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.
Highlights
Tolerance is a state of unresponsiveness of the immune system towards antigens that can elicit an immune response
After 5 days of culture, the inhibition of proliferation was measured compared to the reference condition (PBMC stimulated with mitogens without IFN-beta treatment)
Available treatments are based on a continuous dependence on nonspecific immunosuppressive or immunomodulatory drugs [31,32,33,34,35,36,37,38,39,40,41], exposing patients to potentially serious adverse effects, that may compromise their safety and adherence to therapy [42,43,44,45,46]
Summary
Tolerance is a state of unresponsiveness of the immune system towards antigens that can elicit an immune response. It is a mechanism primarily aimed to avoid the reactivity of the immune system against “self” tissues. When tolerance towards self-antigens is lost, autoimmune diseases, such as multiple sclerosis (MS), can develop [1]. MS is the most common multifocal inflammatory demyelinating disease of the central nervous system (CNS). Available therapies for MS exert their effects through immunomodulatory or immunosuppressive functions. These treatments are focused on reducing the activity of the disease and slowing its progression, but it is a disease that has no cure [2]
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