ACR Meeting Abstracts

ACR Meeting Abstracts

Abstract Number: 1846

Citrullinated Vimentin-reactive Immune-regulatory CD4+CD39+TIGIThi T Cells Expand During Drug Free Remission in HLA-DR Shared-epitope+ ACPA+ Rheumatoid Arthritis

Amy Anderson1, Henrique de Paula Lemos1, Hendrik Nel2, Sofia Sorbet Santiago1, Fiona Rayner3, Abbie Degnan1, Imogen Wilson1, Julie Diboll1, Jasmine Sim1, Andrew Melville4, Stefan Siebert4, Iain McInnes5, Carl Goodyear4, Catharien Hilkens1, Andrew Filer6, Karim Raza6, Christopher Buckley7, Hugh Reid8, Kenneth Baker1, Arthur Pratt3, Jamie Rossjohn8, Ranjeny Thomas9 and John Isaacs1, 1Translational and Clinical Research Institute, NIHR Newcastle Biomedical Research Centre, Newcastle University and The Newcastle Upon Tyne Hospitals NHS Foundation Trust, Newcastle upon Tyne, United Kingdom, 2Frazer Institute, The University of Queensland, Translational Research Institute, Brisbane, Australia, 3Translational and Clinical Research Institute, NIHR Newcastle Biomedical Research Centre, Newcastle University and The Newcastle Upon Tyne Hospitals NHS Foundation Trust, Newcastle upon Tyne, England, United Kingdom, 4School of Infection and Immunity, College of Medical, Veterinary and Life Sciences, University of Glasgow, Glasgow, United Kingdom, 5University of Glasgow, College of Medical Veterinary and Life Sciences, Glasgow, United Kingdom, 6Rheumatology Research Group, Institute for Inflammation and Ageing, NIHR Birmingham Biomedical Research Center and Clinical Research Facility, University of Birmingham, Birmingham, United Kingdom, 7Kennedy Institute of Rheumatology, University of Oxford, Oxford, United Kingdom, 8Department of Biochemistry and Molecular Biology, School of Biomedical Sciences, Monash University, Clayton, Victoria, Australia, 9University of Queensland, Brisbane, Australia

Meeting: ACR Convergence 2024

Keywords: , , , ,

Session Information

Date: Monday, November 18, 2024

Title: T Cell Biology & Targets in Autoimmune & Inflammatory Disease Poster

Session Type: Poster Session C

Session Time: 10:30AM-12:30PM

Background/Purpose: There is a need for immunotherapy that sustains symptom remission without ongoing need for disease modifying drugs (DMARDs). In a phase 1b trial of antigen-specific tolerising immunotherapy in ACPA+ RA patients, expansion of peripheral blood (PB) CD4+ T cells recognising either collagen II259-273 or vimentinCit6459-71 associated with reduced DAS28, suggesting that expanding autoreactive T cells may regulate RA under tolerogenic conditions. In a distinct setting, 50% of patients who stop conventional synthetic (cs)DMARDs maintain “drug-free remission” (DFR) for at least 6 months, potentially also reflecting a state of immune tolerance. The current study compared frequency and phenotype of PB CD4+ T cells recognising citrullinated (cit) vimentin in ACPA+ HLA-DRB1*04:01, *01:01 or *04:04+ RA patients who flared or remained in DFR 6 months after stopping csDMARDs.

Methods: Individuals with RA receiving methotrexate, sulfasalazine and hydroxychloroquine, singly or in combination (csDMARDs), and in clinician-defined remission (DAS28-CRP < 2.4) were recruited into the BIOlogical Factors that Limit sustAined Remission in rhEumatoid arthritis (BIO-FLARE) study1. Treatment was stopped and participants monitored over 24 weeks. Flare was defined as DAS28-CRP ≥3.2 at any visit or DAS28-CRP ≥2.4 twice within 14 days. PBMC were analysed using a 32 marker spectral flow panel, incorporating HLA-DRB1*04:01/01:01-VimentinCit6459-71 or HLA-DRB1*04:04-VimentinCit7166-78 tetramers. Data were analysed using Wilcoxon signed-rank tests.

Results: Nineteen flaring patients were compared with 17 patients remaining in DFR 24 weeks after stopping therapy. At baseline the number and phenotype of cit-vimentin-specific CD4+ T cells was comparable in both groups, except that CD38 expression was higher in the group subsequently maintaining DFR. In each group, cit-vimentin-specific CD25+CD127- Treg increased and expression of CD55 decreased over time. At flare or the preceding time point a lower proportion of cit-vimentin-specific CD4+ T cells expressed CD161, fewer were naïve, and CXCR3 expression was reduced. In the DFR group, cit-vimentin-specific CD4+ T cells expanded, the proportion expressing CD39 increased, whilst expression of TIGIT increased and CCR6 decreased.

Conclusion: Together these data suggest that, in patients achieving DFR, there is ongoing cit-vimentin autoantigen presentation and T cell activation under tolerogenic conditions, expanding antigen-specific CD4+ T cells expressing markers of immune regulation and anergy. Reduced circulating CD161+CXCR3hi antigen-specific T cells during flare suggests migration of effector memory autoreactive T cells to synovial inflammatory sites.  

References

  1. Rayner F et al. BMC Rheumatol. 2021
Disclosures: A. Anderson: None; H. de Paula Lemos: None; H. Nel: None; S. Sorbet Santiago: None; F. Rayner: None; A. Degnan: None; I. Wilson: None; J. Diboll: None; J. Sim: None; A. Melville: None; S. Siebert: AbbVie, 6, Amgen, 6, AstraZeneca, 6, Boehringer-Ingelheim, 5, Bristol-Myers Squibb, 5, Eli Lilly, 5, GlaxoSmithKline, 5, Janssen, 5, 6, Teijin Pharma, 6, UCB, 5; I. McInnes: AbbVie, 2, 5, 6, Amgen, 2, Bristol Myers Squibb, 2, 5, Cabaletta, 2, Celgene, 2, Compugen, 2, Dextera, 2, Eli Lilly, 2, 5, Janssen, 2, 5, Moonlake, 2, Novartis, 2, 5, Pfizer, 2, UCB, 2, 5, 6; C. Goodyear: None; C. Hilkens: None; A. Filer: None; K. Raza: None; C. Buckley: None; H. Reid: None; K. Baker: Pfizer, 5; A. Pratt: None; J. Rossjohn: None; R. Thomas: AbbVie/Abbott, 2, CSL, 2, 5; J. Isaacs: AbbVie/Abbott, 2, 6, AnaptysBio, 2, Annexon, 2, AstraZeneca, 2, Bristol-Myers Squibb(BMS), 2, Dragonfly, 2, Eli Lilly, 1, Galapagos, 2, GlaxoSmithKlein(GSK), 2, 5, Istesso, 2, Janssen, 5, Kira Biotech, 2, Ono Pharma, 2, Pfizer, 5, Revelo, 2, Sanofi, 2, Sonoma Biotherapeutics, 2, Topas, 2, UCB, 1.

To cite this abstract in AMA style:

Anderson A, de Paula Lemos H, Nel H, Sorbet Santiago S, Rayner F, Degnan A, Wilson I, Diboll J, Sim J, Melville A, Siebert S, McInnes I, Goodyear C, Hilkens C, Filer A, Raza K, Buckley C, Reid H, Baker K, Pratt A, Rossjohn J, Thomas R, Isaacs J. Citrullinated Vimentin-reactive Immune-regulatory CD4+CD39+TIGIThi T Cells Expand During Drug Free Remission in HLA-DR Shared-epitope+ ACPA+ Rheumatoid Arthritis [abstract]. Arthritis Rheumatol. 2024; 76 (suppl 9). https://acrabstracts.org/abstract/citrullinated-vimentin-reactive-immune-regulatory-cd4cd39tigithi-t-cells-expand-during-drug-free-remission-in-hla-dr-shared-epitope-acpa-rheumatoid-arthritis/. Accessed .

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