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.