Treatment of Experimental Autoimmune Encephalomyelitis by Sustained Delivery of Low-Dose IFN-α

• Published in: The Journal of immunology (1950) Vol. 203; no. 3; pp. 696 - 704
• Main Authors: Vasquez, Marcos, Consuegra-Fernández, Marta, Aranda, Fernando, Jimenez, Aitor, Tenesaca, Shirley, Fernandez-Sendin, Myriam, Gomar, Celia, Ardaiz, Nuria, Di Trani, Claudia Augusta, Casares, Noelia, Lasarte, Juan Jose, Lozano, Francisco, Berraondo, Pedro
• Format: Journal Article
• Language: English
• Published: United States 01.08.2019
• Subjects: Animals; Apolipoprotein A-I - therapeutic use; Disease Models, Animal; Encephalomyelitis, Autoimmune, Experimental - drug therapy; Encephalomyelitis, Autoimmune, Experimental - immunology; Female; Indoleamine-Pyrrole 2,3,-Dioxygenase - biosynthesis; Interferon-alpha - therapeutic use; Interferon-gamma - biosynthesis; Interleukin-10 - biosynthesis; Interleukin-17 - biosynthesis; Mice; Mice, Inbred C57BL; Monocytes - cytology; Monocytes - immunology; Myelin-Oligodendrocyte Glycoprotein - toxicity; Programmed Cell Death 1 Receptor - biosynthesis; Recombinant Fusion Proteins - therapeutic use; T-Lymphocytes, Regulatory - cytology; T-Lymphocytes, Regulatory - immunology
• ISSN: 0022-1767; 1550-6606
• DOI: 10.4049/jimmunol.1801462

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-β 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-α1, 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-α or AAV-IFN-α 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-α resulted in immunomodulatory effects, consisting of proinflammatory monocyte and T regulatory cell expansion. Moreover, encephalitogenic T lymphocytes from IFN-α-treated mice re-exposed to the myelin oligodendrocyte glycoprotein peptide in vitro showed a reduced proliferative response and cytokine (IL-17A and IFN-γ) 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-α for the treatment of MS and likely other T cell-dependent chronic autoimmune disorders.