title: Citrullinated peptide dendritic cell immunotherapy in HLA risk genotype-positive rheumatoid arthritis patients.
abstract: In animals, immunomodulatory dendritic cells (DCs) exposed to autoantigen can suppress experimental arthritis in an antigen-specific manner. In rheumatoid arthritis (RA), disease-specific anti-citrullinated peptide autoantibodies (ACPA or anti-CCP) are found in the serum of about 70% of RA patients and are strongly associated with HLA-DRB1 risk alleles. This study aimed to explore the safety and biological and clinical effects of autologous DCs modified with a nuclear factor κB (NF-κB) inhibitor exposed to four citrullinated peptide antigens, designated "Rheumavax," in a single-center, open-labeled, first-in-human phase 1 trial. Rheumavax was administered once intradermally at two progressive dose levels to 18 human leukocyte antigen (HLA) risk genotype-positive RA patients with citrullinated peptide-specific autoimmunity. Sixteen RA patients served as controls. Rheumavax was well tolerated: adverse events were grade 1 (of 4) severity. At 1 month after treatment, we observed a reduction in effector T cells and an increased ratio of regulatory to effector T cells; a reduction in serum interleukin-15 (IL-15), IL-29, CX3CL1, and CXCL11; and reduced T cell IL-6 responses to vimentin(447-455)-Cit450 relative to controls. Rheumavax did not induce disease flares in patients recruited with minimal disease activity, and DAS28 decreased within 1 month in Rheumavax-treated patients with active disease. This exploratory study demonstrates safety and biological activity of a single intradermal injection of autologous modified DCs exposed to citrullinated peptides, and provides rationale for further studies to assess clinical efficacy and antigen-specific effects of autoantigen immunomodulatory therapy in RA.
authors.affiliation: University of Queensland Diamantina Institute, Translational Research Institute, Princess Alexandra Hospital, Woolloongabba, Queensland 4102, Australia. University of Queensland School of Medicine, Brisbane, Queensland 4102, Australia.
authors.forename: Helen
authors.initials: H
authors.lastname: Benham
authors.affiliation: University of Queensland Diamantina Institute, Translational Research Institute, Princess Alexandra Hospital, Woolloongabba, Queensland 4102, Australia.
authors.forename: Hendrik J
authors.initials: HJ
authors.lastname: Nel
authors.affiliation: University of Queensland Diamantina Institute, Translational Research Institute, Princess Alexandra Hospital, Woolloongabba, Queensland 4102, Australia.
authors.forename: Soi Cheng
authors.initials: SC
authors.lastname: Law
authors.affiliation: University of Queensland Diamantina Institute, Translational Research Institute, Princess Alexandra Hospital, Woolloongabba, Queensland 4102, Australia.
authors.forename: Ahmed M
authors.initials: AM
authors.lastname: Mehdi
authors.affiliation: University of Queensland Diamantina Institute, Translational Research Institute, Princess Alexandra Hospital, Woolloongabba, Queensland 4102, Australia.
authors.forename: Shayna
authors.initials: S
authors.lastname: Street
authors.affiliation: University of Queensland Diamantina Institute, Translational Research Institute, Princess Alexandra Hospital, Woolloongabba, Queensland 4102, Australia.
authors.forename: Nishta
authors.initials: N
authors.lastname: Ramnoruth
authors.affiliation: University of Queensland Diamantina Institute, Translational Research Institute, Princess Alexandra Hospital, Woolloongabba, Queensland 4102, Australia.
authors.forename: Helen
authors.initials: H
authors.lastname: Pahau
authors.affiliation: Singapore Immunology Network, Agency for Science, Technology and Research, 8A Biomedical Grove, Immunos Building, Level 3, Biopolis, 138673 Singapore, Singapore.
authors.forename: Bernett T
authors.initials: BT
authors.lastname: Lee
authors.affiliation: University of Queensland Diamantina Institute, Translational Research Institute, Princess Alexandra Hospital, Woolloongabba, Queensland 4102, Australia.
authors.forename: Jennifer
authors.initials: J
authors.lastname: Ng
authors.affiliation: University of Queensland Diamantina Institute, Translational Research Institute, Princess Alexandra Hospital, Woolloongabba, Queensland 4102, Australia.
authors.forename: Marion E G
authors.initials: ME
authors.lastname: Brunck
authors.affiliation: University of Queensland Diamantina Institute, Translational Research Institute, Princess Alexandra Hospital, Woolloongabba, Queensland 4102, Australia.
authors.forename: Claire
authors.initials: C
authors.lastname: Hyde
authors.affiliation: Department of Rheumatology, Leiden University Medical Center, Leiden 2333, Netherlands.
authors.forename: Leendert A
authors.initials: LA
authors.lastname: Trouw
authors.affiliation: Department of Biochemistry and Molecular Biology, School of Biomedical Sciences, Monash University, Clayton, Victoria 3800, Australia.
authors.forename: Nadine L
authors.initials: NL
authors.lastname: Dudek
authors.affiliation: Department of Biochemistry and Molecular Biology, School of Biomedical Sciences, Monash University, Clayton, Victoria 3800, Australia.
authors.forename: Anthony W
authors.initials: AW
authors.lastname: Purcell
authors.affiliation: University of Queensland Diamantina Institute, Translational Research Institute, Princess Alexandra Hospital, Woolloongabba, Queensland 4102, Australia.
authors.forename: Brendan J
authors.initials: BJ
authors.lastname: O'Sullivan
authors.affiliation: Singapore Immunology Network, Agency for Science, Technology and Research, 8A Biomedical Grove, Immunos Building, Level 3, Biopolis, 138673 Singapore, Singapore.
authors.forename: John E
authors.initials: JE
authors.lastname: Connolly
authors.affiliation: Queensland Clinical Trials & Biostatistics Centre, School of Population Health, The University of Queensland, Brisbane, Queensland 4006, Australia.
authors.forename: Sanjoy K
authors.initials: SK
authors.lastname: Paul
authors.affiliation: University of Queensland Diamantina Institute, Translational Research Institute, Princess Alexandra Hospital, Woolloongabba, Queensland 4102, Australia.
authors.forename: Kim-Anh
authors.initials: KA
authors.lastname: Lê Cao
authors.affiliation: University of Queensland Diamantina Institute, Translational Research Institute, Princess Alexandra Hospital, Woolloongabba, Queensland 4102, Australia. ranjeny.thomas@uq.edu.au.
authors.forename: Ranjeny
authors.initials: R
authors.lastname: Thomas
mesh_terms: D000368:Aged; D001172:Arthritis, Rheumatoid / Q000276:immunology / Q000628:therapy*; D002956:Citrulline / Q000737:chemistry*; D003713:Dendritic Cells / Q000276:immunology*; D005260:Female; D006680:HLA Antigens / Q000235:genetics*; D006801:Humans; D007167:Immunotherapy; D008297:Male; D008875:Middle Aged; D010455:Peptides / Q000737:chemistry*
chemical_list: D006680:HLA Antigens; D010455:Peptides; D002956:Citrulline