Current advances in using tolerogenic dendritic cells as a therapeutic alternative in the treatment of type 1 diabetes

Table 1 Tolerogenic dendritic cells manufacturing for type 1 diabetes therapy

Protocol	Treatment	DC phenotype	Therapeutic effects in T1D	Ref.
GM-CSF	Apoptotic bodies-loaded	↓ Costimulatory molecules (CD40, CD86); ↓ IL-6; ↓ TNF-α	Reduces disease incidence in NOD mice. Reduces insulitis	Marin-Gallen et al[62], 2010
	Liposomes-loaded	↑ TIM4, CD36; ↓ MHC-II; ↓ Costimulatory molecules (CD40, CD86); ↑ CCR7, CCR2; ↑ DC-SING; ↓ IL-6; ↑ Anti-inflammatory cytokines (IL-10, TGF-β1)	Decreases CD8+ T cell proliferation. Reduces disease incidence in NOD mice. Reduces insulitis	Pujol-Autonell et al[64], 2015
GM-CSF/IL-4	Antisense oligonucleotides	↓ Costimulatory molecules (CD40, CD80, CD86); ↓ NO; ↓ TNF-α, IL-12p70	Prevents diabetes in NOD mice. Reduces insulitis. Promotes Tregs. Increases B cells. Suppresses T cells proliferation: Clinicaltrials.gov identifier: NCT00445913; Clinicaltrials.gov identifier: NCT02354911	Machen et al[50], 2004
				Di Caro et al[51], 2014
				Di Caro et al[52], 2012
				Phillips et al[53], 2008
				Giannoukakis et al[54], 2011
				NIH[68], 2007
				NIH[69], 2015
	Antigen-loaded: Proinsulin	Tolerogenic phenotype (not specifically described)	Delays or halts progressive destruction of β-cell and loss function. -Clinicaltrials.gov identifier: NCT04590872	Nikolic et al[70], 2020
				FACT[71]
	Liposomes-loaded	↓ Costimulatory molecules (CD40, CD86); ↑ PDL1 expression; ↑ VEGF secretion	Arrests autoimmunity in the model of experimental diabetes	Rodriguez-Fernandez et al[61], 2019
				Rodriguez-Fernandez et al[63], 2018
	TLR´s ligand: 1Z1	↑ PD-L1; ↑ IRAK-M; Minimum increases of MHC-II, CD40, CD80, CD83, CD86	Suppresses T cell activation and proliferation. Delays insulitis in NOD mice	Kim et al[67], 2012
GM-CSF/IL-10		↓ Costimulatory molecules; ↓ IL-12, IL-23, IL-6; ↑ IL-10	Reduces insulitis. Prevents spontaneous diabetes in murine models. Induces Tregs. Induces hyporesponsiveness of T cells. Inhibits T cells proliferation	Haase et al[34], 2005
				Tai et al[35], 2011
GM-CSF/IL-4 + IL-10 or TGF-β		Intermediate expression of MHC-II, CD40, CD80, CD86, CD83; ↓ IL-12p70, IL-23, TNF-α; ↑ IL-10; ↑ IL-6; ↑ PD-L1	Decreases T cells infiltration. Reduces T cells proliferation. Induces Tregs. Prolongs the survival of syngeneic Islet graft in NOD mice	Torres-Aguilar et al[24], 2010
				Boks et al[32], 2012
				Thomas et al[33], 2013
GM-CSF/IL-4 + IL-10/TGF-β	Antigen-loaded: Insulin; GAD65	↑ CD1a; ↓ Costimulatory molecules (CD40, CD86); ↓ CD83; ↓ MHC-II; ↓ IL-12; ↓ IL-23; ↑ PGE	Suppresses effector/memory T cells. Induces T cells anergy. Induces Tregs. Induces IL-10 production by T cells. Suppresses T cells proliferation. Induces hyporesponsiveness of T cells	Torres-Aguilar et al[44], 2010
				Segovia-Gamboa et al[58], 2014
GM-CSF/IL-4 + Vitamin D/Dexamethasone	Antigen-loaded: -Proinsulin	↓ MHC-II; ↓ IFN-γ; ↓ CD86; ↑ IL-10; ↑ PD-L1	Controls autoimmunity. Induces Tregs. Inhibits effector T cells. Eliminates CD8+ T cells	Suwandi et al[55], 2020
				Gibson et al[56], 2015
	-GAD65	↓ Costimulatory molecules (CD40, CD86); ↓ CD83; ↓ MHC-II; ↑ CD14; ↑ TLR-2; ↑ PD-L1; ↑ IL-10; ↓ IL-6, TNF-, IL-23, IL-12p70	Decreases Th1/Th17 responses. Suppresses antigen-specific T cell activation and proliferation. Prevents onset diabetes in NOD-SCID mice. Decreases IFN-γ production by T cells	Phillips et al[20], 2017
				Funda et al[57], 2018
GM-CSF/IL-4 + Rapamycin		↓ Costimulatory molecules (CD40, CD80); ↓ IL-6, IL-23; ↑ PD-L1	Induces Tregs. Inhibits T cell proliferation. Reduces Th17 cells	Boks et al[32], 2012
				Navarro-Barriuso et al[39], 2018

T1D: Type 1 diabetes; IL: Interleukin; TNF-α: Tumor necrosis factor alpha; NOD: Non-obese diabetic; GM-CSF: Granulocyte-macrophage colony-stimulating factor; MHC: Major histocompatibility complex; TGF-β1: Transforming growth factor-β1; VEGF: Vascular endothelial-derived growth factor; TLR: Toll-like receptor; PD-L1: Programmed death-ligand 1; IRAK-M: IL-1 receptor-associated kinase M; PGE: Prostaglandin E; IFN-γ: Interferon-γ; DC: Dendritic cell; Treg: Regulatory T cell; GAD65: Glutamic acid decarboxylase 65.