Table-1-.

Summary of the findings of the initial studies on the use of low-dose IL-2 in the treatment of autoimmune conditions in humans. HCV= hepatitis C virus, SC= subcutaneous, Treg= regulatory T cell, Teff= effector T cell, GVHD= graft-versus-host-disease, Tcon= conventional T cell, T1D= type 1 diabetes, SLE= systemic lupus erythematosus, NK= natural killer cell.

Year	Author	Clinical setting	Route, dose, frequency of IL2 administration	Biological effect	Clinical outcome	Side effects
2011	Saadoun et al. (19)	HCV-induced vasculitits	SC, 1 million IU per day for 5 days, followed by three 5-day courses of 3 million IU per day at weeks 3, 6, and 9 (52.5 million IU cumulative dose)	• Increased CD4+CD25hiFoxp3+Tregs • No Teff activation • Decreased inflammatory and oxidative stress mediators • No increased HCV viremia	• No vasculitis flare • Decline in cryoglobulinemia in 9 of 10 patients • Improvement of vasculitis in 8 of 10 patients • First time to show low dose IL-2 could be used as immunoregulatory drug for treatment of autoimmune disease	No serious adverse events
2011	Koreth et al. (15)	Refractory GVHD	SC, 0.3, 1 or 3 million IU per square meter of body-surface area, daily for 8 weeks, followed by a 4-week hiatus (extended treatment if response observed)	• Increased CD4+Foxp3+Tregs with a peak median value at 4 weeks (more than eight times the baseline value) • No effect on Tcon • Treg:Tcon ratio increased to five times the baseline value, declined when treatment stopped	Of the 23 patients, 12 had major responses involving multiple sites with amelioration of the manifestations of chronic GVHD	• Maximum tolerated dose: 1 million IU per square meter • Highest dose induced severe constitutional symptoms
2013	Hartemann et al. (16)	Insulin-dependent T1D	SC, 0.33, 1 or 3 million IU per day, for a 5-day course, followed for 60 days	A dose-dependent increase in Tregs (significant at all doses)	IL2 did not induce deleterious changes in glucose-metabolism variables	• Tolerated at all doses with no serious adverse effects • Dose-dependent • Most common: injection-site reaction and influenza-like syndrome
2014	Castela et al. (20)	Alopecia areata	SC, 1.5 million IU/d for 5 days, followed by three 5-day courses of 3 million IU/d at weeks 3, 6, and 9	Notable increase in Treg cell count in 4 of 5 patients at the end of the treatment compared with baseline	Partial regrowth achieved in 4 of 5 patients	No serious adverse event was reported
2015	Rosenzwajg et al. (21)	T1D	SC, 0.33, 1 or 3 million IU, daily for 5 days • A dose finding trial to define safety and immunological responses	• Expands and activates Tregs at 0.33 and 1 million IU/day without effects on Teffs or NK • Greater expansion of Tregs at the dose of 3 million IU/day but with NK expansion, cytokine/chemokine increase • A clear shift of the peripheral blood immune environment towards a regulatory milieu	• Help delay or prevent the onset of the full-blown disease • Decrease the frequency and severity of disease	• No serious adverse events • More frequent mild to moderate side effects with higher dose (3 million IU/day)
2015	Humrich et al. (22)	SLE  • A 36-year-old female with SLE and high disease activity	SC, 1.5 or 3 million or 3.0 million IU of IL-2, daily for five consecutive days, 4 treatment cycles, separated by washout periods of 9–16 days and followed by a 9-week follow-up period	• Remarkable CD25+Foxp3+CD127lo Treg expansion • Decreased serum levels of anti-dsDNA-antibodies • Very slight and transient decreases in the levels of total Ig • Intact Treg suppressive function on days 57 and 83 by in vitro suppression assays • Marginal effects on other cell subsets	• Rapid and robust reduction of disease activity • No organ manifestations during the treatment cycles • Disease activity remained low • First evidence for clinical efficacy of subcutaneous low-dose IL-2 in SLE • A successful biological treatment strategy	• Well-tolerated • Mild and transient adverse effects: erythema at the injection site, increased day and night sweats, and one episode of fever
2016	Todd et al. (23)	T1D	• 40 participants with T1D • Optimal doses of aldesleukin to induce 10% (minimal) and 20% (maximal) increases in Tregs were 0.101 and 0.497 million IU/m2	• Optimal IL-2 dose that increased Treg frequencies raised by 10% and 20% were defined • Desensitisation of Tregs can occur in some patients receiving daily doses of • Aldesleukin of 1.0 million IU/m2 or more • Following treatment Tregs had a decreased sensitivity to IL-2 that returned to baseline on day 3 after treatment	Not looked at	• Single dose: small self-limiting injection site reaction • Two episodes of rhinitis possibly related to drug administration • Transient lymphopenia • Transient eosinophilia
2016	Spee-Mayer et al. (17)	Refractory SLE	SC, 1.5 million IU, daily for five consecutive days	• Lack of IL-2 production by CD4+ T cells was reversed by stimulation with low doses of IL-2 • Selectively expanded Tregs in vivo • CD56hi NK cells (with immunoregulatory properties) showed a strong response to in vitro and in vivo stimulations with IL-2	Not looked at	Not looked at