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

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....

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Published in:	Proceedings of the National Academy of Sciences - PNAS Vol. 116; no. 17; pp. 8463 - 8470
Main Authors:	Zubizarreta, Irati, Flórez-Grau, Georgina, Vila, Gemma, Cabezón, Raquel, España, Carolina, Andorra, Magi, Saiz, Albert, Llufriu, Sara, Sepulveda, Maria, Sola-Valls, Nuria, Martinez-Lapiscina, Elena H., Pulido-Valdeolivas, Irene, Casanova, Bonaventura, Gines, Marisa Martinez, Tellez, Nieves, Oreja-Guevara, Celia, Español, Marta, Trias, Esteve, Cid, Joan, Juan, Manel, Lozano, Miquel, Blanco, Yolanda, Steinman, Lawrence, Benitez-Ribas, Daniel, Villoslad, Pablo
Format:	Journal Article
Language:	English
Published:	United States National Academy of Sciences 23-04-2019
Series:	PNAS Plus
Subjects:	Adult Antigens Aquaporin 4 Aquaporin 4 - genetics Autoantigens Biological Sciences Cell- and Tissue-Based Therapy - adverse effects Cell- and Tissue-Based Therapy - methods Cells, Cultured Clinical trials Dendritic cells Dendritic Cells - metabolism Dendritic Cells - transplantation Dendritic structure Female Humans Immune Tolerance - genetics Immune Tolerance - immunology Immune Tolerance - physiology Immunological tolerance Immunology Immunotherapy Interleukin 10 Interleukin-10 - metabolism Lymphocytes Lymphocytes T Magnetic resonance imaging Male Medical imaging Middle Aged Multiple sclerosis Multiple Sclerosis - immunology Multiple Sclerosis - therapy Myelin Myelin Proteins - genetics Neuromyelitis Neuromyelitis Optica - immunology Neuromyelitis Optica - therapy Optical Coherence Tomography Peptides PNAS Plus Recombinant Proteins - genetics Recombinant Proteins - immunology Recombinant Proteins - metabolism T-Lymphocytes, Regulatory - metabolism Therapy immune tolerance dendritic cells Tr1 cells multiple sclerosis neuromyelitis optica
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Summary:	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
Bibliography:	ObjectType-Article-1 SourceType-Scholarly Journals-1 ObjectType-Feature-2 content type line 23 Author contributions: I.Z., G.F.-G., G.V., R.C., C.E., M.A., A.S., S.L., M.S., N.S.-V., E.H.M.-L., I.P.-V., B.C., C.O.-G., M.E., M.J., Y.B., L.S., D.B.-R., and P.V. designed research; G.F.-G., G.V., R.C., C.E., M.A., A.S., S.L., M.S., N.S.-V., E.H.M.-L., I.P.-V., B.C., M.M.G., N.T., M.E., E.T., J.C., M.J., M.L., Y.B., D.B.-R., and P.V. performed research; E.H.M.-L. contributed new reagents/analytic tools; I.Z., G.F.-G., G.V., R.C., C.E., M.A., A.S., S.L., M.S., N.S.-V., I.P.-V., B.C., J.C., M.J., M.L., Y.B., L.S., D.B.-R., and P.V. analyzed data; and L.S., D.B.-R., and P.V. wrote the paper. Reviewers: E.F., University of Texas at Austin; and O.S., University of Texas Southwestern Medical Center. 3D.B.-R. and P.V. contributed equally to this work. Contributed by Lawrence Steinman, February 2, 2019 (sent for review December 19, 2018; reviewed by Elliot Frohman and Olaf Stüve) 1I.Z. and G.F.-G. contributed equally to this work.
ISSN:	0027-8424 1091-6490
DOI:	10.1073/pnas.1820039116