Dendritic Cells and Pluripotency: Unlikely Allies in the Pursuit of Immunotherapy

Fairchild, Paul J.; Leishman, Alison J.; Sachamitr, Patty; Telfer, Caroline; Hackett, Simon; Davies, Timothy

doi:10.2217/rme.15.6

Cited by 8 publications

(9 citation statements)

References 75 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…A superior “source cell” might, therefore, be pluripotent stem cells, either embryonic stem cells [126] or induced pluripotent stem cells (iPSC) [127] , typically derived from reprogrammed patient dermal fibroblasts. There are a number of advantages to using iPSC for the generation of tol-DCs [128] . Firstly, DCs differentiated from iPSC display an unusual, naturally tolerogenic phenotype, reminiscent of the phenotype expressed by DCs isolated from foetal tissue.…”

Section: Future Opportunitiesmentioning

confidence: 99%

“…iPSC, unlike DCs, are also amenable to genetic modification, allowing investigators to derive clonal populations of genetically-modified cells that would retain these changes throughout the differentiation process to DCs. Finally, cell viability of iPSC following cryopreservation is far higher than that of terminally differentiated DCs, which would permit patient's cell lines to be cryogenically stored for extended periods, until required [128] .…”

Section: Future Opportunitiesmentioning

confidence: 99%

See 1 more Smart Citation

Harnessing the properties of dendritic cells in the pursuit of immunological tolerance

2017

View full text Add to dashboard Cite

The acquisition of self-perpetuating, immunological tolerance specific for graft alloantigens has long been described as the “holy grail” of clinical transplantation. By removing the need for life-long immunosuppression following engraftment, the adverse consequences of immunosuppressive regimens, including chronic infections and malignancy, may be avoided. Furthermore, autoimmune diseases and allergy are, by definition, driven by aberrant immunological responses to ordinarily innocuous antigens. The re-establishment of permanent tolerance towards instigating antigens may, therefore, provide a cure to these common diseases. Whilst various cell types exhibiting a tolerogenic phenotype have been proposed for such a task, tolerogenic dendritic cells (tol-DCs) are exquisitely adapted for antigen presentation and interact with many facets of the immune system: as such, they are attractive candidates for use in strategies for immune intervention. We review here our current understanding of tol-DC mediated induction and maintenance of immunological tolerance. Additionally, we discuss recent in vitro findings from animal models and clinical trials of tol-DC immunotherapy in the setting of transplantation, autoimmunity and allergy which highlight their promising therapeutic potential, and speculate how tol-DC therapy may be developed in the future.

show abstract

Section: Future Opportunitiesmentioning

confidence: 99%

Section: Future Opportunitiesmentioning

confidence: 99%

Harnessing the properties of dendritic cells in the pursuit of immunological tolerance

2017

View full text Add to dashboard Cite

show abstract

“…Which of these diametrically opposed outcomes prevails depends primarily on the context in which antigen presentation by DCs occurs, steady-state conditions promoting the maintenance of tolerance, while ongoing inflammation favors immunity ( 1 ). These properties have made DCs attractive therapeutic agents for intervening in the progression of an immune response, inspiring numerous clinical trials for vaccination to poorly immunogenic tumor associated antigens (TAAs) as the basis for cancer immunotherapy ( 2 ). Furthermore, the clinical application of DCs has recently extended beyond vaccination to the induction of antigen-specific tolerance for the treatment of autoimmune diseases as diverse as diabetes ( 3 , 4 ), multiple sclerosis ( 5 ), and rheumatoid arthritis ( 6 , 7 ) as well as the prevention of allograft rejection ( 8 , 9 ).…”

Section: Introductionmentioning

confidence: 99%

Directed Differentiation of Human Induced Pluripotent Stem Cells into Dendritic Cells Displaying Tolerogenic Properties and Resembling the CD141+ Subset

et al. 2018

Self Cite

View full text Add to dashboard Cite

The advent of induced pluripotent stem cells (iPSCs) has begun to revolutionize cell therapy by providing a convenient source of rare cell types not normally available from patients in sufficient numbers for therapeutic purposes. In particular, the development of protocols for the differentiation of populations of leukocytes as diverse as naïve T cells, macrophages, and natural killer cells provides opportunities for their scale-up and quality control prior to administration. One population of leukocytes whose therapeutic potential has yet to be explored is the subset of conventional dendritic cells (DCs) defined by their surface expression of CD141. While these cells stimulate cytotoxic T cells in response to inflammation through the cross-presentation of viral and tumor-associated antigens in an MHC class I-restricted manner, under steady-state conditions CD141+ DCs resident in interstitial tissues are focused on the maintenance of homeostasis through the induction of tolerance to local antigens. Here, we describe protocols for the directed differentiation of human iPSCs into a mixed population of CD11c+ DCs through the spontaneous formation of embryoid bodies and exposure to a cocktail of growth factors, the scheduled withdrawal of which serves to guide the process of differentiation. Furthermore, we describe the enrichment of DCs expressing CD141 through depletion of CD1c+ cells, thereby obtaining a population of “untouched” DCs unaffected by cross-linking of surface CD141. The resulting cells display characteristic phagocytic and endocytic capacity and acquire an immunostimulatory phenotype following exposure to inflammatory cytokines and toll-like receptor agonists. Nevertheless, under steady-state conditions, these cells share some of the tolerogenic properties of tissue-resident CD141+ DCs, which may be further reinforced by exposure to a range of pharmacological agents including interleukin-10, rapamycin, dexamethasone, and 1α,25-dihydoxyvitamin D3. Our protocols therefore provide access to a novel source of DCs analogous to the CD141+ subset under steady-state conditions in vivo and may, therefore, find utility in the treatment of a range of disease states requiring the establishment of immunological tolerance.

show abstract

“…Cancer tissues comprise (pre-) cancer (stem) cells, pre-metastatic cancer cells, stromal cells (such as mesenchymal stem cells, cancer-associated fibroblasts[15,16,24] and tumor endothelial cells) and immune cells (such as tumor-associated macrophages[25], dendritic cells[26] and tumor-infiltrating T cells[23]). Therefore, such a cell-derived iPSC line might be useful for immune-cell therapy[27] with cellular vaccines[28], dendritic cells[29-32] or tumor antigen-specific cytotoxic T cells[23], in addition to the development of models of carcinogenesis[33-35] and drug discovery tools[36,37]. For the purposes of regenerative medicine, human iPSCs are ideally generated from normal neonatal tissues[3,38-40] that are typically inexperienced of postnatal aberrant mutations or epigenetic changes.…”

Section: Discussionmentioning

confidence: 99%

Next-generation sequencing traces human induced pluripotent stem cell lines clonally generated from heterogeneous cancer tissue

Ishikawa¹

2017

WJSC

View full text Add to dashboard Cite

AIMTo investigate genotype variation among induced pluripotent stem cell (iPSC) lines that were clonally generated from heterogeneous colon cancer tissues using next-generation sequencing.METHODSHuman iPSC lines were clonally established by selecting independent single colonies expanded from heterogeneous primary cells of S-shaped colon cancer tissues by retroviral gene transfer (OCT3/4, SOX2, and KLF4). The ten iPSC lines, their starting cancer tissues, and the matched adjacent non-cancerous tissues were analyzed using next-generation sequencing and bioinformatics analysis using the human reference genome hg19. Non-synonymous single-nucleotide variants (SNVs) (missense, nonsense, and read-through) were identified within the target region of 612 genes related to cancer and the human kinome. All SNVs were annotated using dbSNP135, CCDS, RefSeq, GENCODE, and 1000 Genomes. The SNVs of the iPSC lines were compared with the genotypes of the cancerous and non-cancerous tissues. The putative genotypes were validated using allelic depth and genotype quality. For final confirmation, mutated genotypes were manually curated using the Integrative Genomics Viewer.RESULTSIn eight of the ten iPSC lines, one or two non-synonymous SNVs in EIF2AK2, TTN, ULK4, TSSK1B, FLT4, STK19, STK31, TRRAP, WNK1, PLK1 or PIK3R5 were identified as novel SNVs and were not identical to the genotypes found in the cancer and non-cancerous tissues. This result suggests that the SNVs were de novo or pre-existing mutations that originated from minor populations, such as multifocal pre-cancer (stem) cells or pre-metastatic cancer cells from multiple, different clonal evolutions, present within the heterogeneous cancer tissue. The genotypes of all ten iPSC lines were different from the mutated ERBB2 and MKNK2 genotypes of the cancer tissues and were identical to those of the non-cancerous tissues and that found in the human reference genome hg19. Furthermore, two of the ten iPSC lines did not have any confirmed mutated genotypes, despite being derived from cancerous tissue. These results suggest that the traceability and preference of the starting single cells being derived from pre-cancer (stem) cells, stroma cells such as cancer-associated fibroblasts, and immune cells that co-existed in the tissues along with the mature cancer cells.CONCLUSIONThe genotypes of iPSC lines derived from heterogeneous cancer tissues can provide information on the type of starting cell that the iPSC line was generated from.

show abstract

Dendritic Cells and Pluripotency: Unlikely Allies in the Pursuit of Immunotherapy

Cited by 8 publications

References 75 publications

Harnessing the properties of dendritic cells in the pursuit of immunological tolerance

Harnessing the properties of dendritic cells in the pursuit of immunological tolerance

Directed Differentiation of Human Induced Pluripotent Stem Cells into Dendritic Cells Displaying Tolerogenic Properties and Resembling the CD141+ Subset

Next-generation sequencing traces human induced pluripotent stem cell lines clonally generated from heterogeneous cancer tissue

Contact Info

Product

Resources

About