Date: Sunday, October 21, 2018
Session Type: ACR Poster Session A
Session Time: 9:00AM-11:00AM
Rheumatoid arthritis (RA) is a common autoimmune disease characterized by chronic joint inflammation, synovial hyperplasia and progressive destruction of cartilage and bone. T follicular helper (Tfh) cells, a CD4+ T cell subset, predominantly located in lymphoid follicles, regulate B cell survival and antibody production in germinal centers. Our previous studies have showed that circulating Tfh cells were significantly increased in active RA patients, correlated with their anti-CCP antibody titer and disease activity. Here, we further investigated the role of Tfh cells in RA pathogenesis in mice with collagen-induced arthritis (CIA) and also examined the therapeutic effect of a small molecule inhibitor (SMI-Tfh) which selectively blocks the Tfh cell signature transcription factor Bcl-6.
CIA model was induced by administrating chicken type II collagen in twenty-four DBA/1 mice. The joints were observed for score of swelling of paws and ankles. Disease progression was monitored daily and recorded by arthritis severity scores weekly. Following the onset of clinical arthritis, mice were treated with SMI-Tfh. Blood, spleen, and affected paws were collected at the end of the study. Pathological changes were examined by staining of tissue sections with hematoxylin and eosin. Immunofluorescent histochemistry (IHC) staining and flow cytometry analysis were performed to identify Tfh cells (CD4+CXCR5+ICOS+) in spleen, paw, and blood. IHC results were analyzed by Image J and flow cytometry results were analyzed by FlowJo software. Statistical analysis was carried out using GraphPad Prism software and the significance was evaluated by t test.
Results: Our results showed paw-swelling onset between days 21-28 and with peak on day 42 after initial immunization in DBA/1 mice. Compared with the ankles of control mice, the joints of CIA mice had increased inflammatory cells in the synovial tissues and destruction of articular cartilage. Tfh cells (CD4+CXCR5+ICOS+) were observed in the blood and the germinal centers of the spleen of CIA mice. Mice treated with SMI-Tfh had significantly reduced paw swelling. SMI-Tfh was nontoxic at the tested dose (50mg/kg). SMI-Tfh treatment also reduced inflammatory cell and Tfh cell infiltration in inflamed joints, and significantly inhibited the numbers of Tfh cells in the blood and in the germinal centers of spleen (p<0.01) in CIA mouse.
Tfh cells originating from splenic lymphoid follicles may contribute to the circulating Tfh cells in the peripheral blood in RA and play an important role in the development of active RA. The small molecule inhibitor SMI-Tfh selectively inhibits Tfh cells in the spleen and in the inflamed joints. It appears to decrease severity in inflammatory arthritis, and may be useful as a new and additional therapeutic modality for RA.
To cite this abstract in AMA style:Bhatia N, Bradley S, McLeod C, Olayemi G, Quinet R, Davis WE, Zakem J, Zhang X. Small Molecule Inhibitor of Bcl-6 Reduces the Tfh Population in Peripheral Blood, Splenic Germinal Center and Ankle Joints in a Collagen-Induced Arthritis Mouse Model of RA [abstract]. Arthritis Rheumatol. 2018; 70 (suppl 10). https://acrabstracts.org/abstract/small-molecule-inhibitor-of-bcl-6-reduces-the-tfh-population-in-peripheral-blood-splenic-germinal-center-and-ankle-joints-in-a-collagen-induced-arthritis-mouse-model-of-ra/. Accessed July 2, 2020.
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ACR Meeting Abstracts - https://acrabstracts.org/abstract/small-molecule-inhibitor-of-bcl-6-reduces-the-tfh-population-in-peripheral-blood-splenic-germinal-center-and-ankle-joints-in-a-collagen-induced-arthritis-mouse-model-of-ra/