Pharmacological manipulation of dendritic cells in the pursuit of transplantation tolerance

Leishman, Alison J.; Silk, Kathryn M.; Fairchild, Paul J.

doi:10.1097/mot.0b013e3283484b42

Cited by 16 publications

(13 citation statements)

References 53 publications

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“…This prospect is, however, contingent on the development of clinically compliant strategies to ensure the stable tolerogenicity of DC generated in this way. While the introduction of transgenes, such as PD-L1, at the ESC stage might confer on the resulting DC an immunomodulatory function [8], the additional regulatory hurdles encountered by the administration to patients of genetically modified cells, has fuelled attempts to identify approved pharmacological agents that coerce DC to adopt a protolerogenic phenotype [10]. …”

Section: Discussionmentioning

confidence: 99%

“…Accordingly, Senju et al generated DC expressing the inhibitory receptor programmed death ligand 1 (PD-L1) by genetic modification of the parent hESC line [8], a similar approach in the mouse having successfully yielded DC capable of preventing the onset of experimental autoimmune encephalomyelitis by induction of tolerance to myelin antigens [9]. While such a strategy is clearly promising, the administration of genetically modified cells to patients poses additional regulatory barriers, suggesting that exposure of DC to pharmacological agents, known to promote a tolerogenic phenotype, may prove to be a more pragmatic approach [10]. …”

Section: Introductionmentioning

confidence: 99%

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Rapamycin Conditioning of Dendritic Cells Differentiated from Human ES Cells Promotes a Tolerogenic Phenotype

Silk

Leishman

Nishimoto

et al. 2012

Journal of Biomedicine and Biotechnology

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While human embryonic stem cells (hESCs) may one day facilitate the treatment of degenerative diseases requiring cell replacement therapy, the success of regenerative medicine is predicated on overcoming the rejection of replacement tissues. Given the role played by dendritic cells (DCs) in the establishment of immunological tolerance, we have proposed that DC, rendered tolerogenic during their differentiation from hESC, might predispose recipients to accept replacement tissues. As a first step towards this goal, we demonstrate that DC differentiated from H1 hESCs (H1-DCs) are particularly responsive to the immunosuppressive agent rapamycin compared to monocyte-derived DC (moDC). While rapamycin had only modest impact on the phenotype and function of moDC, H1-DC failed to upregulate CD40 upon maturation and displayed reduced immunostimulatory capacity. Furthermore, coculture of naïve allogeneic T cells with rapamycin-treated H1-DC promoted an increased appearance of CD25hi Foxp3+ regulatory T cells, compared to moDC. Our findings suggest that conditioning of hESC-derived DC with rapamycin favours a tolerogenic phenotype.

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Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Rapamycin Conditioning of Dendritic Cells Differentiated from Human ES Cells Promotes a Tolerogenic Phenotype

Silk

Leishman

Nishimoto

et al. 2012

Journal of Biomedicine and Biotechnology

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“…In addition to promoting T cell responses, innate immune subsets such as dendritic cells (DCs) and macrophages, induce antigen-specific tolerance by promoting T-cell anergy, deletion or the generation of regulatory T cells (Tregs) [2], [14]. Moreover, M2 (alternate) type macrophages attenuate renal allograft injury by facilitating wound healing and tissue remodeling [15].…”

Section: Fuel Feeds Fate and Functionmentioning

confidence: 99%

T-cell energy metabolism as a controller of cell fate in transplantation

Priyadharshini

Turka²

2015

Current Opinion in Organ Transplantation

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Purpose of review This review highlights some of the recent developments in the novel field of immuno-metabolism and the therapeutic potential of the many regulatory components of this immuno-metabolic network for transplantation. Recent Findings In response to cytokines, changes in nutrients and other alterations in the local milieu, immune cells are capable of changing internal metabolic pathways to meet their energy demands. Recent studies demonstrate that activated T effectors (Th1 and Th17) are supported by aerobic glycolysis, whereas Tregs and CD8 memory T cells favor fatty acid oxidation and lipid biosynthesis through mitochondrial oxidative phosphorylation. These bioenergetic processes are dependent upon the activation of metabolic sensors such as mTOR and AMPK respectively indicating that the crosstalk between immunity and metabolism can shape the fate and function of immune cells. Finally, exciting new studies suggest that differences in the bioenergetic mechanisms within the various immune subsets may selectively be exploited for regulating immune responses. Summary In this review, we will discuss the metabolic signatures adopted by various immune cells during tolerance versus immunity and the promising avenues that can be modulated by targeting metabolic pathways with either nutrition and/or pharmacological intervention for establishing long-term transplantation tolerance.

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“…Notably, IL-10 reduces DC CCR7 expression and lymph node homing ability (68). Upregulation of CCR7 following activation of DCreg by Toll-like receptor (TLR) ligation in vitro may be required to improve the migratory function of these cells (69). Following i.v.…”

Section: Rmc As Cellular Immunotherapeutic Agentsmentioning

confidence: 99%

Regulatory Myeloid Cells in Transplantation

et al. 2014

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Regulatory myeloid cells (RMC) are emerging as novel targets for immunosuppressive (IS) agents and hold considerable promise as cellular therapeutic agents. Herein, we discuss the ability of regulatory macrophages (Mreg), regulatory dendritic cells (DCreg) and myeloid-derived suppressor cells (MDSC) to regulate alloimmunity, their potential as cellular therapeutic agents and the IS agents that target their function. We consider protocols for the generation of RMC and the selection of donor- or recipient-derived cells for adoptive cell therapy. Additionally, the issues of cell trafficking and antigen (Ag) specificity following RMC transfer are discussed. Improved understanding of the immunobiology of these cells has increased the possibility of moving RMC into the clinic to reduce the burden of current IS agents and promote Ag-specific tolerance. In the second half of this review, we discuss the influence of established and experimental IS agents on myeloid cell populations. IS agents believed historically to act primarily on T cell activation and proliferation are emerging as important regulators of RMC function. Better insights into the influence of IS agents on RMC will enhance our ability to develop cell therapy protocols to promote the function of these cells. Moreover, novel IS agents may be designed to target RMC in situ to promote Ag-specific immune regulation in transplantation and usher in a new era of immune modulation exploiting cells of myeloid origin.

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Pharmacological manipulation of dendritic cells in the pursuit of transplantation tolerance

Abstract: Although the rational design of tolerogenic dendritic cells for modulating the outcome of organ transplantation remains ambitious, the use of pharmacological agents to influence their functional phenotype continues to illuminate the basic biology of this critical cell type.

Cited by 16 publications

References 53 publications

Rapamycin Conditioning of Dendritic Cells Differentiated from Human ES Cells Promotes a Tolerogenic Phenotype

Rapamycin Conditioning of Dendritic Cells Differentiated from Human ES Cells Promotes a Tolerogenic Phenotype

T-cell energy metabolism as a controller of cell fate in transplantation

Regulatory Myeloid Cells in Transplantation

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