patient care perspectives

Low-Dose Interleukin 2 and Its Potential in Systemic Lupus Erythematosus

by George C. Tsokos, MD


Low-dose interleukin-2 (IL-2) therapy continues to be studied as a potential approach for systemic lupus erythematosus (SLE), where it may restore regulatory T-cell (Treg) homeostasis and prevent global immunosuppression. Preclinical and early clinical data have been encouraging; however, additional investigation is required.

Expert Commentary

George C. Tsokos, MD

Professor of Medicine
Harvard Medical School
Chief, Division of Rheumatology and Clinical Immunology
Beth Israel Deaconess Medical Center
Boston, MA

Low-dose IL-2 is an investigational treatment approach in SLE that has shown promise in preclinical and early clinical studies.”

George C. Tsokos, MD

As a result of my career-long research on the impact of low IL-2 production in SLE, I have been an advocate for the further exploration and clinical development of low-dose IL-2 as a potential treatment strategy in this patient population. Our group generated data demonstrating the importance of IL-2 in mice with lupus, which piqued the interest of other investigators in the field. We had seen that IL-2–deficient mice develop severe autoimmunity marked by reduced Treg numbers and the systemic expansion of pathogenic T-cell effectors, which suggested that IL-2 is crucial for the maintenance of T-cell–mediated self-tolerance. Our data also suggested that the administration of IL-2 to lupus-prone mice protects against end-organ damage and suppresses inflammation by dually limiting IL-17–producing CD3+CD4-CD8- (double-negative) T cells and expanding Treg.

Low-dose IL-2 is an investigational treatment approach in SLE that has shown promise in preclinical and early clinical studies. Since IL-2 is upstream from several pathways, the administration of low-dose IL-2 allows for the following to occur: (1) the correction of Tregs; (2) the suppression of T helper 17 cell production; (3) the suppression of CD41+ T cells and T follicular helper cells; and (4) the enhancement of cytotoxic responses, which is needed in patients with SLE. In fact, the lack of IL-2 production by the CD41+ T cells of patients with SLE may account for the loss of CD25 expression in Tregs, which could be selectively reversed by stimulation with low doses of IL-2. 

While there is plenty of reason for optimism based on preclinical data, the clinical data have been relatively limited thus far. There is a placebo-controlled, single-center trial conducted by He et al in which 60 patients with active SLE had rapid and significant disease improvement at week 24 with low-dose IL-2 therapy compared with placebo (Systemic Lupus Erythematosus Responder Index 4 response, 66% vs 37%). Total cumulative corticosteroid doses were also reduced more during treatment with low-dose IL-2 than with placebo. With minimal side effects and the opportunity to limit the total cumulative corticosteroid dose, I am optimistic that low-dose IL-2 will become a beneficial supplement in SLE management, but further study is required.


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. Ann Rheum Dis. 2020;79(1):141-149. doi:10.1136/annrheumdis-2019-215396

Humrich JY, Riemekasten G. Low-dose interleukin-2 therapy for the treatment of systemic lupus erythematosus. Curr Opin Rheumatol. 2019;31(2):208-212. doi:10.1097/BOR.0000000000000575

Katsuyama E, Suarez-Fueyo A, Bradley SJ, et al. The CD38/NAD/SIRTUIN1/EZH2 axis mitigates cytotoxic CD8 T cell function and identifies patients with SLE prone to infections. Cell Rep. 2020;30(1):112-123.e4. doi:10.1016/j.celrep.2019.12.014

Li H, Tsokos MG, Bickerton S, et al. Precision DNA demethylation ameliorates disease in lupus-prone mice. JCI Insight. 2018;3(16):e120880. doi:10.1172/jci.insight.120880

Mizui M, Koga T, Lieberman LA, et al. IL-2 protects lupus-prone mice from multiple end-organ damage by limiting CD4-CD8-IL-17-producing T cells. J Immunol. 2014;193(5):2168-2177. doi:10.4049/jimmunol.1400977

Tahvildari M, Dana R. Low-dose IL-2 therapy in transplantation, autoimmunity, and inflammatory diseases. J Immunol. 2019;203(11):2749-2755. doi:10.4049/jimmunol.1900733

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