Understanding the Mechanism of Low-Dose IL-2 Treatment in Systemic Lupus Erythematous Can Help Design A More Personalized Treatment with Less Side Effects in SLE Patients
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.
- Kurata I, Mikami N, Ohyama A, et al. Impaired function of PD-1+ follicular regulatory T cells in systemic lupus erythematosus. Clinical and Experimental Immunology. 2021;206(1):28-35. doi:10.1111/cei.13643
- 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
- Holcar M, Goropevšek A, Avčin T. Altered Homeostasis of Regulatory T Lymphocytes and Differential Regulation of STAT1/STAT5 in CD4+ T Lymphocytes in Childhood-onset Systemic Lupus Erythematosus. The Journal of Rheumatology. 2019;47(4):557-566. doi:10.3899/jrheum.181418
- Hao H, Nakayamada S, Yamagata K, et al. Conversion of T Follicular Helper Cells to T Follicular Regulatory Cells by Interleukin‐2 Through Transcriptional Regulation in Systemic Lupus Erythematosus. Arthritis & Rheumatology. 2020;73(1):132-142. doi:10.1002/art.41457
- Wallace D, Gladman D. Clinical Manifestations and Diagnosis of Systemic Lupus Erythematosus in Adults. (Pisetsky D, Curtis M, eds.). In: Post T, ed. UpToDate. UpToDate; 2021. Accessed April 10, 2022. www.uptodate.com
- Botta D, Fuller MJ, Marquez-Lago TT, et al. Dynamic regulation of T follicular regulatory cell responses by interleukin 2 during influenza infection. Nature Immunology. 2017;18(11):1249-1260. doi:10.1038/ni.3837