Low-dose Interleukin-2 Treatment Research Articles

Pharmacometabolomics applied to low-dose interleukin-2 treatment in amyotrophic lateral sclerosis.

Amyotrophic lateral sclerosis (ALS) is a devastating motor neuron disease. The immunosuppressive functions of regulatory T lymphocytes (Tregs) are impaired in ALS, and correlate to disease progression. The phase 2a IMODALS trial reported an increase in Treg number in ALS patients following the administration of low-dose (ld) interleukin-2 (IL-2). We propose a pharmacometabolomics approach to decipher metabolic modifications occurring in patients treated with ld-IL-2 and its relationship with Treg response. Blood metabolomic profiles were determined on days D1, D64, and D85 from patients receiving 2 MIU of IL-2 (n = 12) and patients receiving a placebo (n = 12). We discriminated the three time points for the treatment group (average error rate of 42%). Among the important metabolites, kynurenine increased between D1 and D64, followed by a reduction at D85. The percentage increase of Treg number from D1 to D64, as predicted by the metabolome at D1, was highly correlated with the observed value. This study provided a proof of concept for metabolic characterization of the effect of ld-IL-2 in ALS. These data could present advances toward a personalized medicine approach and present pharmacometabolomics as a key tool to complement genomic and transcriptional data for drug characterization, leading to systems pharmacology.

Concomitant use of interleukin-2 and tacrolimus suppresses follicular helper T cell proportion and exerts therapeutic effect against lupus nephritis in systemic lupus erythematosus-like chronic graft versus host disease.

Defective interleukin-2 (IL-2) production contributes to immune system imbalance in patients with systemic erythematosus lupus (SLE). Recent clinical studies suggested that low-dose IL-2 treatment is beneficial for SLE and the therapeutic effect is associated with regulatory T cell (Treg) expansion. Pharmacological calcineurin inhibition induces a reduction in the number of Tregs because they require stimulation of T cell receptor signaling and IL-2 for optimal proliferation. However, the activation of T cell receptor signaling is partially dispensable for the expansion of Tregs, but not for that of conventional T cells if IL-2 is present. We examined whether addition of IL-2 restores the Treg proportion even with concurrent use of a calcineurin inhibitor and if the follicular helper T cell (Tfh) proportion is reduced in an SLE-like murine chronic graft versus host disease model. Using a parent-into-F1 model, we investigated the effect of IL-2 plus tacrolimus on Treg and Tfh proportions and the therapeutic effect. Treatment with a combination of IL-2 and tacrolimus significantly delayed the initiation of proteinuria and decreased the urinary protein concentration, whereas tacrolimus or IL-2 monotherapy did not significantly attenuate proteinuria. Phosphorylation of signal transducer and activator of transcription 3, a positive regulator of Tfh differentiation, was reduced by combination treatment, whereas phosphorylation of signal transducer and activator of transcription 5, a negative regulator, was not reduced. Addition of calcineurin inhibitors as adjunct agents may be beneficial for IL-2-based treatment of lupus nephritis.

Low-Dose Interleukin-2 Treatment Increases the Proportion of Regulatory T Cells in Patients with Rheumatic Diseases: A Meta-Analysis

Low-Dose Interleukin-2 Treatment Increases the Proportion of Regulatory T Cells in Patients with Rheumatic Diseases: A Meta-Analysis

Effects of a low-dose IL-2 treatment in HLA-B27 transgenic rat model of spondyloarthritis

Introduction/AimHLA-B27/human β2m transgenic rats (B27-rats) develop an inflammatory disorder resembling spondyloarthritis (SpA) with dysregulated IL-10/IL-17 production by regulatory T cells (Treg). Treg plays a major role in controlling pathogenic inflammatory processes. Interleukin 2 (IL-2), a cytokine which promotes Treg cell survival and function, may thus have therapeutic efficacy in SpA. Here, we tested this hypothesis using a low dose of IL-2 treatment in B27-rat.Material and methodsB27-rats aged 4 weeks (before disease onset) and nontransgenic (NTG) littermates were administered intraperitoneally recombinant human IL-2 (Sanofi®; 2,000IU/injection) or PBS, 3 days per week during 6 weeks. Assessment of treatment effect was performed, based on clinical (weight, diarrhea, arthritis), histological (proximal and distal colon, caecum, ileum and tarsal/ankle joint) scores, and frequency of Treg in the spleen and lymph nodes (LN).ResultsIL-2 administration had no effect on weight gain, either in B27- or NTG-rats. Over the 6 weeks of treatment, the clinical disease score worsened similarly in both IL-2-treated and control groups of B27-rats. The macroscopic and histological evaluation of gut and joints showed marked inflammation in B27-rats; however, no change related to IL-2 treatment was observed. In the B27-rats, the percentage of Treg was moderately increased after IL-2 treatment in the spleen, but neither in mesenteric nor peripheral LN in those rats.ConclusionOur data demonstrate that a low dose of IL-2 administered before disease onset was moderately effective for boosting Treg but failed to prevent SpA development in B27-rat.

Treatment of Active Idiopathic Inflammatory Myopathies by Low-Dose Interleukin-2: A Prospective Cohort Pilot Study.

IntroductionTreatment of idiopathic inflammatory myopathies (IIMs) is challenging due to a lack of safe and efficacious medication. Low-dose interleukin-2 (IL-2) treatment emerges as a new option in active IIMs. This study aims to explore the clinical and immunological effects of low-dose IL-2 in patients with active IIMs.MethodsEighteen patients with active IIMs were enrolled and received 1 × 106 IU of IL-2 subcutaneously every other day for 12 weeks on top of standard care. The primary endpoint for the trial was change in percentage of regulatory T (Treg) cells in total CD4+ T cells at week 12. The secondary endpoints included the International Myositis Assessment and Clinical Studies (IMACS) definition of improvement (DOI), the 2016 American College of Rheumatology (ACR)/European League Against Rheumatism (EULAR) myositis response criteria, safety, and steroid-sparing effect at weeks 12 and 24.ResultsWith low-dose IL-2 treatment, 77.78% (14/18) patients achieved IMACS DOI and 83.33% (15/18) patients met the 2016 ACR/EULAR myositis response criteria at week 12. All individual core set measures (CSMs) including PhGA, PGA and HAQ-DI, muscle enzymes, MMT-8 and extramuscular activity were improved at week 12. The cutaneous dermatomyositis disease area and severity index activity score (CDASI-a) decreased significantly from 7 (4.5, 13) to 2 (0, 7) after IL-2 administration (P < 0.001). Proportion of Treg cells significantly increased with low-dose IL-2 treatment at week 12 (8.97% [5.77, 9.89%] vs. 15.2% [10.4, 17.3%], P = 0.009). There were no serious adverse events.ConclusionsLow-dose IL-2 was effective in active IIMs and well tolerated. The amelioration of disease activity may associate with promotion of Tregs.Trial RegistrationClinicalTrials.gov identifier, NCT04062019.Supplementary InformationThe online version contains supplementary material available at 10.1007/s40744-021-00301-3.

Therapeutic responses and predictors of low-dose interleukin-2 in systemic lupus erythematosus.

Interleukin-2 (IL-2) is effective and well tolerated in patients with systemic lupus erythematosus (SLE). However, patient response to IL-2 therapy varies. Therefore, biomarkers are needed to efficiently identify patients who may respond well to IL-2 treatment. We investigated clinical and immunological biomarkers to predict low-dose IL-2 responses. A pooled post-hoc analysis was performed in SLE patients who received low-dose IL-2 treatment in two clinical trials. Factors predicting responses in clinical and T-cell subset changes were evaluated by logistic regression. Good response (GR) and poor response (PR) were defined according to whether patients achieved or did not achieve an SLE Responder Index-4 (SRI-4), respectively. A good response at 68% was achieved in patients with lower Treg, compared to 0% in patients with higher Treg. In comparison to PR, GR was more strongly associated with low Treg proportions at baseline (12.85±6.07% vs. 9.43±2.82%, p<0.01). There were more patients with skin rash in the GR group than in the PR group (68.75% vs. 30.77%, p=0.042). Multivariate analysis showed that low Treg proportions and skin rash presence were both independently associated with GR to low-dose IL-2 treatment. A nomogram to identify GR probability exhibited a clear discrimination (concordance index, 0.812; 95% confidence interval, 0.64-0.97). Based on the area under the receiver operating characteristic (ROC) curve (AUC) of 0.813, the specificity of a low regulatory T cells (Tregs) proportion (≤13.35%) plus skin rash to predict GR to IL-2 therapy was 100%, with a sensitivity of 68.75%. A low Treg proportion and skin rash indicate GR to low-dose IL-2 treatment in SLE patients.

Low-Dose IL-2 Treatment Affords Protection against Subarachnoid Hemorrhage Injury by Expanding Peripheral Regulatory T Cells.

Subarachnoid hemorrhage (SAH) is considered a devastating disease, leaving survivors with lifelong neurological impairment. With increased knowledge that regulatory T cells (Tregs) provide protection against stroke, novel agents which could expand Treg populations have been assessed in terms of the potential clinical neuroprotection effect. Using a rat SAH model, we investigated the number variation of Tregs induced by SAH and the protective effect of low-dose interleukin-2 (IL-2) treatment on the SAH model. We observed that the number of peripheral Tregs significantly decreased soon after SAH, accompanying with reactivity recovery after 3 days. Our results also revealed that low-dose IL-2 treatment not only elevated Tregs numbers but significantly reduced neuronal injury and improved neurological functions up to 21 days (d) after SAH. Furthermore, compared with PBS-treatment group, cerebral proinflammatory factors and peripheral neutrophils were significantly suppressed by low-dose IL-2 after SAH. Therefore, the results suggest that low-dose IL-2 treatment is a novel and clinically feasible immunotherapy to improve long-term outcomes after SAH, perhaps via up-regulating Treg population to suppress neuroinflammation induced by SAH.

Low-dose IL-2 therapy limits the reduction in absolute numbers of circulating regulatory T cells in rheumatoid arthritis.

Background:Circulating regulatory T cells (Tregs) are responsible for mediating immune tolerance and maintaining immunological homeostasis. Decreases in Tregs may be involved in the onset of rheumatoid arthritis (RA). Low-dose interleukin-2 (IL-2) has been considered for the treatment of inflammatory diseases mediated by T cells. This study focused on the status of circulating CD4+T subsets and the clinical feasibility of IL-2 therapies in patients with RA.Methods:The subjects included 888 patients with RA and 100 healthy controls (HCs); 233 RA patients received IL-2 treatment with 0.5 million international units (MIU)/day from days 1 through 5. The demographic features, disease activity, and levels of CD4+T cells measured by modified flow cytometry were collected in all RA patients before and after treatment.Results:RA patients had lower absolute Treg counts (but not Th17) compared with HCs, which was associated with disease activity; previously treated RA patients had the fewest circulating Tregs (p < 0.05). Patients treated with low-dose IL-2 had a three-fold increase in absolute anti-inflammatory Treg counts, as well as a two-fold increase in the other CD4+T subsets. Moreover, post-treatment levels of markers of disease activity in RA patients treated with IL-2 were significantly lower than the baseline values (p < 0.001), with no apparent side effects.Conclusion:Decreased absolute counts of circulating CD4+T lymphocyte subsets were observed in patients with RA. Circulating Tregs, which mediate immune tolerance, may be involved in the pathogenesis and progression of RA; however, this was ameliorated by low-dose IL-2, without obvious side effects.Plain language summary Low-dose IL-2 treatment for rheumatoid arthritis • Circulating Tregs may be involved in the pathogenesis and progression of RA.• The absolute count of Tregs was significantly correlated with disease activity measures.• Low-dose IL-2 was able to effectively expade Tregs and help for RA patients’ symptoms remission without evaluated side effects.

Increase in trigeminal ganglion neurons that respond to both calcitonin gene-related peptide and pituitary adenylate cyclase-activating polypeptide in mouse models of chronic migraine and posttraumatic headache.

A large body of animal and human studies indicates that blocking peripheral calcitonin gene-related peptide (CGRP) and pituitary adenylate cyclase-activating polypeptide (PACAP) signaling pathways may prevent migraine episodes and reduce headache frequency. To investigate whether recurring migraine episodes alter the strength of CGRP and PACAP signaling in trigeminal ganglion (TG) neurons, we compared the number of TG neurons that respond to CGRP and to PACAP (CGRP-R and PACAP-R, respectively) under normal and chronic migraine-like conditions. In a mouse model of chronic migraine, repeated nitroglycerin (NTG) administration significantly increased the number of CGRP-R and PACAP-R neurons in TG but not dorsal root ganglia. In TG neurons that express endogenous αCGRP, repeated NTG led to a 7-fold increase in the number of neurons that respond to both CGRP and PACAP (CGRP-R&PACAP-R). Most of these neurons were unmyelinated C-fiber nociceptors. This suggests that a larger fraction of CGRP signaling in TG nociceptors may be mediated through the autocrine mechanism, and the release of endogenous αCGRP can be enhanced by both CGRP and PACAP signaling pathways under chronic migraine condition. The number of CGRP-R&PACAP-R TG neurons was also increased in a mouse model of posttraumatic headache (PTH). Interestingly, low-dose interleukin-2 treatment, which completely reverses chronic migraine-related and PTH-related behaviors in mouse models, also blocked the increase in both CGRP-R and PACAP-R TG neurons. Together, these results suggest that inhibition of both CGRP and PACAP signaling in TG neurons may be more effective in treating chronic migraine and PTH than targeting individual signaling pathways.

Low-dose interleukin-2 alleviates dextran sodium sulfate-induced colitis in mice by recovering intestinal integrity and inhibiting AKT-dependent pathways.

Several phase 1/2 clinical trials showed that low-dose interleukin-2 (IL-2) treatment is a safe and effective strategy for the treatment of chronic graft-versus-host disease, hepatitis C virus-induced vasculitis, and type 1 diabetes. Ulcerative colitis (UC) is a chronic inflammatory condition of the colon that lacks satisfactory treatment. In this study, we aimed to determine the effects of low-dose IL-2 as a therapeutic for UC on dextran sulfate sodium (DSS)-induced colitis.Methods: Mice with DSS-induced colitis were intraperitoneally injected with low-dose IL-2. Survival, body weight, disease activity index, colon length, histopathological score, myeloperoxidase activity and inflammatory cytokine levels as well as intestinal barrier integrity were examined. Differential gene expression after low-dose IL-2 treatment was analyzed by RNA-sequencing.Results: Low-dose IL-2 significantly improved the symptoms of DSS-induced colitis in mice and attenuated pro-inflammatory cytokine production and immune cell infiltration. The most effective dose range of IL-2 was 16K-32K IU/day. Importantly, low-dose IL-2 was effective in ameliorating the disruption of epithelial barrier integrity in DSS-induced colitis tissues by restoring tight junction proteins and mucin production and suppressing apoptosis. The colon tissue of DSS-induced mice exposed to low-dose IL-2 mimic gene expression patterns in the colons of control mice. Furthermore, we identified the crucial role of the PI3K-AKT pathway in exerting the therapeutic effect of low-dose IL-2.Conclusions: The results of our study suggest that low-dose IL-2 has therapeutic effects on DSS-induced colitis and potential clinical value in treating UC.

Regulatory T cells promote corneal endothelial cell survival following transplantation via interleukin-10.

The functional competence of corneal endothelial cells (CEnCs) is critical for survival of corneal allografts, but these cells are often targets of the immune response mediated by graft-attacking effector T cells. Although regulatory T cells (Tregs) have been studied for their role in regulating the host's alloimmune response towards the graft, the cytoprotective function of these cells on CEnCs has not been investigated. The aim of this study was to determine whether Tregs suppress effector T cell-mediated and inflammatory cytokine-induced CEnC death, and to elucidate the mechanism by which this cytoprotection occurs. Using 2 well-established models of corneal transplantation (low-risk and high-risk models), we show that Tregs derived from low-risk graft recipients have a superior capacity in protecting CEnCs against effector T cell-mediated and interferon-γ and tumor necrosis factor-α-induced cell death compared to Tregs derived from high-risk hosts. We further demonstrate that the cytoprotective function of Tregs derived from low-risk hosts occurs independently of direct cell-cell contact and is mediated by the immunoregulatory cytokine IL-10. Our study is the first to report that Tregs provide cytoprotection for CEnCs through secretion of IL-10, indicating potentially novel therapeutic targets for enhancing CEnC survival following corneal transplantation.

Low-dose interleukin-2 therapy in refractory systemic lupus erythematosus: an investigator-initiated, single-centre phase 1 and 2a clinical trial

Summary Background An acquired deficiency of interleukin-2 (IL-2) and related defects in regulatory T cell homeostasis are thought to play a crucial role in the pathogenesis of systemic lupus erythematosus. We hypothesised that reconstitution of regulatory T-cell homoeostasis with low doses of IL-2 would be beneficial to patients with systemic lupus erythematosus. Methods In this uncontrolled, phase 1 and 2a trial done in the Department of Rheumatology and Clinical Immunology at Charite—University Medicine Berlin (Berlin, Germany), we assessed the safety and tolerability of low-dose recombinant human IL-2 (aldesleukin) and its effects on regulatory T cells. We recruited patients aged 18–75 years with a confirmed diagnosis of systemic lupus erythematosus and moderate-to-severe disease activity despite previous treatment with at least two conventional therapies. Patients were given four cycles of low-dose aldesleukin daily for 5 days followed by a 9–16 day rest. The primary endpoints were safety and the number of patients who achieved at least a 100% increase in the proportion of CD25hi-expressing cells among circulating CD3 + CD4 + FOXP3 + CD127lo regulatory T cells at day 62 (ie, after four treatment cycles). Secondary endpoints included disease activity as measured by the Safety of Estrogens in Lupus National Assessment-Systemic Lupus Erythematosus Disease Activity Index (SELENA-SLEDAI) and the British Isles Lupus Assessment Group (BILAG) score, disease flares as measured by the SLEDAI flare index, auto-antibody and complement concentrations at day 62. Exploratory endpoints included various cellular and immunological parameters. The trial is registered with WHO/ICTRP, number DRK4858. Findings Between March 31, 2014, and May 27, 2016, 13 patients were screened, of whom ten met eligibility criteria and were enrolled in the trial. Two additional patients were treated between April 1, 2013, and March 11, 2014, in a compassionate use setting. Eleven (92%) of the 12 patients achieved the primary endpoint. 159 adverse events were recorded, 75 (47%) of which were treatment related. Most treatment-related adverse events were transient and mild to moderate (grade 1–2). The most common adverse event was injection-site reaction (20%). No serious adverse events occurred during the treatment period. In ten (83%) of 12 patients, SELENA-SLEDAI scores were lower at day 62 than at baseline, and no severe disease flares were observed during the treatment period. Decreased disease activity correlated with the magnitude of increase in the proportion of activated regulatory T cells. IL-2 treatment resulted in a preferential proliferation of regulatory T cells that retained suppressive capacity. We observed decreases in cells that are involved in the regulation of germinal-centre reactions. Interpretation Low-dose IL-2 therapy is safe and well tolerated and selectively promotes the expansion of functional regulatory T cells in patients with moderate-to-severe systemic lupus erythematosus. Low-dose IL-2 treatment might also be beneficial in reducing disease activity, although larger trials are needed to address efficacy. Funding German Research Foundation.

253-LB: Effect of Combined Low Dose IL-2 plus Polyclonal Tregs in Type 1 Diabetes Patients

Background: Regulatory T cells (Tregs) have been shown to be master regulators of autoimmunity and, as such, Treg cell-based immunotherapeutics have gained increasing interest. We have previously shown that adoptive Treg cell therapy can block autoimmune destruction of beta-islet cells in mouse type 1 diabetes (T1D) model. In addition, we performed a Phase I clinical trial, infusing in vitro expanded autologous Treg cells into patients with recent onset T1D and demonstrated the good safety profile of the therapy with durable insulin production in about 50% of patients treated. Recently, a number of studies have shown that Interleukin-2 (IL-2) is a potent Treg growth factor that promotes Treg expansion after in vivo treatment in a variety of human diseases. It has been suggested that low doses of IL-2 treatment in vivo, selectively expands Tregs without altering effector T cell or NK populations. Objective: To assess safety of combined Tregs and low dose IL-2 treatment in T1D patients. Methods: A phase I protocol was initiated to treat recently diagnosed T1D patients with a single infusion of ex-vivo expanded autologous polyclonal Tregs followed by two 5-days courses of low dose IL-2. Patients were monitored for safety and diabetes-related metabolic profiles. PBMCs were analyzed at different time points by flow cytometry, CyToF and 10X genomic single cell RNAseq to monitor immune cell activation. Results: The overall safety profile was excellent but all 9 patients treated with the combined therapy failed to maintain c-peptide production at pre-treatment levels. Although expansion of endogenous Tregs was shown, a subset of granzyme B (GZMB) producing CD8+ T and NK subsets also expanded after IL-2 administration. Further analysis revealed clonal proliferation in the CD8+ GZMB+ T cell compartment in several patients. Conclusion: These data suggest that the usage of low dose IL-2 together with polyclonal Tregs infusion may induce deleterious GZMB producing immune cells that will aggravate the progression of T1D. Disclosure S. Dong: None. C.T. Mowery: None. K.C. Herold: Consultant; Self; Provention Bio, Roche Pharma. S.E. Gitelman: Advisory Panel; Self; Avortes, Intermountain Therapeutics, Lilly Diabetes, Tolerion, Inc. Research Support; Self; Caladrius Biosciences, Inc., Janssen Research &amp; Development. Other Relationship; Self; Novo Nordisk Inc. J.H. Esensten: None. W. Liu: None. A.P. Lares: None. A.S. Leinbach: Stock/Shareholder; Self; Johnson &amp; Johnson. M.R. Lee: None. V.Q. Nguyen: None. A.L. Putnam: None. J. Ye: None. Q. Tang: Consultant; Self; Third Rock Venture. Research Support; Self; Immune Tolerance Network, JDRF, Juno Therapeutics/Celgene. J. Bluestone: Board Member; Self; Pfizer. Consultant; Self; Celsius, Kadmon Holdings, Inc., Quentis, Vir. Research Support; Self; Merck &amp; Co., Inc. Stock/Shareholder; Self; Rheos, Solid. Other Relationship; Self; Macrogenics.

Low-Dose IL-2 in the Treatment of Lupus.

Recent extensive research on interleukin-2 (IL-2)/IL-2 receptor (IL-2R) biology has revealed its critical role in the regulation of immune tolerance by influencing regulatory T (Treg) cell functions and survival. Since in vivo low-dose IL-2 administration in humans has been confirmed to be safe and effective in expanding Treg, it is likely that it may be considered for the treatment of several autoimmune diseases including systemic lupus erythematousus (SLE). A recent clinical trial demonstrated the safety and efficacy of low-dose IL-2 treatment on SLE. In SLE, T cells show aberrant function such as deficient IL-2 production and abnormal signaling events. Expansion of Treg by IL-2 represents a specific strategy to control self-tolerance; however, restoration of abnormal immune function and responses should be addressed more carefully in patients with SLE considering the complexity of disease etiology and pathogenesis.

Low-dose interleukin-2 treatment selectively modulates CD4(+) T cell subsets in patients with systemic lupus erythematosus.

Systemic lupus erythematosus (SLE) is a potentially life-threatening autoimmune disease characterized by altered balance of activity between effector and regulatory CD4(+) T cells. The homeostasis of CD4(+) T cell subsets is regulated by interleukin (IL)-2, and reduced production of IL-2 by T cells is observed in individuals with SLE. Here we report that treatment with low-dose recombinant human IL-2 selectively modulated the abundance of regulatory T (Treg) cells, follicular helper T (TFH) cells and IL-17-producing helper T (TH17) cells, but not TH1 or TH2 cells, accompanied by marked reductions of disease activity in patients with SLE.

In Vivo Expansion of Regulatory T Cells by Low-Dose Interleukin-2 Treatment Increases Allograft Survival in Corneal Transplantation

Corneal allograft survival dramatically decreases in hosts with inflamed or vascularized recipient beds. We have previously shown that in rejected corneal allografts regulatory T cells (Treg) demonstrate diminished Foxp3 expression and immunoregulatory function. Treatment with low doses of IL-2 selectively expands Treg and has been proposed for the treatment of autoimmune diseases. In this study, we investigated the effect of low-dose IL-2 administration on Treg function and corneal allograft survival. Allogeneic corneal transplantation was performed on inflamed host beds. Low-dose systemic IL-2 was administered starting 3 days before grafting until 6 weeks after transplantation. Frequencies of Treg and their immunosuppressive function and antigen specificity were assessed using flow cytometry, in vitro proliferation assays, and adoptive transfer experiments. Frequencies of effector T cells (Teff) and graft infiltrating immune cells were measured at 2 weeks posttransplantation. Long-term allograft survival was evaluated for up to 9 weeks using Kaplan-Meier survival analysis. Treatment with low-dose IL-2 significantly increased frequencies of CD4CD25Foxp3 Treg and their immunosuppressive function. It also suppressed alloimmune response as shown by the decreased CD4 IFNγ T cell frequencies and graft infiltration of CD45 and CD4 cells. Clinical evaluation of the grafts showed significant improvement in long-term corneal allograft survival in the IL-2 treated group compared with controls. Our study is the first to report that treatment with low-dose IL-2 increases survival of corneal allografts. We propose that IL-2-mediated Treg expansion can be an effective tool to prevent alloimmunity and to improve long-term allograft survival in transplantation.

Low-dose interleukin-2 as a regulatory immunotherapy for systemic lupus erythematosus

Accumulating evidence that interleukin-2 (IL-2) is requisite for the maintenance and expansion of regulatory T cells (Treg) has yielded low-dose IL-2 therapy for several autoimmune diseases such as type 1 diabetes and systemic lupus erythematosus (SLE) (1,2). He and colleagues recently reported in Nat Med the efficacy of low-dose IL-2 treatment in 38 active SLE patients (3). They described that IL-2 treatment significantly ameliorated the clinical severity associated with expansion of Treg and decrease of follicular helper T (T FH ) cells and IL-17-producing helper T (T H 17) cells.

Low Dose of Interleukin-2 Therapy Could Prevent Chronic Graft-Versus-Host Disease: A Randomized Study

Acknowledgments: This study was supported by the grants from the National Natural Science Foundation of China (Grant No. 81270644 and 81230013), the Major State Basic Research Development Program of China (973 Program No. 2013CB733700), doctoral funding from The Ministry of Education of China (grant no. 20110001110039) and collaborative innovation center of Hematology, China. The authors thank all of the core facilities at the Peking University Institute of Hematology for sample collection.Background: There were good evidences that natural killer cells and T regulatory cells, which were expanded and stimulated by the application of interleukin-2 (IL-2). It was found that low dose of IL-2 administration was associated with preferential, sustained Treg cell expansion in vivo and amelioration of the manifestations of chronic graft-versus-host disease (GVHD).The aim of this randomized study were to confirm that low dose of IL-2 early application post transplantation can prevent chronic GvHD occurrence following allogeneic hematopoietic stem cell transplantation (all-HSCT) in patients with standard risk acute leukemia.Methods: This was a single-centre, prospective, open-label, randomized control trial. Standard risk leukemia patients over 15 years old (except Ph+ ALL and T-ALL) undergone unmanipulated blood and marrow allo-HSCT following day 60 post-transplantation were randomly assigned (in a 1:1 ratio, by a computer-generated randomisation list) into treated group (with low dose IL-2 treatment) or controlled group (without any intervention post-transplantation). Interleukin-2 treatment (daily 1¡Á106IU per square meter of body-surface area) repeats every 14 days for 4 to 6 courses in the absence of disease progression or unacceptable toxicity. Blood tests were performed before IL2 treatment and weekly for the first two weeks and then every other week until the completion of 6 course therapy to monitor the immunologic impact of ultra-low dose subcutaneous IL-2 in patients after transplantation.Results: This study begins at Jan 2012, and 360 patients were estimated to enroll. Interim analyses were planned post near 25% of total numbers of patients¡¯ enrollment. Until July16th, 2014, there were 88 patients (43 patients in test group and 45 patients in control group) were randomized in this trial. The follow-up of 79 patients exceeded 180 days. Interim analysis showed that the cumulative incidence of sever chronic GVHD in IL2 group were significantly lower than those in control group (P=0.05, Figure 1A), meanwhile, transplantation related mortality (TRM) were also lower in IL2 group compared to those in control group (P=0.04, Figure 1B). No significantly differences were found in cumulative incidence of relapse between IL2 group and control group. The overall survival of two groups was comparable. Low dose of IL-2 in vivo application augmented reconstituted CD4+CD25highCD127-/low T regulatory cells and natural killer cells. Meanwhile, cytotoxicity of NK cells in IL2 group was significantly higher than the control group during the IL2 treatment period. IL2 therapy has no effect on reconstitution of absolute number of CD3+T cells, CD4+ T cells, CD8+ T cells, as well as conventional T cells, Th1 cells, Th17 cells reconstitution.Conclusion: Low dose of IL2 could expand CD4+CD25highCD127-/lowT regulatory cells and natural killer cells and prevent chronic graft-versus-host disease. This trial is registered with ClinicalTrials.gov, number NCT01517347. [Display omitted] DisclosuresNo relevant conflicts of interest to declare.

Low-dose interleukin-2 therapy: a driver of an imbalance between immune tolerance and autoimmunity.

For many years, the role of interleukin-2 (IL-2) in autoimmune responses was established as a cytokine possessing strong pro-inflammatory activity. Studies of the past few years have changed our knowledge on IL-2 in autoimmune chronic inflammation, suggesting its protective role, when administered at low-doses. The disrupted balance between regulatory and effector T cells (Tregs and Teffs, respectively) is a characteristic of autoimmune diseases, and is dependent on homeostatic cytokines, including IL-2. Actually, inherent defects in the IL-2 signaling pathway and/or levels leading to Treg compromised function and numbers as well as Th17 expansion have been attributed to autoimmune disorders. In this review, we discuss the role of IL-2 in the pathogenesis of autoimmune diseases. In particular, we highlight the impact of the dysregulated IL-2 pathway on disruption of the Treg/Th17 balance, reversal of which appears to be a possible mechanism of the low-dose IL-2 treatment. The negative effects of IL-2 on the differentiation of follicular helper T cells (Tfh) and pathogenic Th17 cells, both of which contribute to autoimmunity, is emphasized in the paper as well. We also compare the current IL-2-based therapies of animal and human subjects with immune-mediated diseases aimed at boosting the Treg population, which is the most IL-2-dependent cell subset desirable for sufficient control of autoimmunity. New perspectives of therapeutic approaches focused on selective delivery of IL-2 to inflamed tissues, thus allowing local activity of IL-2 to be combined with its reduced systemic and pleiotropic toxicity, are also proposed in this paper.

Sustained stimulation and expansion of Tregs by IL2 control autoimmunity without impairing immune responses to infection, vaccination and cancer

Interleukin 2 (IL2) is the key cytokine supporting survival and function of regulatory T cells (Tregs). We recently reported that low-dose IL2 safely expands/stimulates Tregs and improves autoimmune conditions in humans. Further development of IL2 in autoimmune diseases will require chronic IL2 administration, which could affect beneficial effector immune responses regulated by Tregs. We used recombinant adeno-associated viral vector (rAAV)-mediated gene transfer to continuously release IL2 in mice and assessed its long-term effects on immune responses. A single rAAV-IL2 injection enabled sustained stimulation and expansion of Tregs without inducing Teff activation and prevented diabetes in NOD mice. After several weeks of IL2 production, mice responded normally to a viral challenge and to vaccination, and had pregnancies with offspring that developed normally. They showed no change in the occurrence and growth of chemically-induced tumors. Altogether, chronic low-dose IL2 treatment does not affect beneficial effector immune responses at doses that prevent autoimmune diabetes.