Regulatory T Cell Responses to High-Dose Methylprednisolone in Active Systemic Lupus Erythematosus

Abstract

Background/PurposeA slight increase in the proportion of circulating regulatory T (Treg) cells has been reported in systemic lupus erythematosus (SLE) patients taking oral prednisone. The effects of intravenous (IV) high dose methylprednisolone (MP) on Tregs have not yet been described, especially in active SLE.MethodsWe prospectively analyzed the proportion of circulating CD4+ Treg cell subsets defined as follows: (1) naïve Treg (nTreg) FoxP3lowCD45RA+ cells; (2) effector Treg (eTreg) FoxP3highCD45RA− cells; and (3) non-suppressive FoxP3lowCD45RA− cells (non-regulatory Foxp3low T cells). Peripheral blood mononuclear cells of patients with active SLE were analyzed before the first infusion of IV high dose MP (day 0) and the following days (day 1, day 2, ±day 3 and ±day 8). The activity of SLE was assessed by the SLEDAI score.ResultsSeventeen patients were included. Following MP infusions, the median (range) percentage of eTregs significantly increased from 1.62% (0.53–8.43) at day 0 to 2.80% (0.83–14.60) at day 1 (p = 0.003 versus day 0), 4.64% (0.50–12.40) at day 2 (p = 0.06 versus day 1) and 7.50% (1.02–20.70) at day 3 (p = 0.008 versus day 2), and declined to baseline values at day 8. Expanding eTreg cells were actively proliferating, as they expressed Ki-67. The frequency of non-regulatory FoxP3low T cells decreased from 6.39% (3.20–17.70) at day 0 to 4.74% (1.03–9.72) at day 2 (p = 0.005); nTreg frequency did not change. All patients clinically improved immediately after MP pulses. The absence of flare after one year of follow up was associated with a higher frequency of eTregs at day 2.ConclusionIV high dose MP induces a rapid, dramatic and transient increase in circulating regulatory T cells. This increase may participate in the preventive effect of MP on subsequent flares in SLE.

Comparative Study of Immunomodulatory Agents to Induce Human T Regulatory (Treg) Cells: Preferential Treg-Stimulatory Effect of Prednisolone and Rapamycin

“…In the present study we verified the ability of various pharmacological agents with suggested modulatory effect on Treg cell development/activity: rapamycin (Fanigliulo et al 2015;Li et al 2014), prednisolone (Karagiannidis et al 2004Mathian et al 2015), atorvastatin (Forero-Peña and Gutierrez 2013), inosine pranobex, sodium butyrate (Fontenelle and Gilbert 2012), and glatiramer acetate (Haas et al 2009;Hong et al 2005) to facilitate/augment generation of iTreg cells in standard in vitro cultures, with the aim to further investigations for clinical application.…”

Significant association between FOXP3 gene polymorphism and steroid‐resistant acute rejection in living donor liver transplantation

“…GCR has been described as an enhancer of FOXP3 gene expression . Several studies in both transplant and nontransplant fields have reported the capability of steroids to enhance Foxp3 expression in vitro and in vivo to generate Tregs . Mathian et al and Karagiannidis et al found that systemic administration of MP induced dramatic and rapid but transient increases in circulatory Tregs in patients with asthma and systemic lupus erythematosus, respectively.…”

Regulatory T cell subsets in patients with medulloblastoma at diagnosis and during standard irradiation and chemotherapy (PBTC N-11)

“…While our control patients with CM also received a single dose of dexamethasone pre-operatively, we were not able to control for differences in steroid doses and duration of exposure prior to surgery in the study population. However, high-dose methylprednisolone has been shown to actually increase both the naïve and effector T regs several fold within 48 hours after treatment possibly related to increased transcription of Foxp3 following glucocorticoid receptor stimulation, that return to baseline in a week [21]. It is therefore unlikely that both the reduced number and fraction of T regs in our patients with MBL and PFT are due to higher doses of steroid exposure.…”