Selective Inhibition of Tfh Cells By a Small Molecule Inhibitor Abrogates Progression of Experimental Inflammatory Arthritis

Frank Migliore¹, Sedrick Bradley¹, Linh Hellmers¹, Quretul Quresh², Jerald M. Zakem³, William E. Davis³, Tamika Webb-Detiege¹, Zongbing You⁴, Robert Quinet² and Xin Zhang⁵, ¹Ochsner Clinic Foundation, New Orleans, LA, ²Rheumatology, Ochsner Medical Center, New Orleans, LA, ³University of Queensland School of Medicine, Brisbane, Australia, ⁴Tulane University Health Science Center, New Orleans, LA, ⁵Laboratory of Cellular Immunology, Institution of Translational Research, Ochsner Medical Center, New Orleans, LA

Meeting: 2017 ACR/ARHP Annual Meeting

Date of first publication: September 18, 2017

Keywords: Animal models, T cells and rheumatoid arthritis

Session Information

Date: Sunday, November 5, 2017

Title: Rheumatoid Arthritis – Animal Models Poster I

Session Type: ACR Poster Session A

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

Background/Purpose:

Rheumatoid arthritis (RA) is a systemic inflammatory autoimmune disease characterized by progressive infiltration of the joints by T cells and other leukocytes, production of mediators of inflammation, and the eventual destruction of joints. T follicular helper (Tfh) cells are a unique subset of CD4⁺ T cells, predominantly located in B cell follicles, and regulate the survival of B cells and antibody production in germinal centers. Our previous studies have showed that circulating Tfh cells were significantly increased in active RA patients, correlating with the percentage of plasmablasts, anti-CCP antibody titer, and disease activity in active RA patients, indicating that Tfh cells may play an important role in RA pathogenesis. The purpose of this study is to investigate the therapeutic potential of a small molecule inhibitor targeting Tfh cells in mice with collagen-induced arthritis (CIA).

Methods:

CIA was induced in twenty-four DBA/1 mice by immunization with chicken type II collagen. Following the onset of clinical arthritis, mice were treated with a small molecule inhibitor (SMI-Tfh) selective blockage of Tfh cell signature transcription factor Bcl-6. Disease progression was monitored daily and recorded by arthritis severity scores weekly. Blood, spleen, and affected paws were collected at the end of the study. Tfh cells in spleen and blood were defined by their signature surface markers (CD4⁺CXCR5⁺ICOS⁺) via flow cytometry and analyzed using FlowJo software. The immune cells were further confirmed in mice spleen by immunohistochemistry staining. Statistical analysis was carried out using GraphPad Prism software and the significance was evaluated by t test.

Results:

Mice developed arthritis four weeks after immunization with type II collagen. Treatment with SMI-Tfh (50mg/kg) significantly reduced the disease progression/activity(as measured by paw swelling) in mice with CIA. SMI-Tfh significantly inhibited the frequency of Tfh cells in spleen (P<0.01), but not the frequency of circulating Tfh cells in CIA mice (P>0.05). In addition, SMI-Tfh also inhibited B cell proliferation induced by Tfh cells and antibody production in vitro.

Conclusion:

The small molecule inhibitor SMI-Tfh selectively inhibits Tfh cells and abrogates progression/activity of inflammatory arthritis in CIA mouse model. Treatment with our small molecule SMI-Tfh in CIA mice provides a potential strategy for joint protection and may be beneficial in RA patients. This is first report that a small molecule targeting Tfh cells in RA may be an approach worth further investigation in RA.

Disclosure: F. Migliore, None; S. Bradley, None; L. Hellmers, None; Q. Quresh, None; J. M. Zakem, None; W. E. Davis, None; T. Webb-Detiege, None; Z. You, None; R. Quinet, None; X. Zhang, None.

To cite this abstract in AMA style:

Migliore F, Bradley S, Hellmers L, Quresh Q, Zakem JM, Davis WE, Webb-Detiege T, You Z, Quinet R, Zhang X. Selective Inhibition of Tfh Cells By a Small Molecule Inhibitor Abrogates Progression of Experimental Inflammatory Arthritis [abstract]. Arthritis Rheumatol. 2017; 69 (suppl 10). https://acrabstracts.org/abstract/selective-inhibition-of-tfh-cells-by-a-small-molecule-inhibitor-abrogates-progression-of-experimental-inflammatory-arthritis/. Accessed .

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