SAT0108 RESPONSE TO ABATACEPT IS ASSOCIATED WITH THE INHIBITION OF PROTEASOME Β1I EXPRESSION IN T CELLS OF PATIENTS WITH RHEUMATOID ARTHRITIS
Authors: K. Ghannam, L. Martinez Gamboa, C. Kedor, L. Spengler, G. R. Burmester, E. Feist
Journal: Annals of the Rheumatic Diseases (2020)

Background: Abatacept (CTLA4-Ig) is a biological DMARD (bDMARD) for treatment of rheumatoid arthritis (RA) and selectively modulates the co-stimulatory signal by CD28: CD80/CD86 interaction required for T cell activation. CD28 mediated signaling regulates many T cell functions including cytokine production. The role of proteasome was approved in many autoimmune diseases, and the effect of Abatacept on modifying cytokines including interferon-γ that alters proteasome proteolytic activities was shown in RA. Objectives: To characterize the effect of Abatacept on the expression and proteolytic activity of the immunoproteasome. Methods: Effects of Abatacept on the proteasome system were investigated in 39 patients with rheumatoid arthritis over a period of 24 weeks. Using real time PCR, transcript expression levels of constitutive and corresponding immunoproteasome catalytic subunits were investigated at baseline (T0), week 16 (T16) and week 24 (T24) in sorted blood cells. Proteasomal activity and induction of apoptosis after proteasome inhibition were also evaluated in cellular subsets. Results: Upon treatment with Abatacept, remission or low disease activity according to DAS28 was achieved in 55 % of patients at T16 and in 70 % at T24. By Two- (time and type of response) way ANOVA, a significant reduction of proteasome immunosubunit β1i expression was shown only in CD4+ and CD8+ T cells of prolonged responders at both T16 and T24 ( P = 0.0390 and P = 0.0198, respectively). One-way ANOVA analysis for each response group separately confirmed the results and showed significant reduction at T24; P = 0.0396 difference between T0 and T24, P = 0.0260 between T16 and T24 in CD4+ T cells of the same group. Abatacept did not influence chymotrypsin like activity of proteasome, which is carried out by the subunit β5i and had no effect on induction of apoptosis under exposure to a proteasome inhibitor in-vitro. Conclusion: Treatment with Abatacept showed a clear effect on the expression of the proteasome immunosubunit β1i. This phenomenon was only seen in CD4+ and CD8+ T cells of prolonged responding patients with RA suggesting an association between persistent induction of β1i and failure to the T cell directed therapy with Abatacept. References: [1]Keating, G.M., Abatacept: A Review of its Use in the Management of Rheumatoid Arthritis. Drugs, 2013. 73(10): p. 1095-1119. [2]Ferrington, D.A. and D.S. Gregerson, Immunoproteasomes: Structure, Function, and Antigen Presentation. Progress in molecular biology and translational science, 2012. 109: p. 75-112. [3]Marti, L., et al., Alterations in Cytokine Profile and Dendritic Cells Subsets in Peripheral Blood of Rheumatoid Arthritis Patients before and after Biologic Therapy. Annals of the New York Academy of Sciences, 2009. 1173: p. 334-42. Disclosure of Interests: Khetam Ghannam: None declared, Lorena Martinez Gamboa: None declared, Claudia Kedor Consultant of: Advisory Board for Novartis Pharma GmbH, Lydia Spengler: None declared, Gerd Rüdiger Burmester Consultant of: AbbVie Inc, Eli Lilly, Gilead, Janssen, Merck, Roche, Pfizer, and UCB Pharma, Speakers bureau: AbbVie Inc, Eli Lilly, Gilead, Janssen, Merck, Roche, Pfizer, and UCB Pharma, Eugen Feist Consultant of: Novartis, Roche, Sobi, Lilly, Pfizer, Abbvie, BMS, MSD, Sanofi, Speakers bureau: Novartis, Roche, Sobi, Lilly, Pfizer, Abbvie, BMS, MSD, Sanofi