Human Dendritic Cells and Transplant Outcome

Solari, Mario G.; Thomson, Angus W.

doi:10.1097/tp.0b013e318173a768

Cited by 37 publications

(27 citation statements)

References 112 publications

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“…The importance of tolerogenic DCs and its association with transplantation outcomes has been long recognized [15,42]. Our results support a tolerogenic role for MMF and suggest additional mechanisms of action of this drug, including inhibition of T-cell proliferation via the indirect pathway by means of the drug's effects on the maturation profile of DCs.…”

Section: Discussionsupporting

confidence: 60%

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Mycophenolic acid inhibits maturation and function of human dendritic cells and B cells

et al. 2009

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Section: Discussionsupporting

confidence: 60%

“…After allotransplantation, the initiation of an immune response involves intricate interactions between T cells and antigenpresenting cells (APCs) [15]. The indirect pathway of antigen presentation is important in acute and chronic rejection after organ transplantation [16 -20].…”

Section: Introductionmentioning

confidence: 99%

Mycophenolic acid inhibits maturation and function of human dendritic cells and B cells

et al. 2009

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“…47 A recent study showed that depletion of p-preDCs from bone marrow grafts resulted in an acceleration of mortality from GVHD, while the depletion of mature p-preDCs from granulocyte colony-stimulating factormobilized splenic grafts had no effect. These data suggest that donor bone marrow p-preDCs, but not mature p-preDCs, attenuate acute GVHD.…”

Section: Discussionmentioning

confidence: 99%

CD8α+ plasmacytoid precursor DCs induce antigen-specific regulatory T cells that enhance HSC engraftment in vivo

Huang

Bozulic

Miller

et al. 2011

Blood

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CD8-positive/T-cell receptor-negative (CD8 ؉ /TCR ؊ ) graft facilitating cells (FCs) are a novel cell population in bone marrow that potently enhance engraftment of hemopoietic stem cells (HSCs). Previously, we showed that the CD11c ؉ /B220 ؉ / CD11b ؊ plasmacytoid-precursor dendritic cell (p-preDC) FC subpopulation plays a critical but nonredundant role in facilitation. In the present study, we investigated the mechanism of FC function. We report that FCs induce antigen-specific CD4 ؉ / CD25 ؉ /FoxP3 ؉ regulatory T cells ( IntroductionRecently, a great deal of interest has focused on the therapeutic potential of cell-based therapies to induce tolerance. Of greatest interest is the subpopulation of bone marrow-derived plasmacytoidprecursor dendritic cells (p-preDCs) and the regulatory T cells (Tregs) that they induce. A major limitation to the use of p-preDCs and Tregs in vivo has been the failure to identify an approach to prevent them from losing their tolerogenic properties and becoming immunogenic after transplantation. We recently demonstrated that CD8␣-positive/T-cell receptor-negative (CD8␣ ϩ /TCR Ϫ ) graft facilitating cells (FCs) enhance the engraftment of hematopoietic stem cells (HSCs) and tolerance induction in allogeneic recipients. [1][2][3] FCs suppress graft-versus-host disease (GVHD) in vivo by producing CD4 ϩ /CD25 ϩ /FoxP3 ϩ Tregs 4 and induce Tregs in vitro in the presence of CpG. 5 The majority of CD8␣ ϩ /TCR Ϫ FCs share the B220 ϩ /CD11c ϩ /CD11b Ϫ p-preDC phenotype, and we have demonstrated the first in vivo engraftment-enhancing and tolerancepromoting effect of the p-preDC FC subpopulation. 2 Although removal of p-preDC FCs from total FCs completely abrogates facilitation, p-preDC FCs alone do not replace FCs to provide the full in vivo biologic effect of facilitation. The mechanism of FC function has yet to be precisely characterized.CD4 ϩ /CD25 ϩ /FoxP3 ϩ Tregs play a critical role in the maintenance of self-tolerance. 6 Defects in Treg development or homeostasis result in systemic autoimmunity, 7 whereas adoptive transfer of Tregs as a therapeutic method can control ongoing autoimmune diseases. [8][9][10] Recently, several studies have demonstrated an important role for Tregs in mediating transplantation tolerance in animal models, 11-14 but little is known about the mechanism of Treg development and homeostasis. [15][16][17] p-preDCs may be important in the generation of Tregs, as evidenced by their potential to facilitate engraftment of HSCs 2,18 and to prolong heart allograft survival. 19,20 In addition, in vitro activation of p-preDCs with CpGoligodeoxynucleotides (CpG-ODNs) induces the production of Tregs in vitro. 5,21 We therefore evaluated whether the mechanism of FC function in vivo is to induce Tregs.In the present study, we first evaluated whether FCs enhance allogeneic HSC engraftment in diabetes-prone nonobese diabetic (NOD) mice. Second, we investigated whether FCs induce the production of Tregs and examined their function using in vivo transplantation models and in vitr...

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“…Analysis of peripheral blood DC in organ or BM transplant patients may be a helpful immune monitoring tool [103, 104]; reviewed in ref [6]. Higher incidences of circulating pDC relative to mDC are found in operationally tolerant pediatric liver allograft recipients and in patients on low dose immunosuppressive drug therapy undergoing prospective drug weaning, compared with patients on maintenance immunosuppression.…”

Section: Evidence Of Immune Regulation By DC In Humans and In Climentioning

confidence: 99%

Tolerogenic dendritic cells and their role in transplantation

Ezzelarab

Thomson

2011

Seminars in Immunology

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146

130

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The pursuit of clinical transplant tolerance has led to enhanced understanding of mechanisms underlying immune regulation, including the characterization of immune regulatory cells, in particular antigen-presenting cells (APC) and regulatory T cells (Treg), that may play key roles in promoting operational tolerance. Dendritic cells (DC) are highly-efficient APC that have been studied extensively in rodents and humans, and more recently in non-human primates. Owing to their ability to regulate both innate and adaptive immune responses, DC are considered to play crucial roles in directing the alloimmune response towards transplant tolerance or rejection. Mechanisms via which they can promote central and peripheral tolerance include clonal deletion, the induction of Treg, and inhibition of memory T cell responses. These properties have led to the use of tolerogenic DC as a therapeutic strategy to promote organ transplant tolerance. In rodents, infusion of donor- or recipient-derived tolerogenic DC can extensively prolong donor-specific allograft survival, in association with regulation of the host T cell response. In clinical transplantation, progress has been made in monitoring DC in relation to graft outcome, including studies in operational liver transplant toleranceAlthough clinical trials involving immunotherapeutic DC for patients with cancer are ongoing, implementation of human DC therapy in clinical transplantation will require assessment of various critical issues. These include cell isolation and purification techniques, source, route and timing of administration, and combination immunosuppressive therapy. With ongoing non-human primate studies focused on DC therapy, these logistics can be investigated seeking the optimal approaches. The scientific rationale for implementation of tolerogenic DC therapy to promote clinical transplant tolerance is strong. Evaluation of technical and therapeutic logistic issues is an important next step prior to the application of “therapeutic” DC in clinical organ transplantation.

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Human Dendritic Cells and Transplant Outcome

Cited by 37 publications

References 112 publications

Mycophenolic acid inhibits maturation and function of human dendritic cells and B cells

Mycophenolic acid inhibits maturation and function of human dendritic cells and B cells

CD8α+ plasmacytoid precursor DCs induce antigen-specific regulatory T cells that enhance HSC engraftment in vivo

Tolerogenic dendritic cells and their role in transplantation

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