Session Type: ACR Poster Session C
Session Time: 9:00AM-11:00AM
Background/Purpose: Inflammatory (M1) macrophages and T helper 17 (TH17) cells are central to rheumatoid arthritis (RA) pathogenesis. Although the growth hormone [GH]/insulin-like growth factor 1 axis is involved in joint repair, little is known of the GH function in control of innate and adaptive immunity. To analyze the potential clinical and immunological effects of GH treatment in RA, we use a murine collagen-induced arthritis (CIA) model, compile data on disease development, and study the molecular and cellular mechanisms involved.
We tested the in vivoinhibitory effect of GH in a murine CIA model. Disease was induced in 8- to 10-week-old transgenic C57BL/6J mice expressing bovine GH (Tg-bGH), Wild type (WT) littermates, and DBA1 mice, by intradermal immunization with 200 mg chicken type II collagen (CII) in complete Freund’s adjuvant.
To assess clinical effectiveness in DBA1 mice, we administered recombinant human (rh)GH subcutaneously for 20 days as a therapeutic regime. At disease onset, DBA1 mice with a clinical arthritis score >1 (scale: 0-12) were randomized to receive rhGH treatment (100 mg/kg/day; n = 10) or vehicle (n= 10). Statistical differences were analyzed by ANOVA and Mann-Whitney U-test. P values <0.05 were considered significant.
GH effect was analyzed by flow cytometry (FC) to detect Treg (FoxP3+), Th1 (IFNg+) and Th17 (IL17+) CD4 T cells in secondary lymphoid tissues. T cell responses were evaluated in vitroby CII-induced proliferation as measured by incorporation of the colorimetric reagent WST-1. Serum levels of anti-CII antibodies were determined by ELISA. T cell differentiation was determined in various tissues by quantitative PCR using probes for the specific transcription factors t-bet, RORgT and FoxP3, and for Th1/Th17/Treg-specific cytokines. To test the ability of dendritic cells (DC) from WT and Tg-bGH mice to present antigen to T cells from OT-II mice, we loaded DC with the ovoalbumin peptide 329-337 and assessed T cell activation and proliferation by FC and CellTrace Violet dilution.
We found significant reduction in GH transgenic compared to control mice in disease incidence (25% vs. 70%) and onset time (34.5±1.7 vs. 23.2±3.5; p<0.001), and a tendency to lower clinical scores (1.5±0.7 vs. 3.8±1.8 at day 37 post-immunization, p=0.13). GH treatment of arthritic DBA1 mice ameliorated disease, with a reduced cumulative arthritis score (2.5±0.8) compared to the vehicle group (4.0±0.6)(p=0.06).
The molecular mechanism involves an increased Treg/Th17 ratio and a shift to a non-pathogenic phenotype in Th17 cells and in joint-infiltrated macrophages in Tg-bGH mice; these mice had a M2 (non-inflammatory) macrophage profile compared to M1 in WT counterparts. Although serum anti-CII antibodies and in vitrocollagen-induced T cell proliferation were low in Tg-bGH mice, DC showed no differences in phenotype or in antigen-presenting activity; anti-CD3+IL2-induced T cell activation was similar in both mouse groups.
Conclusion: GH prevents and has therapeutic effects in CIA by modulating macrophage and Th17 cell differentiation. Targeting the GH signaling pathway could thus be a therapeutic approach to RA treatment.
To cite this abstract in AMA style:Villares RJ, Criado G, Gomariz RP, Juarranz Y, Leceta J, Cascio G, Pablos JL, Mellado M. Protective and Therapeutic Effects of Growth Hormone on Collagen-Induced Arthritis [abstract]. Arthritis Rheumatol. 2015; 67 (suppl 10). https://acrabstracts.org/abstract/protective-and-therapeutic-effects-of-growth-hormone-on-collagen-induced-arthritis/. Accessed October 28, 2021.
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ACR Meeting Abstracts - https://acrabstracts.org/abstract/protective-and-therapeutic-effects-of-growth-hormone-on-collagen-induced-arthritis/