PMID- 37901231
OWN - NLM
STAT- MEDLINE
DCOM- 20231031
LR  - 20231102
IS  - 1664-3224 (Electronic)
IS  - 1664-3224 (Linking)
VI  - 14
DP  - 2023
TI  - Tolerogenic dendritic cells generated in vitro using a novel protocol mimicking 
      mucosal tolerance mechanisms represent a potential therapeutic cell platform for 
      induction of immune tolerance.
PG  - 1045183
LID - 10.3389/fimmu.2023.1045183 [doi]
LID - 1045183
AB  - Dendritic cells (DCs) are mediators between innate and adaptive immunity and 
      vital in initiating and modulating antigen-specific immune responses. The most 
      important site for induction of tolerance is the gut mucosa, where TGF-beta, 
      retinoic acid, and aryl hydrocarbon receptors collaborate in DCs to induce a 
      tolerogenic phenotype. To mimic this, a novel combination of compounds - the 
      synthetic aryl hydrocarbon receptor (AhR) agonist IGN-512 together with TGF-beta and 
      retinoic acid - was developed to create a platform technology for induction of 
      tolerogenic DCs intended for treatment of several conditions caused by unwanted 
      immune activation. These in vitro-generated cells, designated ItolDCs, are 
      phenotypically characterized by their low expression of co-stimulatory and 
      activating molecules along with high expression of tolerance-associated markers 
      such as ILT3, CD103, and LAP, and a weak pro-inflammatory cytokine profile. When 
      co-cultured with T cells and/or B cells, ItolDC-cultures contain higher 
      frequencies of CD25+Foxp3+ regulatory T cells (Tregs), CD49b+LAG3+ 'type 1 
      regulatory (Tr1) T cells, and IL-10-producing B cells and are less T cell 
      stimulatory compared to cultures with matured DCs. Factor VIII (FVIII) and 
      tetanus toxoid (TT) were used as model antigens to study ItolDC antigen-loading. 
      ItolDCs can take up FVIII, process, and present FVIII peptides on HLA-DR. By 
      loading both ItolDCs and mDCs with TT, antigen-specific T cell proliferation was 
      observed. Cryo-preserved ItolDCs showed a stable tolerogenic phenotype that was 
      maintained after stimulation with LPS, CD40L, or a pro-inflammatory cocktail. 
      Moreover, exposure to other immune cells did not negatively impact ItolDCs' 
      expression of tolerogenic markers. In summary, a novel protocol was developed 
      supporting the generation of a stable population of human DCs in vitro that 
      exhibited a tolerogenic phenotype with an ability to increase proportions of 
      induced regulatory T and B cells in mixed cultures. This protocol has the 
      potential to constitute the base of a tolDC platform for inducing 
      antigen-specific tolerance in disorders caused by undesired antigen-specific 
      immune cell activation.
CI  - Copyright (c) 2023 Dao Nyesiga, Pool, Englezou, Hylander, Ohlsson, Appelgren, 
      Sundstedt, Tillerkvist, Romedahl and Wigren.
FAU - Dao Nyesiga, Gillian
AU  - Dao Nyesiga G
AD  - Idogen AB, Lund, Sweden.
AD  - Department of Biomedical Sciences, Faculty of Health and Society, Malmo 
      University, Malmo, Sweden.
FAU - Pool, Lieneke
AU  - Pool L
AD  - Idogen AB, Lund, Sweden.
FAU - Englezou, Pavlos C
AU  - Englezou PC
AD  - Idogen AB, Lund, Sweden.
FAU - Hylander, Terese
AU  - Hylander T
AD  - Idogen AB, Lund, Sweden.
FAU - Ohlsson, Lars
AU  - Ohlsson L
AD  - Department of Biomedical Sciences, Faculty of Health and Society, Malmo 
      University, Malmo, Sweden.
FAU - Appelgren, Daniel
AU  - Appelgren D
AD  - Department of Health, Medicine and Caring Sciences, Faculty of Medicine and 
      Health Sciences, Linkoping University, Linkoping, Sweden.
FAU - Sundstedt, Anette
AU  - Sundstedt A
AD  - Idogen AB, Lund, Sweden.
FAU - Tillerkvist, Kristina
AU  - Tillerkvist K
AD  - Idogen AB, Lund, Sweden.
FAU - Romedahl, Hanne R
AU  - Romedahl HR
AD  - Idogen AB, Lund, Sweden.
FAU - Wigren, Maria
AU  - Wigren M
AD  - Idogen AB, Lund, Sweden.
LA  - eng
PT  - Journal Article
PT  - Research Support, Non-U.S. Gov't
DEP - 20231013
PL  - Switzerland
TA  - Front Immunol
JT  - Frontiers in immunology
JID - 101560960
RN  - 0 (Transforming Growth Factor beta)
RN  - 5688UTC01R (Tretinoin)
SB  - IM
MH  - Humans
MH  - *Immune Tolerance
MH  - *Transforming Growth Factor beta/metabolism
MH  - Tretinoin/metabolism
MH  - Dendritic Cells
MH  - Mucous Membrane
PMC - PMC10613069
OTO - NOTNLM
OT  - antigen loading
OT  - antigen-specific response
OT  - cell therapy
OT  - immune tolerance
OT  - regulatory B cells (Bregs)
OT  - regulatory T cells (Tregs)
OT  - tolerogenic dendritic cells (tolDCs)
COIS- Authors LP, PE, HR and MW are co-inventors of the technology of the patent 
      application (now acquired and further developed by Cell4Cure AB) regarding the 
      generation of ItolDC. Authors GD, LP, PE, TH, AS, KT, HR, and MW were employed by 
      Idogen AB. The remaining authors declare that the research was conducted in the 
      absence of any commercial or financial relationships that could be construed as a 
      potential conflict of interest.
EDAT- 2023/10/30 06:47
MHDA- 2023/10/31 06:42
PMCR- 2023/01/01
CRDT- 2023/10/30 04:47
PHST- 2022/09/15 00:00 [received]
PHST- 2023/08/25 00:00 [accepted]
PHST- 2023/10/31 06:42 [medline]
PHST- 2023/10/30 06:47 [pubmed]
PHST- 2023/10/30 04:47 [entrez]
PHST- 2023/01/01 00:00 [pmc-release]
AID - 10.3389/fimmu.2023.1045183 [doi]
PST - epublish
SO  - Front Immunol. 2023 Oct 13;14:1045183. doi: 10.3389/fimmu.2023.1045183. 
      eCollection 2023.