دورية أكاديمية
Randomized phase I trial of antigen- specific tolerizing immunotherapy with peptide/calcitriol liposomes in ACPA plus rheumatoid arthritis
| العنوان: | Randomized phase I trial of antigen- specific tolerizing immunotherapy with peptide/calcitriol liposomes in ACPA plus rheumatoid arthritis |
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| المؤلفون: | Sonigra, A, Nel, HJ, Wehr, P, Ramnoruth, N, Patel, S, van Schie, KA, Bladen, MW, Mehdi, AM, Tesiram, J, Talekar, M, Rossjohn, J, Reid, HH, Stuurman, FE, Roberts, H, Vecchio, P, Gourley, I, Rigby, M, Becart, S, Toes, RE, Scherer, HU, Cao, K-AL, Campbell, K, Thomas, R |
| بيانات النشر: | AMER SOC CLINICAL INVESTIGATION INC |
| سنة النشر: | 2022 |
| المجموعة: | The University of Melbourne: Digital Repository |
| الوصف: | BACKGROUNDAntigen-specific regulation of autoimmune disease is a major goal. In seropositive rheumatoid arthritis (RA), T cell help to autoreactive B cells matures the citrullinated (Cit) antigen-specific immune response, generating RA-specific V domain glycosylated anti-Cit protein antibodies (ACPA VDG) before arthritis onset. Low or escalating antigen administration under "sub-immunogenic" conditions favors tolerance. We explored safety, pharmacokinetics, and immunological and clinical effects of s.c. DEN-181, comprising liposomes encapsulating self-peptide collagen II259-273 (CII) and NF-κB inhibitor 1,25-dihydroxycholecalciferol.METHODSA double-blind, placebo-controlled, exploratory, single-ascending-dose, phase I trial assessed the impact of low, medium, and high DEN-181 doses on peripheral blood CII-specific and bystander Cit64vimentin59-71-specific (Cit-Vim-specific) autoreactive T cell responses, cytokines, and ACPA in 17 HLA-DRB1*04:01+ or *01:01+ ACPA+ RA patients on methotrexate.RESULTSDEN-181 was well tolerated. Relative to placebo and normalized to baseline values, Cit-Vim-specific T cells decreased in patients administered medium and high doses of DEN-181. Relative to placebo, percentage of CII-specific programmed cell death 1+ T cells increased within 28 days of DEN-181. Exploratory analysis in DEN-181-treated patients suggested improved RA disease activity was associated with expansion of CII-specific and Cit-Vim-specific T cells; reduction in ACPA VDG, memory B cells, and inflammatory myeloid populations; and enrichment in CCR7+ and naive T cells. Single-cell sequencing identified T cell transcripts associated with tolerogenic TCR signaling and exhaustion after low or medium doses of DEN-181.CONCLUSIONThe safety and immunomodulatory activity of low/medium DEN-181 doses provide rationale to further assess antigen-specific immunomodulatory therapy in ACPA+ RA.TRIAL REGISTRATIONAnzctr.org.au identifier ACTRN12617001482358, updated September 8, 2022.FUNDINGInnovative Medicines Initiative 2 Joint ... |
| نوع الوثيقة: | article in journal/newspaper |
| اللغة: | English |
| تدمد: | 2379-3708 |
| العلاقة: | pii: 160964; Sonigra, A., Nel, H. J., Wehr, P., Ramnoruth, N., Patel, S., van Schie, K. A., Bladen, M. W., Mehdi, A. M., Tesiram, J., Talekar, M., Rossjohn, J., Reid, H. H., Stuurman, F. E., Roberts, H., Vecchio, P., Gourley, I., Rigby, M., Becart, S., Toes, R. E. ,. Thomas, R. (2022). Randomized phase I trial of antigen- specific tolerizing immunotherapy with peptide/calcitriol liposomes in ACPA plus rheumatoid arthritis. JCI INSIGHT, 7 (20), https://doi.org/10.1172/jci.insight.160964Test.; http://hdl.handle.net/11343/335214Test |
| الإتاحة: | https://doi.org/10.1172/jci.insight.160964Test http://hdl.handle.net/11343/335214Test |
| حقوق: | CC BY ; https://creativecommons.org/licenses/by/4.0Test |
| رقم الانضمام: | edsbas.C8B07F38 |
| قاعدة البيانات: | BASE |
Full Text Finder | تدمد: | 23793708 |
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