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Abstract Number: 2040

Galectin-3 Is a Regulator of 4-1BB/CD137 Activity and Associates with Outcome in Rheumatoid Arthritis.

Morten Aagaard Nielsen1, Tue Wenzel Kragstrup2, Kristian Stengaard-Pedersen3, Kim Hørslev-Petersen4, Merete Lund Hetland5, Mikkel Østergaard6, Peter Junker7, Malene Hvid8, Ulf Nilsson9, John Stegmayr10, Hakon Leffler11 and Bent Deleuran1, 1Department of Biomedicine, Aarhus University, Aarhus, Denmark, 2Randers Regional Hospital, Randers, Denmark, 3Department of Rheumatology, Aarhus University Hospital, Department of Clinical Medicine, Aarhus, Denmark, 4King Christian X Hospital for Rheumatic Diseases, Graasten, Denmark, 5Copenhagen Center for Arthritis Research, Center for Rheumatology and Spine Diseases, The DANBIO Registry, Glostrup, Denmark, 6Center for Rheumatology and Spine Diseases, Rigshospitalet Glostrup Copenhagen Center for Arthritis Research, Copenhagen, Denmark, 7Department of Rheumatology C, Odense University Hospital, Odense, Denmark, 8Department of Clinical Medicine, Aarhus University, Aarhus, Denmark, 9Deptment of Chemistry, Center for analysis and Synthesis, Lund, Sweden, 10Department of Laboratory Medicine, Division of Microbiology, Immunology, and Glycobiology (MIG), Lund University, LUND, Sweden, 11Department of Laboratory Medicine, Division of Microbiology, Immunology and Glycobiology - MIG, Lund University, LUND, Sweden

Meeting: ACR/ARHP Annual Meeting 2018

Keywords: ,

Session Information

Date: Tuesday, October 23, 2018

Title: Rheumatoid Arthritis – Etiology and Pathogenesis Poster III

Session Type: ACR Poster Session C

Session Time: 9:00AM-11:00AM

Background/Purpose:

Galectin-3 (Gal-3) and the co-stimulatory T cell receptor and glycoprotein 4-1BB are both considered important in inflammation and immune responses. This had led to the investigation of Gal-3 inhibitors in fibrotic diseases and agonistic anti-4-1BB antibodies in cancer treatment. We and others have previously shown that galectins are capable of binding to receptors of the TNF superfamily thereby modulating inflammatory signals1.

Purpose: To investigate the interplay between 4-1BB and Gal-3 in rheumatoid arthritis (RA).

Methods:

Gal-3 was measured in plasma samples from newly diagnosed, active and treatment-naïve RA (eRA) patients at baseline and after 3 months of aggressive treatment (the OPERA trial, n=97)2 and plasma and synovial fluid samples from chronic RA (cRA) patients (n=17) by ELISA. The 28-joint disease activity score with CRP (DAS28CRP) and radiographic damage (i.e. total Sharp score (TSS)) were used to evaluate treatment outcomes over a 2-year period. Plasma samples from age and gender matched healthy controls (HC) (n=48) were also included.
Fluorescence polarization analyses were used to evaluate the binding between 4-1BB and Gal-3. Synovial fluid mononuclear cells (SFMCs) from patients with chronic RA (n=8) were cultured for 24 hours, co-incubated with either 4-1BB, 4-1BB ligand, Gal-3, or a combination hereof.

Results:

Plasma levels of Gal-3 were increased in eRA (mean: 8.1 ng/ml (CI: 7.6-8.6))compared to HC (mean: 6.4 ng/ml (5.9-6.9)) (p < 0.0001). Gal-3 correlated with DAS28CRP at baseline (ρ = 0.27) (p < 0.05). A decrease in Gal-3 levels from baseline to 3 months were significantly correlated with high disease activity after 2 years of treatment evaluated by DAS28CRP (ρ = 0.23)and radiographic damage evaluated by DTSS (0-24 months) (ρ =0.26) both (p < 0.05). After 3 months of intensive treatment, the plasma levels of Gal-3 were still elevated (mean: 8.3 ng/ml (7.8-8.7)) compared with HC (p < 0.0001). In cRA, Gal-3 levels in synovial fluid were tripled (mean: 30.9 ng/ml (18.3-43.5)) compared with levels found in plasma (mean: 9.1 ng/ml (7.8-10.4)) (p< 0.01). Gal-3 was capable of binding 4-1BB (Kd=1.43 mM (1-1.86 mM)). A mutant Gal-3 (Gal-3 R186S) with severely reduced affinity for endogenous glycans,did not bind to 4-1BB, thus excluding that the 4-1BB and Gal-3 binding is influenced by a protein-protein interaction. Shedding of 4-1BB was increased by addition of Gal-3 (p < 0.05). When SFMC cultures were stimulated with a combination of 4-1BBL and Gal-3, the level of MCP-1 decreased by 50% compared to MCP-1 production from untreated cultures and cultures stimulated with either 4-1BBL or Gal-3 separately (p < 0.05).

Conclusion:

In early RA patients, persistent high plasma levels of Gal-3 during the first 3 months of treatment were associated with lower disease activity and less radiographic progression after 2 years of treatment. Explaining some of these associations, Gal-3 was found to be a new binding partner to 4-1BB, modulating both shedding and function of this receptor in RA. These observations support that Gal-3 is implicated in RA disease pathology at least partly by interacting with the 4-1BB receptor.

References:

  1. Nielsen MA et al. Rheumatology. 2016
  2. Hørslev-Petersen K et al. Ann rheum Dis. 2013
Disclosure: M. A. Nielsen, None; T. W. Kragstrup, None; K. Stengaard-Pedersen, None; K. Hørslev-Petersen, None; M. L. Hetland, None; M. Østergaard, None; P. Junker, None; M. Hvid, None; U. Nilsson, Galecto Biotech AB, Sweden, 1, 2, 5; J. Stegmayr, None; H. Leffler, Galecto Biotech, 1, 2, 5; B. Deleuran, None.

To cite this abstract in AMA style:

Nielsen MA, Kragstrup TW, Stengaard-Pedersen K, Hørslev-Petersen K, Hetland ML, Østergaard M, Junker P, Hvid M, Nilsson U, Stegmayr J, Leffler H, Deleuran B. Galectin-3 Is a Regulator of 4-1BB/CD137 Activity and Associates with Outcome in Rheumatoid Arthritis. [abstract]. Arthritis Rheumatol. 2018; 70 (suppl 9). https://acrabstracts.org/abstract/galectin-3-is-a-regulator-of-4-1bb-cd137-activity-and-associates-with-outcome-in-rheumatoid-arthritis/. Accessed .

ACR Meeting Abstracts - https://acrabstracts.org/abstract/galectin-3-is-a-regulator-of-4-1bb-cd137-activity-and-associates-with-outcome-in-rheumatoid-arthritis/