Journal
JOURNAL OF IMMUNOLOGY
Volume 203, Issue 3, Pages 696-704Publisher
AMER ASSOC IMMUNOLOGISTS
DOI: 10.4049/jimmunol.1801462
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Funding
- Instituto de Salud Carlos III - Fondos Feder [PI16/00668]
- Worldwide Cancer Research [14-1275]
- Fundacio La Marato TV3 [201319-30]
- Spanish Ministerio de Economia y Competitividad - European Development Regional Fund A Way to Achieve Europe [SAF2016-80535-R, SAF2016-78568-R]
- Instituto de Salud Carlos III by Miguel Servet II contract [CPII15/00004]
- Sara Borrell Program [CD15/00016]
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Multiple sclerosis (MS) is a chronic autoimmune disease with no curative treatment. The immune regulatory properties of type I IFNs have led to the approval of IFN-beta for the treatment of relapsing-remitting MS. However, there is still an unmet need to improve the tolerability and efficacy of this therapy. In this work, we evaluated the sustained delivery of IFN-alpha 1, either alone or fused to apolipoprotein A-1 by means of an adeno-associated viral (AAV) system in the mouse model of myelin oligodendrocyte glycoprotein-induced experimental autoimmune encephalomyelitis. These in vivo experiments demonstrated the prophylactic and therapeutic efficacy of the AAV-IFN-alpha or AAV-IFN-alpha fused to apolipoprotein A-1 vectors in experimental autoimmune encephalomyelitis, even at low doses devoid of hematological or neurologic toxicity. The sustained delivery of such low-dose IFN-alpha resulted in immunomodulatory effects, consisting of proinflammatory monocyte and T regulatory cell expansion. Moreover, encephalitogenic T lymphocytes from IFN-alpha-treated mice re-exposed to the myelin oligodendrocyte glycoprotein peptide in vitro showed a reduced proliferative response and cytokine (IL-17A and IFN-gamma) production, in addition to upregulation of immunosuppressive molecules, such as IL-10, IDO, or PD-1. In conclusion, the results of the present work support the potential of sustained delivery of low-dose IFN-alpha for the treatment of MS and likely other T cell-dependent chronic autoimmune disorders.
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