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Proc Natl Acad Sci U S A. 2019 Apr 23;116(17):8463-8470. doi: 10.1073/pnas.1820039116. Epub 2019 Apr 8.

Immune tolerance in multiple sclerosis and neuromyelitis optica with peptide-loaded tolerogenic dendritic cells in a phase 1b trial.

Author information

1
Center of Neuroimmunology, Institut d'Investigacions Biomediques August Pi Sunyer, 08036 Barcelona, Spain.
2
Department of Immunology, Hospital Clinic, 08036 Barcelona, Spain.
3
Service of Neurology, Hospital Clinic, University of Barcelona, 08036 Barcelona, Spain.
4
Department of Neurology, Hospital La Fe, 46009 Valencia, Spain.
5
Department of Neurology, Hospital Gregorio Marañon, 28009 Madrid, Spain.
6
Department of Neurology, Hospital de Valladolid, 47005 Valladolid, Spain.
7
Department of Neurology, Hospital Clinico San Carlos, 28040 Madrid, Spain.
8
Advanced Therapies Unit, Hospital Clinic, 08036 Barcelona, Spain.
9
Banc de Sang i Teixits, 08005 Barcelona, Spain.
10
Apheresis Unit, Department of Hemotherapy and Hemostasis, Hospital Clinic, 08036 Barcelona, Spain.
11
Department of Neurology, Stanford University, Stanford, CA 94305 steinman@stanford.edu pvilloslada@clinic.ub.es.
12
Center of Neuroimmunology, Institut d'Investigacions Biomediques August Pi Sunyer, 08036 Barcelona, Spain; steinman@stanford.edu pvilloslada@clinic.ub.es.

Abstract

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 (NMOSDs). 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 1b 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.

KEYWORDS:

Tr1 cells; dendritic cells; immune tolerance; multiple sclerosis; neuromyelitis optica

Conflict of interest statement

Conflict of interest statement: E.F. and L.S. published an obituary on two leaders in MS [Kildebeck EJ, et al. (2017) The emergence of neuroepidemiology, neurovirology and neuroimmunology: The legacies of John F. Kurtzke and Richard “Dick” T. Johnson. J Neurol 264:817–828]. I.Z. has received travel reimbursement from Genzyme, Biogen, and Merck for national and international meetings over the last 3 y. E.H.M.-L. has received speaker honoraria from Biogen, Roche, Novartis, and Sanofi and a travel reimbursement from Biogen, Roche, Novartis, and Sanofi. E.H.M.-L. has participated in advisory boards for Roche and Sanofi. A.S. has received compensation for consulting services and speaker honoraria from Bayer-Schering, Merck-Serono, Biogen-Idec, Sanofi-Aventis, Teva Pharmaceutical Industries Ltd., Roche, and Novartis. S.L. has received speaker honoraria and travel reimbursement from Biogen, Merck, Novartis, and Teva. I.P.-V. has received travel reimbursement from Roche Spain and Genzyme-Sanofi, European Academy of Neurology, and the European Committee for Treatment and Research in Multiple Sclerosis for international and national meetings over the last 3 y; I.P.-V. holds a patent for an affordable eye-tracking system to measure eye movement in neurologic diseases and holds stock in Aura Innovative Robotics. N.S.-V. received compensation for consulting services and speaker honoraria from Genzyme-Sanofi, Biogen idec, Merck-Serono, and Bayer-Schering. P.V. holds stocks and has received compensation from Bionure Farma SL; Health Engineering SL; Spiral Therapeutics, Inc.; and QMenta SL. L.S. received compensation from Novartis, Celgene, Bionure, Tolerion, Katexco, Atreca, and TG Therapeutics. All other authors declare no conflict of interest.

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