Safety and feasibility of intradermal injection with tolerogenic dendritic cells pulsed with proinsulin peptide—for type 1 diabetes

Nikolić, Tatjana; Zwaginga, Jaap Jan; Uitbeijerse, Bas S; Woittiez, Nicky J C; Koning, Eelco Jp de; Aanstoot, Henk‐Jan; Roep, Bart O.

doi:10.1016/s2213-8587(20)30104-2

Cited by 71 publications

(61 citation statements)

References 6 publications

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“…TolDCs display a differential transcriptome compared with inflammatory DCs that is unaffected by health status or production location Stability of a cellular product, including reproducible production between different international centers and between healthy subjects and T1D patients, is important for its implementation in the clinic. Therefore, the authors produced tolDCs from healthy subjects and T1D patients that passed validated quality control criteria (low CD86 expression, high CD52 expression [27]) in two international production centers. Subsequently, for more in-depth analysis, a transcriptome study was conducted comparing gene expression by RNA-seq between DCs produced at LUMC and COH.…”

Section: Toldcs Retain Semi-mature Functional Aspects and Metabolism mentioning

confidence: 99%

1,25-dihydroxyvitamin D3 induces stable and reproducible therapeutic tolerogenic dendritic cells with specific epigenetic modifications

et al. 2021

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Autologous, antigen-specific, tolerogenic dendritic cells (tolDCs) are presently assessed to reverse and possibly cure autoimmune diseases such as type 1 diabetes (T1D). Good Manufacturing Practice production and clinical implementation of such cell therapies critically depend on their stability and reproducible production from healthy donors and, more importantly, patient-derived monocytes. Here the authors demonstrate that tolDCs (modulated using 1,25-dihydroxyvitamin D3 and dexamethasone) displayed similar features, including protein, transcriptome and epigenome profiles, between two international clinical centers and between T1D and healthy donors, validating reproducible production. In addition, neither phenotype nor function of tolDCs was affected by repeated stimulation with inflammatory stimuli, underscoring their stability as semi-mature DCs. Furthermore, tolDCs exhibited differential DNA methylation profiles compared with inflammatory mature DCs (mDCs), and this was already largely established prior to maturation, indicating that tolDCs are locked into an immature state. Finally, approximately 80% of differentially expressed known T1D risk genes displayed a corresponding differential DNA methylome in tolDCs versus mDCs and metabolic and immune pathway genes were also differentially methylated and expressed. In summary, tolDCs are reproducible and stable clinical cell products unaffected by the T1D status of donors. The observed stable, semi-mature phenotype and function of tolDCs are exemplified by epigenetic modifications representative of immature-stage cells. Together, the authors' data provide a strong basis for the production and clinical implementation of tolDCs in the treatment of autoimmune diseases such as T1D.

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Section: Toldcs Retain Semi-mature Functional Aspects and Metabolism mentioning

confidence: 99%

1,25-dihydroxyvitamin D3 induces stable and reproducible therapeutic tolerogenic dendritic cells with specific epigenetic modifications

et al. 2021

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“…Monocyte derived tolerogenic DCs (tolDcs) from patients under sub-optimal glycemic control display reduced tolerogenic capabilities compared to those from patients under optimal control (45)(46)(47)(48). However, this glycemia dependent difference may not necessarily be a general difference between health and disease, and could be a consequence, rather than causally related to T1D immunopathogenesis.…”

Section: Myeloid Cells In Circulation In Health and Diseasementioning

confidence: 99%

“…However, this glycemia dependent difference may not necessarily be a general difference between health and disease, and could be a consequence, rather than causally related to T1D immunopathogenesis. We recently showed that tolDCs generated from T1D patients' blood induce immune tolerance indifferently from those from healthy individuals, proving that they still possess their immune-regulatory capacity (47).…”

Section: Myeloid Cells In Circulation In Health and Diseasementioning

confidence: 99%

Islet-Resident Dendritic Cells and Macrophages in Type 1 Diabetes: In Search of Bigfoot’s Print

Zirpel

Roep

2021

Front. Endocrinol.

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The classical view of type 1 diabetes assumes that the autoimmune mediated targeting of insulin producing ß-cells is caused by an error of the immune system. Malfunction and stress of beta cells added the target tissue at the center of action. The innate immune system, and in particular islet-resident cells of the myeloid lineage, could function as a link between stressed ß-cells and activation and recognition by the adaptive immune system. We survey the role of islet-resident macrophages and dendritic cells in healthy islet homeostasis and pathophysiology of T1D. Knowledge of islet-resident antigen presenting cells in rodents is substantial, but quite scarce in humans, in particular regarding dendritic cells. Differences in blood between healthy and diseased individuals were reported, but it remains elusive to what extend these contribute to T1D onset. Increasing our understanding of the interaction between ß-cells and innate immune cells may provide new insights into disease initiation and development that could ultimately point to future treatment options. Here we review current knowledge of islet-resident macrophages and dendritic cells, place these in context of current clinical trials, and guide future research.

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“…An alternative approach to infusing ex vivo-expanded Tregs is to use tolerogenic APCs to expand Tregs in vivo by exploiting infectious tolerance, an approach which bypasses the risk of compromising Treg stability during ex vivo expansion [80]. Several clinical studies have now assessed tolAPC therapy in treating type 1 diabetes [81,82], rheumatoid arthritis [83,84], Crohn's disease [85], multiple sclerosis and neuromyelitis optica spectrum disorders [86] and preventing kidney transplant rejection [74]. These studies used multiple methods to derive autologous, "immature" tolDCs (or regulatory macrophages [74]) from patient monocytes, some involving disease-relevant antigen pulsing prior to injection [82,84,86].…”

Section: In Vivo Expansion Of Treg Cellsmentioning

confidence: 99%

“…Several clinical studies have now assessed tolAPC therapy in treating type 1 diabetes [81,82], rheumatoid arthritis [83,84], Crohn's disease [85], multiple sclerosis and neuromyelitis optica spectrum disorders [86] and preventing kidney transplant rejection [74]. These studies used multiple methods to derive autologous, "immature" tolDCs (or regulatory macrophages [74]) from patient monocytes, some involving disease-relevant antigen pulsing prior to injection [82,84,86]. Studies to date showed these therapies were well tolerated with small increases in peripheral Treg numbers [81,[84][85][86].…”

Section: In Vivo Expansion Of Treg Cellsmentioning

confidence: 99%

Cross talk between human regulatory T cells and antigen‐presenting cells: Lessons for clinical applications

et al. 2020

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Regulatory T cells (Tregs) have a critical role in maintaining self‐tolerance and immune homeostasis. There is much interest in using Tregs as a cell therapy to re‐establish tolerance in conditions such as inflammatory bowel disease and type 1 diabetes, with many ongoing clinical studies testing the safety and efficacy of this approach. Manufacturing of Tregs for therapy typically involves ex vivo expansion to obtain sufficient cell numbers for infusion and comes with the risk of altering the activity of key biological processes. However, this process also offers an opportunity to tailor Treg function to maximize in vivo activity. In this review, we focus on the roles of antigen‐presenting cells (APCs) in the generation and function of Tregs in humans. In addition to stimulating the development of Tregs, APCs activate Tregs and provide signals that induce specialized functional and homing marker expression. Cross talk between Tregs and APCs is a critical, often under‐appreciated, aspect of Treg biology, with APCs mediating the key properties of infectious tolerance and bystander suppression. Understanding the biology of human Treg‐APC interactions will reveal new ways to optimize Treg‐based therapeutic approaches.

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Safety and feasibility of intradermal injection with tolerogenic dendritic cells pulsed with proinsulin peptide—for type 1 diabetes

Abstract: overdiagnosis after 2012 remains yet largely unknown, the extent of overdiagnosis indicates an urgent need to closely monitor its evolution worldwide and the impact of recent guidelines.

Cited by 71 publications

References 6 publications

1,25-dihydroxyvitamin D3 induces stable and reproducible therapeutic tolerogenic dendritic cells with specific epigenetic modifications

1,25-dihydroxyvitamin D3 induces stable and reproducible therapeutic tolerogenic dendritic cells with specific epigenetic modifications

Islet-Resident Dendritic Cells and Macrophages in Type 1 Diabetes: In Search of Bigfoot’s Print

Cross talk between human regulatory T cells and antigen‐presenting cells: Lessons for clinical applications

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