Effect of tofacitinib on the activation of t lymphocytes in patients with rheumatoid arthritis.

ONOFRIO LI; ALAMINO V; ZACCA ER; FERRERO P; ACOSTA C; ALVAREZ FERREIRA MC; GARCIA ORO C; RETA ARBO L; WERNER M; ONETTI L; CADILE I; MUSSANO E; MONTES CL; GRUPPI A; ACOSTA RODRIGUEZ EV

Congreso; Reunión Conjunta SAIC.SAI.AAFE.NANOMED.Ar. 17; 2021

Tofacitinib (Tofa) is a Jak1/3 inhibitor that blocks the intracellular signaling ofinflammatory cytokines and is used as 3rd line of treatment in Rheumatoid Arthritis (RA).Tofa is very effective to achieve disease remission but it is associated to higher incidenceof herpes zoster reactivation likely due to alterations in cellular immunity. While severalstudies have evaluated on the effects of Tofa on the immune system in the context ofRA, knowledge about its impact on the activation and differentiation of T lymphocytes(TL) is scarce. We aimed to study this aspect in vivo and in vitro by determining thefunctional status of TL in different groups of treated RA patients (Tx RA) and the effectof Tofa in the activation of T cells from healthy donors (HD), respectively. Thirty-one HDand 106 RA patients were recruited in the Rheumatology Service (HNC) to evaluatenumerous biochemical and immunological parameters. Principal component analysisshowed that 82 of these variables explain around 70% of the variance, with variablesrelated to the activation and differentiation of TL as the main difference between HD anddifferent groups of Tx RA. Compared to HD, Tofa Tx RA patients presented a significantincrease in the % of populations with terminal differentiation characteristics includingCD27-CD28- of CD4+ TL (p <0.01) and KLRG1+CD57+ CD4+ and CD8+ TL (p<0,05).In addition, in vitro studies showed that Tofa reduced the activation of purified CD4+ andCD8+ TL as evidenced by a decrease in the upregulation of CD25, T-bet and thefrequency of Ki-67+ cells. These effect were a dose-dependent and observed in total,naïve and, mainly, memory TL. Interestingly, Tofa increased the expression of senescentmarker p21 in memory CD8+ TL. Altogether, our findings suggest that Tofa-inducedreplicative immunosenescence could underlie the biological effects of this drug in RAand be also involved in side effects, restraining the activity of memory TL involved in viralcontrol.