Combined Therapy of Vitamin D3-Tolerogenic Dendritic Cells and Interferon-β in a Preclinical Model of Multiple Sclerosis

Abstract

Autologous antigen-specific therapies based on tolerogenic dendritic cells (tolDC) offer the possibility to treat autoimmune diseases by restoring homeostasis and targeting specifically autoreactive responses. Here, we explore the hypothesis that systemic inflammation occurring in autoimmune diseases, such as multiple sclerosis (MS), can generate a disease-specific environment able to alter the functionality of tolDC. In this context in fact, a combined therapy of tolDC with an immunomodulatory treatment could potentiate the beneficial effect of this antigen-specific cell therapy. For this purpose, we analyzed the efficacy of a combined therapy based on the use of vitamin D3 (VitD3)-tolDC plus interferon beta (IFN-beta) in MS. VitD3-tolDC were generated from healthy donors and MS patients and co-cultured with allogeneic peripheral blood mononuclear cells, in the presence or absence of IFN-beta. In vitro, VitD3-tolDC treatment reduced the percentage of activated T cells and allogeneic proliferation, whereas VitD3-tolDC+IFN-beta treatment enhanced the suppressive ability of VitD3-tolDC and, additionally, induced a shift towards a Th2 profile. To determine the clinical benefit of the combined therapy, C57BL/6-experimental autoimmune encephalomyelitis (EAE)-induced mice were treated with antigen-specific VitD3-tolDC and/or IFN-beta. Treatment of EAE mice with combined therapy ameliorated the disease course compared to each monotherapy. These results suggest that a combined therapy based on antigen-specific VitD3-tolDC and IFN-beta may represent a promising strategy for MS patients.

Neurological Benefits, Clinical Challenges, and Neuropathologic Promise of Medical Marijuana: A Systematic Review of Cannabinoid Effects in Multiple Sclerosis and Experimental Models of Demyelination

“…Other approaches that have shown promise in targeting antigen-specific autoreactive responses in EAE include the optimization of antigen-specific cell therapies. For example, the presence of interferon beta (IFN-beta) can enhance the suppressive effects of MOG 35-55loaded, vitamin D3-tolerogenic dendritic cells (VitD3-tolIDC-MOG) on activated T cells, resulting in shifts towards anti-inflammatory Th2 profiles and amelioration of clinical signs of EAE [195]. Through activation of the CB1 and PPARα receptors, cannabinoids promote human tolerogenic dendritic cells, with the capacity to prime FOXP3 + Tregs, through mechanisms involving the induction of functional autophagy and activation of AMPK, with subsequent increased mitochondrial oxidative phosphorylation [196].…”

Efficacy of different intensity of aquatic exercise in enhancing remyelination and neuronal plasticity using cuprizone model in male Wistar rats

“…A combination of agents that modify the course of the disease and have various effects on immunity is used for treatment at different phases of the disease. 4,5 Vitamin plus interferon therapy and the use of medical cannabis have also been studied as methods of treatment in MS. 6,7 This disease leads to a widespread demyelination caused by selective involvement of oligodendrocytes and axonal loss. Additional psychobehavioral symptoms such as anxiety, dementia and depression are also observed.…”

Regulatory Cells in Multiple Sclerosis: From Blood to Brain

“…A recent in vitro study analyzed the efficacy of a combined therapy based on the use of vitD3-TolDC together with IFN-β in PBMCs from MS individuals whose results showed enhanced suppressive ability of vitD3-TolDC, representing a promising strategy for MS patients [ 87 ].…”