Intestinal enteroids/organoids: A novel platform for drug discovery in inflammatory bowel diseases

Table 2 Current therapeutic approaches in inflammatory bowel diseases focused on immune cells

Effects on immune cells	Drug type	Drug name/approach	Mechanism of action	Ref.
Inhibits pro-inflammatory cytokine production	Classic anti-inflammatory drugs	5-ASA Corticosteroid	NF-kB inactivation	[77,78]
	JAK inhibitors	Tofacitinib (JAK1/2/3)	Inhibits differentiation of Th1, Th2, and Th17 cells by inhibition of JAK/STAT pathway	[90,91]
		Filgotinib (JAK1)		[173]
	ROR-γt inhibitor	GSK805	Inhibits differentiation of Th17 cells but not ILC3s by inhibition of transcription factor ROR-γt	[92]
	GATA3 specific DNAzyme (DNA antisense molecule)	Rectal delivery	Inhibits differentiation of Th2 cells by inhibition of transcription factor GATA3 expression	[93]
	Anti-p40 subunit IL-12/IL-23	Ustekinumab	Inhibits differentiation of Th1 and Th17 cells by neutralization of IL-12/IL-23	[5,86]
	PDE4 inhibitors	Apremilast, roflumilast	Increases intracellular cAMP which inhibits NF-kB (PDE4 degrades cAMP)	[174-176]
Induces apoptosis	Classic immunosuppressive agents	Azathioprine 6-mercaptopurine	Metabolized purine analogue induces apoptosis by small GTPase RAC1 inactivation	[79]
		Cyclosporine A	Activates caspase 8 signaling	[80,81]
		Tacrolimus (FK506)	Inhibits calcineurin/NFAT pathway	[177]
		Methotrexate	Cleavage of PARP but not caspase 3 activation	[82]
	Anti-IL-6/IL-6R	PF-04236921 (anti-IL-6)	Inhibits IL-6/STAT3 signaling which mediates resistance against apoptosis	[87-89]
		Tocilizumab (anti-IL-6R)
Blocks pro-inflammatory cytokines released from immune cells	Anti-TNF-α	Infliximab, adalimumab, golimumab, certolizumab pegol	Neutralizing antibody against TNF-α	[83]
Blocks trafficking or homing of immune cells toward inflamed gut	Gut specific anti-integrin	Vedolizumab (anti-α4β7) Etrolizumab (anti-β7)	Neutralizing antibody against integrin	[6-8,94,95]
	Chemokine receptor (CCR9) inhibitor	Vercirnon (CCX282-B)	inhibits CCL25 (CCR9 ligand) directed chemotaxis	[96,97]
	Anti-cell adhesion molecules	PF-00547659	Neutralizing antibody against MAdCAM-1 (gut specific ligand for integrin α4β7) in vascular endothelial cells	[98,99]
		Alicaforsen	ICAM-1 antisense oligonucleotide which inhibits ICAM-1 production in vascular endothelial cells	[100]
	S1P1/S1P5 receptor agonist/functional antagonist	Ozanimod	Induces internalization and degradation of S1P receptor, and subsequently inhibit S1P/NF-kB/STAT3 pathway	[101-103]
Activates endogenous anti-inflammatory mechanisms	Anti-SMAD7 oligonucleotide	Mongersen	Activates anti-inflammatory TGFβ/SMAD3 signaling by degradation of SMAD7 mRNA	[104]
	Mesenchymal stem cells	Transplantation	Directs T cell differentiation toward anti-inflammatory phenotype (Th2 cells, Treg) and inhibits T cell proliferation, cytokine production, and migration	[77,105,106,178]
	Treg	Transplantation	Secretion of anti-inflammatory cytokines (TGFβ and IL-10)	[107]

5-ASA: 5-Aminosalicylic acid; NF-kB: Nuclear factor kappa B; JAK: Janus kinase; STAT: Signal transducer and activator of transcription; ROR: RAR-related orphan receptor; Th: T helper; ILC3: Group3 innate lymphoid cells; GATA3: GATA binding protein 3; PDE4: Phosphodiesterase 4; cAMP: cyclic adenosine 3’5’-monophosphate; RAC1: Rac family small GTPase 1; NFAT: Nuclear factor of activated T cells; PARP: Poly (ADP-ribose) polymerase; CCR9: C-C motif chemokine receptor 9; MAdCAM-1: Mucosal vascular addressin cell adhesion molecule 1; ICAM-1: Intercellular adhesion molecule 1; S1P: Sphingosine-1-phosphate; SMAD: SMAD family member; Treg: Regulatory T cells.