PMID- 26041704 OWN - NLM STAT- MEDLINE DCOM- 20160226 LR - 20220409 IS - 1946-6242 (Electronic) IS - 1946-6234 (Linking) VI - 7 IP - 290 DP - 2015 Jun 3 TI - Citrullinated peptide dendritic cell immunotherapy in HLA risk genotype-positive rheumatoid arthritis patients. PG - 290ra87 LID - 10.1126/scitranslmed.aaa9301 [doi] AB - 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 kappaB (NF-kappaB) 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. CI - Copyright (c) 2015, American Association for the Advancement of Science. FAU - Benham, Helen AU - Benham H AD - 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. FAU - Nel, Hendrik J AU - Nel HJ AD - University of Queensland Diamantina Institute, Translational Research Institute, Princess Alexandra Hospital, Woolloongabba, Queensland 4102, Australia. FAU - Law, Soi Cheng AU - Law SC AD - University of Queensland Diamantina Institute, Translational Research Institute, Princess Alexandra Hospital, Woolloongabba, Queensland 4102, Australia. FAU - Mehdi, Ahmed M AU - Mehdi AM AD - University of Queensland Diamantina Institute, Translational Research Institute, Princess Alexandra Hospital, Woolloongabba, Queensland 4102, Australia. FAU - Street, Shayna AU - Street S AD - University of Queensland Diamantina Institute, Translational Research Institute, Princess Alexandra Hospital, Woolloongabba, Queensland 4102, Australia. FAU - Ramnoruth, Nishta AU - Ramnoruth N AD - University of Queensland Diamantina Institute, Translational Research Institute, Princess Alexandra Hospital, Woolloongabba, Queensland 4102, Australia. FAU - Pahau, Helen AU - Pahau H AD - University of Queensland Diamantina Institute, Translational Research Institute, Princess Alexandra Hospital, Woolloongabba, Queensland 4102, Australia. FAU - Lee, Bernett T AU - Lee BT AD - Singapore Immunology Network, Agency for Science, Technology and Research, 8A Biomedical Grove, Immunos Building, Level 3, Biopolis, 138673 Singapore, Singapore. FAU - Ng, Jennifer AU - Ng J AD - University of Queensland Diamantina Institute, Translational Research Institute, Princess Alexandra Hospital, Woolloongabba, Queensland 4102, Australia. FAU - Brunck, Marion E G AU - Brunck ME AD - University of Queensland Diamantina Institute, Translational Research Institute, Princess Alexandra Hospital, Woolloongabba, Queensland 4102, Australia. FAU - Hyde, Claire AU - Hyde C AD - University of Queensland Diamantina Institute, Translational Research Institute, Princess Alexandra Hospital, Woolloongabba, Queensland 4102, Australia. FAU - Trouw, Leendert A AU - Trouw LA AD - Department of Rheumatology, Leiden University Medical Center, Leiden 2333, Netherlands. FAU - Dudek, Nadine L AU - Dudek NL AD - Department of Biochemistry and Molecular Biology, School of Biomedical Sciences, Monash University, Clayton, Victoria 3800, Australia. FAU - Purcell, Anthony W AU - Purcell AW AD - Department of Biochemistry and Molecular Biology, School of Biomedical Sciences, Monash University, Clayton, Victoria 3800, Australia. FAU - O'Sullivan, Brendan J AU - O'Sullivan BJ AD - University of Queensland Diamantina Institute, Translational Research Institute, Princess Alexandra Hospital, Woolloongabba, Queensland 4102, Australia. FAU - Connolly, John E AU - Connolly JE AD - Singapore Immunology Network, Agency for Science, Technology and Research, 8A Biomedical Grove, Immunos Building, Level 3, Biopolis, 138673 Singapore, Singapore. FAU - Paul, Sanjoy K AU - Paul SK AD - Queensland Clinical Trials & Biostatistics Centre, School of Population Health, The University of Queensland, Brisbane, Queensland 4006, Australia. FAU - Le Cao, Kim-Anh AU - Le Cao KA AD - University of Queensland Diamantina Institute, Translational Research Institute, Princess Alexandra Hospital, Woolloongabba, Queensland 4102, Australia. FAU - Thomas, Ranjeny AU - Thomas R AD - University of Queensland Diamantina Institute, Translational Research Institute, Princess Alexandra Hospital, Woolloongabba, Queensland 4102, Australia. ranjeny.thomas@uq.edu.au. LA - eng SI - ANZCTR/ACTRN12610000373077 PT - Journal Article PT - Research Support, Non-U.S. Gov't PL - United States TA - Sci Transl Med JT - Science translational medicine JID - 101505086 RN - 0 (HLA Antigens) RN - 0 (Peptides) RN - 29VT07BGDA (Citrulline) SB - IM CIN - Nat Rev Rheumatol. 2015 Aug;11(8):443. PMID: 26100972 MH - Aged MH - Arthritis, Rheumatoid/immunology/*therapy MH - Citrulline/*chemistry MH - Dendritic Cells/*immunology MH - Female MH - HLA Antigens/*genetics MH - Humans MH - *Immunotherapy MH - Male MH - Middle Aged MH - Peptides/*chemistry EDAT- 2015/06/05 06:00 MHDA- 2016/02/27 06:00 CRDT- 2015/06/05 06:00 PHST- 2015/06/05 06:00 [entrez] PHST- 2015/06/05 06:00 [pubmed] PHST- 2016/02/27 06:00 [medline] AID - 7/290/290ra87 [pii] AID - 10.1126/scitranslmed.aaa9301 [doi] PST - ppublish SO - Sci Transl Med. 2015 Jun 3;7(290):290ra87. doi: 10.1126/scitranslmed.aaa9301.