Table 2 Multiple sclerosis treatment approaches using Treg augmentation based on pre-clinical models
From: Regulatory T cells in multiple sclerosis and myasthenia gravis
Therapeutic modality | Intended Treg augmentation | Approach | Outcome | Reference |
|---|---|---|---|---|
IL-10 | Upregulate Tr1, increase Tregs through DC modulation | EAE (MOG 1-125) Dark Agouti rats. pcDNA IL-10 Gene therapy on day 0 and 3 | ↓ clinical score ↓ sensory loss ↓ microglial/ macrophage and astrocyte activation | [143] |
IL-35 | Induction of iTr35 | EAE (MOG 35-55) C57BL/6. Adoptive transfer of iTreg induced with rIL-35 | ↓ clinical score ↑ life span ↑ iTr35 | [80] |
Bifunctional Peptide Inhibitors | Inhibit CD28 co-stimulation to promote CTLA-4 co-stimulation | EAE (MOG 35-55) C57BL/6. Injection of B7AP-PLP (anti-CD28 linked to PLP; 100 nmol) on days 4, 7, and 10 | No clinical signs ↓ change in weight ↓ IL-6,-17 ↑ IL-2, -4, -5 | [155] |
IDO Metabolite | Increase Tregs, increased CCL2-mediated migration to CNS | EAE (MOG 35-55) C57BL/6. 3-HAA (downstream IDO metabolite) treatment daily | ↓ clincal Signs ↓ disease peak ↑ FoxP3+ Tregs ↓ IL-17, IFN-gamma | [110] |
CXCL11 | Increase Tr1 migration to CNS, increase IL-10 expression, polarize Tr1 | EAE (MOG 35-55 and PLP129-151) in C57BL/6 and SJL/j mice, respectively. CXCL11-IgG every other day and adoptive transfer of CD4+ cells from CXCL11-IgG treated EAE SJL/j mice | ↓ clinical score ↓ histological score Prevented relapse ↑ Tr1 ↓ IFN-gamma, IL-17 | [122] |
IL-27 | Proliferation of Tr1, upregulate CXCR3 on FoxP3 Tregs for migration to CNS | EAE (MOG 35-55) C57BL/6. Adoptive transfer of CD4+ cells treated with MOG, IL-12, and IL-27 (control: MOG and IL-12) | ↓ clinical score ↑ Tr1 | [154] |
WT C57BL/6 J. Injection of IL-27 DNA plasmids | ↑ CXCR3 on Tregs and not Teff | [124] | ||
Emperically supported treatments using EAE and other experimental data | ||||
OX40L Jagged-1 Co-treatment | Selectively expand Tregs in TCR-independent manner, activate CD46 for induction of Tr1 | EAE (MOG 35-55) C57BL/6. Jagged1-Fc on days 0, 2, 4, 6, 8 | ↓ clinical scores ↓ disease peak ↑ IL-10, -4 | [159] |
EAE (PLP 139-151) SJL/j. Alpha OX40 agonist on days 10, 12, and 14. | ↓ clinical scores ↑ Tregs ↑ IL-2, -6, -17, and IFN-g in the CNS | [167] | ||
Site-specific CCL17 Injection | Selectively recruit Tregs to neuroinflammatory sites via CCR4 | EAE (MOG 35-55) C57BL/6. IL-4 gene therapy injection into cisterna magna on day of onset (12-16 days) | ↓ clinical scores ↑ IL-4 ↑ CCL17 ↑ Tregs in brain and spinal cord | [119] |
Ex vivo human Treg transmigration assay with porcine aortic endothelial cells coated with CCL17 | ↑ Treg adhesion ↑ Treg transmigration via CCR4 | [172] | ||