scholarly journals THU0051 LOW-DOSE INTERLEUKIN-2 SELECTIVELY EXPAND AND ACTIVATE REGULATORY T CELLS ACROSS 13 AUTOIMMUNE DISEASES.

2020 ◽  
Vol 79 (Suppl 1) ◽  
pp. 237.1-238
Author(s):  
M. Rosenzwajg ◽  
R. Lorenzon ◽  
P. Cacoub ◽  
F. Pitoiset ◽  
S. Aractingi ◽  
...  
Keyword(s):  
T Cells ◽  
Regulatory T Cells ◽  
Autoimmune Diseases ◽  
Inflammatory Disease ◽  
Low Dose ◽  
Therapeutic Potential ◽  
Interleukin 2 ◽  
Clinical Effects ◽  
Research Support ◽  
Open Label

Background:Regulatory T cells (Tregs) prevent autoimmunity and control inflammation. As low-dose interleukin-2 (ld-IL2) expands and activates Tregs, it has a broad therapeutic potential for any autoimmune or inflammatory disease (AIID). We performed a disease-finding “basket trial” (TRANSREGNCT01988506) in patients affected by one of 11 different AIID and reported the outcome of the first 46 patients (Rosenzwajg et al, ARD 2019).Objectives:Here we analyzed and discussed results from deep immunophenotyping, of 78 patients, to comprehensively study the effect of ld-IL2 on the immune system of patients affected by various AIIDMethods:We performed a prospective, open label, phase I-IIa study in 78 patients with a mild to moderate form of one of 13 selected AIID. All patients received ld-IL2 (1 million IU/day) for 5 days, followed by fortnightly injections for 6 months. Deep immunophenotyping was performed before and after 5 days of ld-IL2.Results:ld-IL2 significantly expands both memory Tregs as well as naïve Tregs, including recent thymic emigrant Tregs. It also activates Tregs as demonstrated by the significantly increased expression of HLA-DR, CD39, CD73, GITR, CTLA-4. Similar results were observed across the different AIID.Conclusion:ld-IL2 “universally” improves Treg fitness across 13 autoimmune and inflammatory disease.References:[1]Rosenzwajg M#, Lorenzon R#, Cacoub P, Pham HP, Pitoiset F, El Soufi K, RIbet C, Bernard C, Aractingi S, Banneville B, Beaugerie L, Berenbaum F, Champey J, Chazouilleres O, Corpechot C, Fautrel B, Mekinian A, Regnier E, Saadoun D, Salem JE, Sellam J, Seksik P, Daguenel-Nguyen A, Doppler V, Mariau J, Vicaut E, Klatzmann D. Immunological and clinical effects of low-dose interleukin-2 across 11 autoimmune diseases in a single, open clinical trial. Ann Rheum Dis. 2019 Feb;78(2):209-217. doi: 10.1136/annrheumdis-2018-214229. Epub 2018 Nov 24.Disclosure of Interests:Michelle Rosenzwajg: None declared, Roberta Lorenzon: None declared, Patrice cacoub: None declared, Fabien Pitoiset: None declared, Selim Aractingi: None declared, Beatrice Banneville Speakers bureau: Lilly, Novartis, Laurent Beaugerie: None declared, Francis Berenbaum Grant/research support from: TRB Chemedica (through institution), MSD (through institution), Pfizer (through institution), Consultant of: Novartis, MSD, Pfizer, Lilly, UCB, Abbvie, Roche, Servier, Sanofi-Aventis, Flexion Therapeutics, Expanscience, GSK, Biogen, Nordic, Sandoz, Regeneron, Gilead, Bone Therapeutics, Regulaxis, Peptinov, 4P Pharma, Paid instructor for: Sandoz, Speakers bureau: Novartis, MSD, Pfizer, Lilly, UCB, Abbvie, Roche, Servier, Sanofi-Aventis, Flexion Therapeutics, Expanscience, GSK, Biogen, Nordic, Sandoz, Regeneron, Gilead, Sandoz, Julien Champey: None declared, Olivier Chazouilleres: None declared, Christophe Corpechot: None declared, Bruno Fautrel Grant/research support from: AbbVie, Lilly, MSD, Pfizer, Consultant of: AbbVie, Biogen, BMS, Boehringer Ingelheim, Celgene, Lilly, Janssen, Medac MSD France, Nordic Pharma, Novartis, Pfizer, Roche, Sanofi Aventis, SOBI and UCB, Arsene Mekinian: None declared, Elodie Regnier: None declared, david Saadoun: None declared, Joe-Elie Salem: None declared, Jérémie SELLAM: None declared, Philippe Seksik: None declared, David Klatzmann Consultant of: ILTOO Pharma

scholarly journals Immunological and clinical effects of low-dose interleukin-2 across 11 autoimmune diseases in a single, open clinical trial

2018 ◽  
Vol 78 (2) ◽  
pp. 209-217 ◽  
Author(s):  
Michelle Rosenzwajg ◽  
Roberta Lorenzon ◽  
Patrice Cacoub ◽  
Hang Phuong Pham ◽  
Fabien Pitoiset ◽  
...  
Keyword(s):  
Clinical Trial ◽  
Autoimmune Diseases ◽  
Clinical Efficacy ◽  
T Cell Activation ◽  
Lupus Erythematosus ◽  
Cell Activation ◽  
Low Dose ◽  
Therapeutic Potential ◽  
Interleukin 2 ◽  
Clinical Effects

ObjectiveRegulatory T cells (Tregs) prevent autoimmunity and control inflammation. Consequently, any autoimmune or inflammatory disease reveals a Treg insufficiency. As low-dose interleukin-2 (ld-IL2) expands and activates Tregs, it has a broad therapeutic potential.AimWe aimed to assess this potential and select diseases for further clinical development by cross-investigating the effects of ld-IL2 in a single clinical trial treating patients with 1 of 11 autoimmune diseases.MethodsWe performed a prospective, open-label, phase I–IIa study in 46 patients with a mild to moderate form of either rheumatoid arthritis, ankylosing spondylitis, systemic lupus erythematosus, psoriasis, Behcet’s disease, granulomatosis with polyangiitis, Takayasu’s disease, Crohn’s disease, ulcerative colitis, autoimmune hepatitis and sclerosing cholangitis. They all received ld-IL2 (1 million IU/day) for 5 days, followed by fortnightly injections for 6 months. Patients were evaluated by deep immunomonitoring and clinical evaluation.Resultsld-IL2 was well tolerated whatever the disease and the concomitant treatments. Thorough supervised and unsupervised immunomonitoring demonstrated specific Treg expansion and activation in all patients, without effector T cell activation. Indication of potential clinical efficacy was observed.ConclusionThe dose of IL-2 and treatment scheme used selectively activate and expand Tregs and are safe across different diseases and concomitant treatments. This and preliminary indications of clinical efficacy should licence the launch of phase II efficacy trial of ld-IL2 in various autoimmune and inflammatory diseases.Trial registration numberNCT01988506.

scholarly journals The numbers of peripheral regulatory T cells are reduced in patients with psoriatic arthritis and are restored by low-dose interleukin-2

2020 ◽  
Vol 11 ◽  
pp. 204062232091601 ◽  
Author(s):  
Jia Wang ◽  
Sheng-Xiao Zhang ◽  
Yu-Fei Hao ◽  
Meng-Ting Qiu ◽  
Jing Luo ◽  
...  
Keyword(s):  
T Cells ◽  
Psoriatic Arthritis ◽  
Regulatory T Cells ◽  
Low Dose ◽  
Interleukin 2 ◽  
Health Assessment ◽  
Life Quality ◽  
T Cell Subsets ◽  
Physician Global Assessment ◽  
Disease Indicators

Background: Although regulatory T cells (Tregs) play crucial roles in the maintenance of immune hemostasis, the numbers of peripheral Tregs in patients with psoriatic arthritis (PsA) remain unclear. We measured these numbers and the efficacy and safety of low-dose interleukin-2 (IL-2) therapy. Methods: We recruited 95 PsA patients, of whom 22 received subcutaneous low-dose IL-2 [0.5 million international units (MIU) per day for 5 days] combined with conventional therapies. The absolute numbers of cells in peripheral CD4+ T cell subsets were measured via modified flow cytometry. Clinical and laboratory indicators were compared before and after treatment. Results: PsA patients had lower peripheral Treg numbers than healthy controls ( p < 0.01), correlating significantly and negatively with the levels of disease indicators ( p < 0.05). Although low-dose IL-2 significantly increased the Th17 and Treg numbers in PsA patients compared with the baseline values, the Treg numbers rose much more rapidly than those of Th17 cells, re-balancing the Th17 and Treg proportions. Low-dose IL-2 combination therapy rapidly reduced PsA disease activities as indicated by the DAS28 instrument, thus the number of tender joints, visual analog scale pain, physician global assessment, the dermatology life quality index score, and the health assessment questionnaire score (all p < 0.05). Conclusion: PsA patients exhibited low Treg numbers. Low-dose IL-2 combination treatment increased these numbers and relieved disease activity without any apparent side effects. Additional studies are required to explore the long-term immunoregulatory utility of IL-2 treatment.

Low-dose Interleukin-2 in the Treatment of Autoimmune Disease

2014 ◽  
Vol 10 (02) ◽  
pp. 157 ◽  
Author(s):  
John Koreth ◽  
Jerome Ritz ◽  
George C Tsokos ◽  
Alberto Pugliese ◽  
Thomas R Malek ◽  
...  
Keyword(s):  
T Cells ◽  
Autoimmune Diseases ◽  
Lupus Erythematosus ◽  
Low Dose ◽  
Cell Function ◽  
Interleukin 2 ◽  
The Us ◽  
High Doses ◽  
And Function ◽  
Preclinical And Clinical Studies

CD4+ regulatory T cells (Tregs) act to maintain peripheral immune tolerance. Decreased numbers or defective function of Tregs has been implicated in the pathogenesis of various autoimmune diseases. Interleukin-2 (IL-2) at high doses is approved by the US Food and Drug Administration (FDA) as an immune stimulant to induce anti-tumor cytotoxicity. However, at physiologic doses, IL-2 is necessary for the expansion and function of Tregs. Treatment with low-dose IL-2 can selectively enhance Treg function while avoiding the activation of effector T cells and ameliorate immune inflammation. Administration of low doses of IL-2 to patients suffering from chronic graft versus host disease (cGvHD) or chronic hepatitis C-mediated vasculitis resulted in significant clinical benefit, which was linked to improved Treg cell function. Preclinical studies suggest that low-dose IL-2 may offer benefit in other autoimmune diseases including systemic lupus erythematosus and type 1 diabetes. Ongoing preclinical and clinical studies indicate a wider potential role for low-dose IL-2 based Treg therapeutics in human autoimmune diseases.

scholarly journals Targeting regulatory T cells with Interleukin-2 treatment in type 1 diabetes: a response-adaptive, non-randomised, open-label trial of repeat doses of Aldesleukin (DILfrequency)

2017 ◽  
Author(s):  
Eleonora Seelig ◽  
James Howlett ◽  
Linsey Porter ◽  
Lucy Truman ◽  
James Heywood ◽  
...  
Keyword(s):  
T Cells ◽  
Type 1 Diabetes ◽  
Steady State ◽  
Regulatory T Cells ◽  
Interleukin 2 ◽  
Dose Frequency ◽  
Open Label ◽  
Adaptive Trial ◽  
Optimal Regimen

SummaryBackgroundType 1 diabetes (T1D) results from loss of immune regulation leading to the development of autoimmunity to pancreatic beta-cells, involving autoreactive T effector cells (Teffs). Regulatory T cells (Tregs), that prevent autoimmunity, require Interleukin-2 (IL-2) for maintenance of immunosuppressive functions and, alterations in the IL-2 pathway predispose to T1D. Using an adaptive trial design we aimed to determine the optimal regimen of aldesleukin (recombinant human IL-2) to physiologically enhance Tregs while limiting expansion of autoreactive Teffs.MethodsDILfrequency is a single-center, non-randomised, open-label, response-adaptive study of participants aged 18 to 70 years with T1D. The initial learning phase allocated 12 participants to six different predefined dose-frequency regimens. Then, three cohorts of 8 participants were sequentially allocated dose-frequencies, based on repeated interim analyses of all accumulated trial data. The co-primary endpoints were percentage change in Tregs, Teffs and, CD25 (α subunit of the IL-2 receptor) expression by Tregs, from baseline to steady state. Trial registration ISRCTN40319192 and ClinicalTrials.gov (NCT02265809).Findings115 participants were assessed between November 17th 2014 and May 22nd 2016, 38 participants were enrolled with 36 completing treatment. The optimal regimen to maintain a steady state increase in Tregs of 30% and CD25 expression of 25% without Teff expansion is 0.26 × 106 IU/m2 (95% CI (−0.007 to 0.485)) every 3 days (1.3 to 4.4). Tregs and CD25 were dose-frequency responsive, while Teffs were not. The commonest adverse event was injection site reaction (464/694 events), with a single participant developing transient eosinophilia at the highest dose (0.47 × 106 IU/m2).InterpretationThis response-adaptive trial defined a well-tolerated aldesleukin regimen that specifically induces Treg expansion that can now be trialled to treat T1D.FundingSir Jules Thorn Trust, Wellcome, JDRF, SNSF, NIHR

Low-dose interleukin-2 expands the number of circulating regulatory T cells in patients with treatment-refractory autoimmune hepatitis

2018 ◽  
Vol 68 ◽  
pp. S460-S461
Author(s):  
T.Y. Lim ◽  
E. Codela ◽  
E. Gray ◽  
M. Heneghan ◽  
M. Martinez-Llordella ◽  
...  
Keyword(s):  
T Cells ◽  
Regulatory T Cells ◽  
Autoimmune Hepatitis ◽  
Low Dose ◽  
Interleukin 2 ◽  
Treatment Refractory

Effects of Daily Low Dose IL-2 Therapy on Homeostatic Regulation of CD4+Foxp3+ Regulatory T Cells In Patients with Chronic Graft-Versus-Host Disease

Blood ◽  
2010 ◽  
Vol 116 (21) ◽  
pp. 895-895
Author(s):  
Ken-ichi Matsuoka ◽  
John Koreth ◽  
Haesook T. Kim ◽  
O. Gregory Bascug ◽  
Sean McDonough ◽  
...  
Keyword(s):  
T Cells ◽  
Regulatory T Cells ◽  
Low Dose ◽  
Interleukin 2 ◽  
Absolute Number ◽  
Dependent Manner ◽  
Ki 67 ◽  
Hematopoietic Stem ◽  
Baseline Levels ◽  
The Absolute

Abstract Abstract 895 CD4+FoxP3+ regulatory T cells (Treg) play a central role in the maintenance of tolerance after allogeneic hematopoietic stem cell transplantation (HSCT) and recent studies have demonstrated that Treg deficiency leads to the development of chronic GHVD (cGVHD). Interleukin-2 (IL-2) is known to promote thymic generation and maintenance of peripheral Treg and IL-2 deficiency results in a profound deficiency of Treg in vivo. Based on these findings we initiated a clinical trial to evaluate the safety, clinical efficacy and immunologic effects of low dose recombinant IL-2 in patients with steroid-refractory cGVHD. We recently reported the clinical outcomes of this trial demonstrating that IL-2 administration preferentially increased Treg in patients with active cGVHD and resulted in clinical improvement with only minor toxicities (Koreth et al, ASBMT 2010). However, the mechanisms responsible for Treg expansion in patients during IL-2 administration have not been characterized. To elucidate these mechanisms, we examined phenotypic and functional characteristics of Treg in 14 patients who received daily subcutaneous IL-2 (3×105-3×106IU/m2/day) for 8 weeks. Peripheral blood samples were obtained before and at 1, 2, 4, 6, 8, 10 and 12 weeks after starting IL-2. Treg were compared to conventional CD4+FoxP3- T cells (Tcon) within individual patient samples and examined for expression of Ki-67, PD-1 and BCL-2. In some experiments, Treg and Tcon were further divided into subpopulations by the expression of CD45RA and CD31. Absolute numbers of functionally suppressive Treg increased 5-fold in the first 4 weeks of therapy. Treg numbers then slowly decreased despite continued IL-2 therapy, but remained 2-fold higher than baseline at 8 weeks. Absolute numbers of Tcon increased 2-fold in the first 4 weeks and then returned to baseline levels at 8 weeks. This resulted in a sustained increase of Treg/Tcon ratio for the entire duration of therapy, which persisted for at least 4 weeks after treatment was completed. Plasma IL-2 levels peaked at 1 week and gradually declined despite continued treatment at the same dose. Nevertheless, IL-2 levels remained significantly higher than baseline throughout treatment (median 1.4pg/ml at baseline and 18.1pg/ml at 8 weeks, p<0.05). The proliferative response to IL-2 was examined by measuring expression of Ki-67 in each subset. Initially, Ki-67 expression in Treg rapidly increased in an IL-2 dose-dependent manner. Ki-67 also increased in Tcon but at a significantly lower level (median 20.0% Treg vs 6.7% Tcon, p=0.0001). Increased Ki-67 was seen in both CD45RA+CD31+ recent thymic emigrant Treg (RTE-Treg) and CD45RA- activated/memory Treg (MEM-Treg) at similar levels (median 20.1% and 18.5%, respectively, p=0.54). Treg proliferation peaked in the first week of IL-2, and rapidly returned to baseline levels in weeks 2–3. Despite changes in proliferation, the absolute number of RTE-Treg remained significantly elevated (median 1.05/ul at baseline, 9.43/ul at 4 weeks, p=0.001). In contrast, the absolute number of RTE-Tcon did not change. Phenotypic analysis of Treg showed that expression of both PD-1 and BCL-2 increased during IL-2 therapy (%PD-1+ Treg; median 15.7% at baseline and 38.3% at 8 weeks, p=0.02: relative BCL-2 MFI; median 1.00 at baseline and 1.59 at 8 weeks, p=0.04). To determine the functional effects of these changes on susceptibility to apoptosis, Treg and Tcon were purified and cultured with or without agonistic FAS antibody, and apoptosis was measured using Annexin-V staining. Remarkably, Treg obtained during IL-2 therapy were relatively resistant to apoptosis compared to baseline. In summary, these results indicate that the selective expansion of Treg during prolonged IL-2 administration is characterized by a series of homeostatic changes. Initial high levels of IL-2 lead to selective and rapid Treg proliferation. Treg proliferation is not maintained as numbers of Treg increase and IL-2 levels decrease. Subsequent maintenance of increased Treg appears to be mediated primarily by increased resistance to apoptosis and prolonged survival. Increased thymic output of Treg also appears to support this peripheral homeostatic process. These findings demonstrate the complex effects of IL-2 on Treg homeostasis and provide important information for developing strategies to promote immune tolerance. Disclosures: No relevant conflicts of interest to declare.

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