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

ONOFRIO LUISINA; ALAMINO VA; ZACCA ESTEFANÍA; FERRERO PAOLA; ACOSTA CRISTINA; CLARA ALVAREZ FERREIRA; GARCÍA ORO AGUSTINA; RETA ARBÓ LUCAS; WERNER MARINA; ONETTI LAURA; CADILE IGNACIO; EDUARDO MUSSANO; MONTES CAROLINA; ADRIANA GRUPPI; ACOSTA RODRÍGUEZ EVA

Congreso; Reunión Conjunta SAIC. SAI. AAFE. NANOMED-AR; 2021

Tofacitinib (Tofa) is a Jak1/3 inhibitor that blocks the intracellular signaling of inflammatory 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 incidence of herpes zoster reactivation likely due to alterations in cellular immunity. While several studies have evaluated on the effects of Tofa on the immune system in the context of RA, 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 the functional status of TL in different groups of treated RA patients (Tx RA) and the effect of Tofa in the activation of T cells from healthy donors (HD), respectively. Thirty-one HD and 106 RA patients were recruited in the Rheumatology Service (HNC) to evaluate numerous biochemical and immunological parameters. Principal component analysis showed that 82 of these variables explain around 70% of the variance, with variables related to the activation and differentiation of TL as the main difference between HD and different groups of Tx RA. Compared to HD, Tofa Tx RA patients presented a significant increase in the % of populations with terminal differentiation characteristics including CD27-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+ and CD8+ TL as evidenced by a decrease in the upregulation of CD25, T-bet and the frequency 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 senescent marker p21 in memory CD8+ TL. Altogether, our findings suggest that Tofa-induced replicative immunosenescence could underlie the biological effects of this drug in RA and be also involved in side effects, restraining the activity of memory TL involved in viral control.