Quang Nguyen

Introduction: Systemic Lupus Erythematosus (SLE), a systemic autoimmune disorder, presents a variety of conditions such as arthritis, renal failure, and cardiovascular diseases. A clinical trial in 2019 studied the low-dose IL-2 in the treatment of SLE and concluded low-dose IL-2 demonstrated therapeutic effects in SLE patients with tolerable side effect.⁵ Methods: The research relies heavily on several experimental studies, all of which contribute to the hypothesized mechanism of action of low-dose IL-2 in SLE. In a study, peripheral blood mononuclear cells were gathered from Japanese SLE patients and healthy donors (HCs) to collect CD4+ T cells.¹ Follicular regulatory T (TFH) cells’ effect on follicular helper T (TFH) cells’ activity was analyzed using cell proliferation assay. DNA methylation analysis of forehead box protein 3 (FoxP3) genes was performed. Another study measured the percentage of FoxP3 cells after incubating T helper (Th) cells with IL-7.³ A different study collected TFH cells from healthy donors and incubated with IL-2 and other cytokines, and then measured the expression the different markers, including FoxP3+ and Bcl-6+. Additionally, the effects of high-dose IL-2 and low-dose IL-2 treatments were introduced on mice that had been infected with influenza to examine changes in expression of certain genes.⁶ Results: Hypermethylation in SLE-TFR cells is observed. It was concluded that “epigenetic modulation could explain the suppressed FoxP3 transcription and functional declines observed in SLE-TFR cells.”¹ Of note, even though the percentages of FoxP3+ cells in childhood-onset SLE (cSLE) and HC groups were not statistically different, the cell population in the SLE group significantly lack CD25. ³ While both IL-2 and IL-7 can increase FoxP3 expression, IL-2 has a unique role, which is to provide FoxP3+ cells continuous activation.³ Additionally, in the presence of IL-2, TFH cells become FoxP3+ and Bcl-6+, characteristic of TFR-like cells, which means they possess the regulatory features from T regulatory (Treg) cells and TFH cells.⁴ Especially, in the low-dose IL-2 treatment, there was a higher expression of Bcl-6 and lower expression of CD25 compared to the high-dose IL-2 treatment.⁶ Conclusion: The progression of SLE is influenced by the ratio of TFH cells to TFR cells, which can be adjusted through a low-dose IL-2. Future studies could a) explore the therapeutic effects as well as side effects at different dosages of low-dose IL-2, and b) design an algorithm that determines the optimal dosage for each individual patient to minimize the side effects of the drugs.

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2. He J, Zhang R, Shao M, et al. Efficacy and safety of low-dose IL-2 in the treatment of systemic lupus erythematosus: a randomised, double-blind, placebo-controlled trial. Annals of the Rheumatic Diseases. 2019;79(1):141-149. doi:10.1136/annrheumdis-2019-215396
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