scholarly journals SAT0163 Absolute number of peripheral cd4-cd25+foxp3+t cells decreases and restores after low-dose interleukin-2 treatment in rheumatoid arthritis

2018 ◽  
Author(s):  
X. Jia ◽  
H. An ◽  
K. Fan ◽  
F. Li ◽  
C. Gao ◽  
...  
Keyword(s):  
Rheumatoid Arthritis ◽  
T Cells ◽  
Low Dose ◽  
Interleukin 2 ◽  
Absolute Number

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.

scholarly journals Low-Dose IL-2 Therapy Limits the Reduction in Absolute Numbers of Circulating Regulatory T Cells in Rheumatoid Arthritis

2020 ◽  
Author(s):  
Sheng-Xiao Zhang ◽  
Jia Wang ◽  
Cai-Hong Wang ◽  
Rui-Huan Jia ◽  
Ming Yan ◽  
...  
Keyword(s):  
Rheumatoid Arthritis ◽  
T Cells ◽  
Side Effects ◽  
Regulatory T Cells ◽  
Disease Activity ◽  
Immune Tolerance ◽  
Low Dose ◽  
Interleukin 2 ◽  
Fold Increase ◽  
T Subsets

Abstract 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 of at 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.Conclusions 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.

scholarly journals AB0588 INFECTION AGGRAVATED DECREASE OF THE LEVEL OF TH17 AND TREG CELLS AND LOW-DOSE IL-2 REBALANCED TH17/TREG IN THE PERIPHERAL BLOOD OF PATIENTS WITH IDIOPATHIC INFLAMMATORY MYOPATHY

2020 ◽  
Vol 79 (Suppl 1) ◽  
pp. 1591.3-1591
Author(s):  
Y. Liang ◽  
H. Y. Wen ◽  
Y. Duan ◽  
Y. Liu ◽  
Z. Yu ◽  
...  
Keyword(s):  
T Cells ◽  
Low Dose ◽  
Lymphocyte Subsets ◽  
Absolute Number ◽  
Treg Cells ◽  
Idiopathic Inflammatory Myopathies ◽  
Inflammatory Myopathies ◽  
Infection Group ◽  
The Absolute ◽  
Organ Infection

Background:Idiopathic inflammatory myopathies (IIM) are featured by a series of clinical presentation such as proximal muscle weakness, increased serum levels of creatine kinase and other muscle enzymes and involvement of other organs and systems[1, 2], which results in high morbidity and early mortality[3]. We have known the changes of the level of Th17 and Treg cells in IIM in previous studies[4-6]. However, whether infection affects lymphocyte subsets or not and whether the effect of low-dose interleukin-2 (IL-2) can be influenced by the use of immunosuppressants or not are still unclear.Objectives:The study aimed to explore the changes of lymphocyte subsets in patients of IIM with or without important organ infection, and the restoration of Th17/Treg after receiving low-dose IL-2.Methods:A total of 118 IIM patients were enrolled and classified into infection group and non-infection group based on the important organ infection. Of them, 48 cases were treated with low dose IL-2 (5.0*105IU for 5 days). The absolute number of peripheral total T, B, CD4+T, CD8+T, NK, Th1, Th2, Th17 and Treg cell subsets were analyzed by flow cytometry combined with absolute counting beads. Clinical data, laboratory examinations and the levels of peripheral lymphocyte subsets were analyzed retrospectively.Results:In these patients, especially in the infection group, the absolute number of T, CD4+T, CD8+T, NK, Th1, Th2, Th17 and Treg cells were significantly decreased as compared with that in the healthy controls, which were significantly increased by low dose IL-2 (especially Treg cells) treatment. The levels of ESR, LDH and HBDH and the ratio of Th17/Treg were significantly lower than those before IL-2 treatment (Z=-2.237, -2.083, -2.140, -3.663,P=0.025, 0.037, 0.032, 0.000). The 48 cases who received IL-2 treatment were divided into 2 groups according to whether they used immunosuppressants. There was no significant difference in the absolute number of T, B, CD4+T, CD8+T, Th1, Th2, Th17 and Treg cells, the proportion of Th17 and Treg cells and the ratio of Th17/Treg between the 2 groups (P>0.05).Conclusion:Global decrease in lymphocyte subsets was found in IIM patients, especially those who had important organ infection. A significant re-balance of Th17/Treg was observed after receiving treatment with low-dose IL-2. Furthermore, the restoration of lymphocyte subsets showed similar degree after treatment with or without immunosuppressants. Low-dose IL-2 may become a potential therapy for IIM patients. The mechanism of lymphocyte decrease in IIM is required further to study.References:[1]Clark K E N, Isenberg D A. A review of inflammatory idiopathic myopathy focusing on polymyositis[J]. European Journal of Neurology, 2017.[2]Tieu J, Lundberg IE, Limaye V. Idiopathic inflammatory myositis. Best Pract Res Clin Rheumatol. 2016. 30(1): 149-68.[3]Mandel DE, Malemud CJ, Askari AD. Idiopathic Inflammatory Myopathies: A Review of the Classification and Impact of Pathogenesis. Int J Mol Sci. 2017. 18(5).[4]Zhang SX, Wang J, Sun HH, et al. Circulating regulatory T cells were absolutely decreased in dermatomyositis/polymyositis patients and restored by low-dose IL-2. Ann Rheum Dis. 2019 .[5]Espinosa-Ortega F, Gómez-Martin D, Santana-De Anda K, Romo-Tena J, Villaseñor-Ovies P, Alcocer-Varela J. Quantitative T cell subsets profile in peripheral blood from patients with idiopathic inflammatory myopathies: tilting the balance towards proinflammatory and pro-apoptotic subsets. Clin Exp Immunol. 2015. 179(3): 520-8.[6]Feng M, Guo H, Zhang C, et al. Absolute reduction of regulatory T cells and regulatory effect of short-term and low-dose IL-2 in polymyositis or dermatomyositis. Int Immunopharmacol. 2019. 77: 105912.Acknowledgments:Thanks for the support of my teachers, classmates and my family.Disclosure of Interests:None declared

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

2021 ◽  
Vol 13 ◽  
pp. 1759720X2110113
Author(s):  
Sheng-Xiao Zhang ◽  
Jia Wang ◽  
Cai-Hong Wang ◽  
Rui-Huan Jia ◽  
Ming Yan ◽  
...  
Keyword(s):  
Rheumatoid Arthritis ◽  
T Cells ◽  
Side Effects ◽  
Regulatory T Cells ◽  
Disease Activity ◽  
Immune Tolerance ◽  
Low Dose ◽  
Fold Increase ◽  
Plain Language ◽  
T Subsets

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.

scholarly journals Restoration of HBV-specific CD8+ T-cell responses by sequential low-dose IL-2 treatment in non-responder patients after IFN-α therapy

2021 ◽  
Vol 6 (1) ◽  
Author(s):  
Dongyao Wang ◽  
Binqing Fu ◽  
Xiaokun Shen ◽  
Chuang Guo ◽  
Yanyan Liu ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
Hepatitis B ◽  
Immune Function ◽  
Low Dose ◽  
Hbeag Seroconversion ◽  
Interleukin 2 ◽  
Unmet Need ◽  
T Cell Response ◽  
Serological Response

AbstractPatients with chronic hepatitis B (CHB) undergoing interferon (IFN)-α-based therapies often exhibit a poor HBeAg serological response. Thus, there is an unmet need for new therapies aimed at CHB. This study comprised two clinical trials, including 130 CHB patients, who were treatment-naïve; in the first, 92 patients were systematically analyzed ex vivo for interleukin-2 receptor (IL-2R) expression and inhibitory molecules expression after receiving Peg-IFN-α-2b therapy. In our second clinical trial, 38 non-responder patients, in whom IFN-α therapy had failed, were treated with or without low-dose IL-2 for 24 weeks. We then examined the hepatitis B virus (HBV)-specific CD8+ T-cell response and the clinical outcome, in these patients. Although the majority of the participants undergoing Peg-IFN-α-2b therapy were non-responders, we observed a decrease in CD25 expression on their CD4+ T cells, suggesting that IFN-α therapy may provide a rationale for sequential IL-2 treatment without increasing regulatory T cells (Tregs). Following sequential therapy with IL-2, we demonstrated that the non-responders experienced a decrease in the numbers of Tregs and programmed cell death protein 1 (PD-1) expression. In addition, sequential IL-2 administration rescued effective immune function, involving signal transducer and activator of transcription 1 (STAT1) activation. Importantly, IL-2 therapy significantly increased the frequency and function of HBV-specific CD8+ T cells, which translated into improved clinical outcomes, including HBeAg seroconversion, among the non-responder CHB patients. Our findings suggest that sequential IL-2 therapy shows efficacy in rescuing immune function in non-responder patients with refractory CHB.

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