have previously shown that recipient’s DCs are instrumental for development of CAV [15]. Besides their role in T cell immunity, DCs resident in secondary lymphoid organs are critical for induction of peripheral T cell tolerance in the steady-state [16], a property that could be exploited therapeutically to restrain the indirect alloresponse that leads to CAV [17]

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