期刊
PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA
卷 116, 期 17, 页码 8463-8470出版社
NATL ACAD SCIENCES
DOI: 10.1073/pnas.1820039116
关键词
immune tolerance; dendritic cells; neuromyelitis optica; multiple sclerosis; Tr1 cells
资金
- GAEM Foundation
- La Caixa Foundation [LCF/PR/GN12/10250001]
- Guthy Jackson Charity Foundation
- Institut de Salud Carlos III [Fond Europeo de Desarrollo Regional (FEDER) funds Otra manera de hacer Europa] [PI15/0061]
- Institut de Salud Carlos III [Red Espanola de Esclerosis multiple Grants] [RD16/0015/0002, RD16/0015/0003, RD16/0015/0015]
- Centres Excellencia Recerca Catalunya Programme/Generalitat de Catalunya
- Institut de Salud Carlos III, Spain [CM16/00113]
- Institut de Salud Carlos III, Spain
- FEDER, Predoctoral Grant for Health Research [FI16/00251]
There are adaptive T-cell and antibody autoimmune responses to myelin-derived peptides in multiple sclerosis (MS) and to aquaporin-4 (AQP4) in neuromyelitis optica spectrum disorders (NMOSD5). Strategies aimed at antigen-specific tolerance to these autoantigens are thus indicated for these diseases. One approach involves induction of tolerance with engineered dendritic cells (tolDCs) loaded with specific antigens. We conducted an in-human phase lb clinical trial testing increasing concentrations of autologous tolDCs loaded with peptides from various myelin proteins and from AQP4. We tested this approach in 12 patients, 8 with MS and 4 with NMOSD. The primary end point was the safety and tolerability, while secondary end points were clinical outcomes (relapses and disability), imaging (MRI and optical coherence tomography), and immunological responses. Therapy with tolDCs was well tolerated, without serious adverse events and with no therapy-related reactions. Patients remained stable clinically in terms of relapse, disability, and in various measurements using imaging. We observed a significant increase in the production of IL-10 levels in PBMCs stimulated with the peptides as well as an increase in the frequency of a regulatory T cell, known as Tr1, by week 12 of follow-up. In this phase 1b trial, we concluded that the i.v. administration of peptide-loaded dendritic cells is safe and feasible. Elicitation of specific IL-10 production by peptide-specific T cells in MS and NMOSD patients indicates that a key element in antigen specific tolerance is activated with this approach. The results warrant further clinical testing in larger trials.
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