Elsevier

International Immunopharmacology

Volume 65, December 2018, Pages 470-482
International Immunopharmacology

Galectin-1-induced tolerogenic dendritic cells combined with apoptotic lymphocytes prolong liver allograft survival

https://doi.org/10.1016/j.intimp.2018.10.019Get rights and content

Highlights

  • Galectin-1-induced DCs (DCgal-1s) work as a regulatory cell therapy for transplantation.

  • Combined DCgal-1s and apoptotic lymphocytes (AL) treatment exhibited better immunoinhibitory function.

  • TGF-β1 and TGF-β2 were significantly increased in the allografts of long-term survival recipients.

Abstract

Donor-derived tolerogenic dendritic cells (DCs) and apoptotic lymphocytes (ALs) are practical tools for controlling rejection after transplantation by targeting direct and indirect allorecognition pathways, respectively. To date, few studies have investigated the combination of donor-derived tolerogenic DCs and ALs infusion in organ transplantation protection. In the present study, we generated galectin-1-induced tolerogenic DCs (DCgal-1s) and ultraviolet irradiation-induced ALs with stable immune characteristics in vitro and potential immune regulatory activity in vivo. A rat model of acute liver transplant rejection was established, and the intrinsic tolerogenic profiles associated with the short-term alleviation of rejection and the long-term maintenance of tolerance in the absence of immunosuppressive drugs were evaluated. The DCgal-1-AL treatment prolonged allograft survival more significantly than a transfusion of DCgal-1s or ALs alone. This benefit was associated with CD4+ Treg cell expansion and decreased interferon (IFN)-γ+ T cell levels. Moreover, DCgal-1-AL treatment led to different cytokine/chemokine changes in the allograft and peripheral blood, that indicated an alleviation of local and systemic inflammation on day 7 post-transplantation. TGF-β1 and TGF-β2 were significantly increased in the long-term surviving allografts after DCgal-1-AL treatment. Our results indicate that the combination of DCgal-1s with ALs effectively prolongs liver allograft survival and represents a novel therapeutic strategy for liver transplant rejection.

Introduction

Dendritic cells (DCs) are antigen-presenting cells that play essential roles in transplant incompatibility [1,2]. Donor- and recipient-derived DCs elite a T lymphocyte response via synergistic pathways: direct allorecognition, in which donor-derived DCs present alloantigens, and indirect allorecognition, in which recipient-derived DCs process alloantigens [3,4]. Theoretically, it is feasible to modulate both donor- and recipient-DC presentations for the management of rejection posttransplantation.

The use of tolerogenic DCs (Tol-DCs) represents a “compelling method” to alleviate rejection events post-transplantation by altering the direct pathway of DC-T cell interactions [5,6]. In transplantation, donor-derived allogeneic Tol-DCs with deficiency in MHC/co-stimulatory molecule expression and proinflammatory factor production endow T cells with tolerogenic function [7,8]. Various therapeutics, including dexamethasone, vitamin D3 and rapamycin, have been introduced to trigger a Tol-DC phenotype [[9], [10], [11]]. In fact, the infusion of Tol-DCs in organ transplantation has not been fully evaluated [12]. Moreover, previous studies have revealed that simply increasing the infusion dose of Tol-DCs does not result in better transplantation outcomes, and a combination of transfusion methods might have more beneficial effects [12,13]. The combination of Tol-DCs with a steroid-sparing regimen of cytotoxic T lymphocyte Ag4 (CTLA4) Ig or rapamycin has been considered an effective option, but the off-target effects of non-specific immune reactions have been criticized [6,14]. Therefore, a novel regimen for Tol-DC regulation in transplantation needs to be identified and validated from bench to bedside.

Galectin-1, a homodimeric protein and a member of the β‑galactoside binding family, regulates the apoptosis of activated T cells and enhances Treg cell responses [15,16]. In addition, galectin-1 exerts an immunosuppressive function on DCs. Galectin‑1‑induced DCs (DCgal-1) promote T cell tolerance in autoimmune neuroinflammation, whereas DCs lacking galectin-1 induce an immunogenic response [17,18]. We have reported that galectin-1 administration prolongs mouse liver allograft survival and that this is associated with increased T cell apoptosis and the inhibition of DC-mediated allostimulation [19]. However, DCgal-1 has not been implicated or studied in the domain of organ transplantation rejection.

Apoptotic lymphocytes (ALs) exert potent immune regulatory effects on DCs [20]. After the internalization of ALs, DCs downregulate the expression of proinflammatory cytokines but upregulate the secretion of IL-10 and TGF-β and the induction of Tregs [[21], [22], [23]]. Intravenous injection of donor allogeneic ALs can modify the function of recipient DCs and prolong cardiac allograft survival [24]. Hence, ALs effectively intervene in the indirect pathway of allorecognition and improve transplantation outcomes.

Taken together, these data prompted us to investigate the therapeutic potential and possible mechanisms of donor-derived DCgal-1s combined with ALs in liver transplant rejection, by targeting both direct and indirect recognition pathways. Our results first demonstrate that the combination of DCgal-1s with ALs effectively prolongs liver allograft survival and represents a novel therapeutic strategy for liver transplant rejection.

Section snippets

Animals

Male Dark Agouti (DA) rats and Lewis rats (8–10 weeks of age and 230–270 g in weight) were separately purchased from the Zhejiang Academy of Medical Sciences and Beijing Vital River Laboratory Animal Technology Co., Ltd., and maintained under specific pathogen-free conditions. All experiments were conducted under permission of the Animal Ethics Review Committees of Zhejiang University First Affiliated Hospital.

Study design

An acute rejection model of orthotopic liver transplantation was established by using

DCgal-1s maintain tolerant immunophenotype in vitro

The surface marker phenotype of DCgal-1 was determined. The FCM results revealed strong expression of CD11b and CD11c in DCgal-1s, DCcons, and mDCs, consistent with a previous study [27]. CD68 was nearly absent, CD103 was found at a low level, and CD172a was comparably expressed in all DC types (Fig. S1A). The analysis of the activation markers revealed that DCgal-1s expressed low levels of major histocompatibility complex (MHC) II, CD80, and CD86, which did not reach the levels expressed by

Discussion

In this study, we evaluated galectin-1-induced DCs as a regulatory cell therapy for transplantation. We found that combined DCgal-1s and AL treatment exhibited better immunoinhibitory function against liver rejection than either DCgal-1 or AL infusion alone.

Some types of Tol-DCs have been applied in acute liver rejection to achieve prolonged survival, suggesting that Tol-DCs alone are effective [12,28]. In addition to the reduced expression of MHC II/costimulatory molecules on surface and

Disclosure

The authors of this manuscript declare no conflict of interest.

Funding source

National Natural Science Foundation of China (91542205, 81721091, 81400673), Natural Science Foundation of Zhejiang Province (2016F82G2010038, LY18H030002), China Postdoctoral Science Foundation (2017M610374).

Authorship

Yifan Peng, Yufu Ye study design, research performance, data collection, data analysis, manuscript writing.

Junjun Jia statistical analysis, manuscript writing.

Zhentao Yang data collection, data analysis.

Yong He, Xiaolu Zhu, Hechen Huang animal model.

Lei Geng, Shengyong Yin, Wei Wang data analysis, manuscript revision.

Lin Zhou, Shusen Zheng conception direction, study design.

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    These authors contributed equally to this work.

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