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Frontiers in Immunology 2021Regulatory T cells (Treg) are crucial for the maintenance of peripheral tolerance and for the control of ongoing inflammation and autoimmunity. The cytokine... (Review)
Review
Regulatory T cells (Treg) are crucial for the maintenance of peripheral tolerance and for the control of ongoing inflammation and autoimmunity. The cytokine interleukin-2 (IL-2) is essentially required for the growth and survival of Treg in the peripheral lymphatic tissues and thus plays a vital role in the biology of Treg. Most autoimmune and rheumatic diseases exhibit disturbances in Treg biology either at a numerical or functional level resulting in an imbalance between protective and pathogenic immune cells. In addition, in some autoimmune diseases, a relative deficiency of IL-2 develops during disease pathogenesis leading to a disturbance of Treg homeostasis, which further amplifies the vicious cycle of tolerance breach and chronic inflammation. Low-dose IL-2 therapy aims either to compensate for this IL-2 deficiency to restore a physiological state or to strengthen the Treg population in order to be more effective in counter-regulating inflammation while avoiding global immunosuppression. Here we highlight key findings and summarize recent advances in the clinical translation of low-dose IL-2 therapy for the treatment of autoimmune and rheumatic diseases.
Topics: Animals; Autoimmune Diseases; Humans; Immune Tolerance; Immunotherapy; Interleukin-2; Mice; Rheumatic Diseases; T-Lymphocytes, Regulatory; Treatment Outcome
PubMed: 33868284
DOI: 10.3389/fimmu.2021.648408 -
Clinical Immunology (Orlando, Fla.) Sep 2020The interleukin (IL)-2 - IL-2 receptor (IL-2R) pathway is important in immunity, but is also involved in maintenance of self-tolerance. This paradox is further... (Review)
Review
The interleukin (IL)-2 - IL-2 receptor (IL-2R) pathway is important in immunity, but is also involved in maintenance of self-tolerance. This paradox is further complicated by shedding of the IL-2Rα chain, revealing soluble (s)IL-2R. Binding of IL-2 to sIL-2R may either reduce or enhance responses depending on the target cell being involved in immunity or self-tolerance. Since sIL-2R levels are increasingly measured in clinical practice, it is detrimental for clinical interpretation to understand the possible functional impact of IL-2R shedding. In this review the role of the IL-2 - IL-2R pathway is explored and the conflicting results on the function of sIL-2R are summarized. Finally, the added value of measuring sIL-2R in different types of diseases is being elaborated upon in terms of diagnosis, follow-up, and prognosis. Adequate interpretation of results is hampered by the apparent gap in our knowledge about the functional role of sIL-2R in immunity and tolerance.
Topics: Animals; Disease; Health; Humans; Interleukin-2; Receptors, Interleukin-2; Signal Transduction
PubMed: 32619646
DOI: 10.1016/j.clim.2020.108515 -
Annals of the Rheumatic Diseases Jan 2020Open-labelled clinical trials suggested that low-dose IL-2 might be effective in treatment of systemic lupus erythematosus (SLE). A double-blind and placebo-controlled... (Randomized Controlled Trial)
Randomized Controlled Trial
OBJECTIVES
Open-labelled clinical trials suggested that low-dose IL-2 might be effective in treatment of systemic lupus erythematosus (SLE). A double-blind and placebo-controlled trial is required to formally evaluate the safety and efficacy of low-dose IL-2 therapy.
METHODS
A randomised, double-blind and placebo-controlled clinical trial was designed to treat 60 patients with active SLE. These patients received either IL-2 (n=30) or placebo (n=30) with standard treatment for 12 weeks, and were followed up for additional 12 weeks. IL-2 at a dose of 1 million IU or placebo was administered subcutaneously every other day for 2 weeks and followed by a 2-week break as one treatment cycle. The primary endpoint was the SLE Responder Index-4 (SRI-4) at week 12. The secondary endpoints were other clinical responses, safety and dynamics of immune cell subsets.
RESULTS
At week 12, the SRI-4 response rates were 55.17% and 30.00% for IL-2 and placebo, respectively (p=0.052). At week 24, the SRI-4 response rate of IL-2 group was 65.52%, compared with 36.67% of the placebo group (p=0.027). The primary endpoint was not met at week 12. Low-dose IL-2 treatment resulted in 53.85% (7/13) complete remission in patients with lupus nephritis, compared with 16.67% (2/12) in the placebo group (p=0.036). No serious infection was observed in the IL-2 group, but two in placebo group. Besides expansion of regulatory T cells, low-dose IL-2 may also sustain cellular immunity with enhanced natural killer cells.
CONCLUSIONS
Low-dose IL-2 might be effective and tolerated in treatment of SLE.
TRIAL REGISTRATION NUMBER
ClinicalTrials.gov Registries (NCT02465580 and NCT02932137).
Topics: Adult; Antirheumatic Agents; Double-Blind Method; Female; Humans; Interleukin-2; Lupus Erythematosus, Systemic; Lupus Nephritis; Male; Middle Aged; Recombinant Proteins; Treatment Outcome; Young Adult
PubMed: 31537547
DOI: 10.1136/annrheumdis-2019-215396 -
Frontiers in Immunology 2021Autoimmune diseases affect roughly 5-10% of the total population, with women affected more than men. The standard treatment for autoimmune or autoinflammatory diseases... (Review)
Review
Autoimmune diseases affect roughly 5-10% of the total population, with women affected more than men. The standard treatment for autoimmune or autoinflammatory diseases had long been immunosuppressive agents until the advent of immunomodulatory biologic drugs, which aimed at blocking inflammatory mediators, including proinflammatory cytokines. At the frontier of these biologic drugs are TNF-α blockers. These therapies inhibit the proinflammatory action of TNF-α in common autoimmune diseases such as rheumatoid arthritis, psoriasis, ulcerative colitis, and Crohn's disease. TNF-α blockade quickly became the "standard of care" for these autoimmune diseases due to their effectiveness in controlling disease and decreasing patient's adverse risk profiles compared to broad-spectrum immunosuppressive agents. However, anti-TNF-α therapies have limitations, including known adverse safety risk, loss of therapeutic efficacy due to drug resistance, and lack of efficacy in numerous autoimmune diseases, including multiple sclerosis. The next wave of truly transformative therapeutics should aspire to provide a cure by selectively suppressing pathogenic autoantigen-specific immune responses while leaving the rest of the immune system intact to control infectious diseases and malignancies. In this review, we will focus on three main areas of active research in immune tolerance. First, tolerogenic vaccines aiming at robust, lasting autoantigen-specific immune tolerance. Second, T cell therapies using Tregs (either polyclonal, antigen-specific, or genetically engineered to express chimeric antigen receptors) to establish active dominant immune tolerance or T cells (engineered to express chimeric antigen receptors) to delete pathogenic immune cells. Third, IL-2 therapies aiming at expanding immunosuppressive regulatory T cells .
Topics: Animals; Autoantigens; Autoimmune Diseases; Cell- and Tissue-Based Therapy; Dendritic Cells; Humans; Immune Tolerance; Immunologic Factors; Immunomodulation; Immunotherapy; Interleukin-2; T-Lymphocytes; Vaccines
PubMed: 33854514
DOI: 10.3389/fimmu.2021.657768 -
Clinical and Experimental Immunology Mar 2023Immune homeostasis is heavily dependent on the action of regulatory T cells (Tregs) which act to suppress the activation of many immune cell types including autoreactive... (Review)
Review
Immune homeostasis is heavily dependent on the action of regulatory T cells (Tregs) which act to suppress the activation of many immune cell types including autoreactive conventional T cells. A body of evidence has shown that Tregs are intrinsically defective in many common autoimmune diseases, and gene polymorphisms which increase the susceptibility of autoimmune disease development have implicated the interleukin-2 (IL-2) signaling pathway as a key dysregulated mechanism. IL-2 is essential for Treg function and survival, and Tregs are highly sensitive to low levels of this cytokine in their environment. This review will revisit the rationale behind using low-dose IL-2 as a therapy to treat autoimmune diseases and evaluate the outcomes of trials to date. Furthermore, novel engineered IL-2 therapies with increased Treg specificity have shown promise in pre-clinical studies and human clinical trials for some agents have begun. Future studies will determine whether low-dose IL-2 or engineered IL-2 therapies can change the course of autoimmune and inflammatory diseases in patients.
Topics: Humans; Interleukin-2; T-Lymphocytes, Regulatory; Autoimmune Diseases; Cytokines; Immunotherapy
PubMed: 36399073
DOI: 10.1093/cei/uxac105 -
European Review For Medical and... Oct 2012Interleukin-2(IL-2), also called T-cell growth factor and primarily produced by antigen-activated T cells, is a kind of lymphoid factor with immunoregulatory effect... (Review)
Review
BACKGROUND
Interleukin-2(IL-2), also called T-cell growth factor and primarily produced by antigen-activated T cells, is a kind of lymphoid factor with immunoregulatory effect which can promote T-cell-dependent immune responses. IL-2 was first used as a therapeutic approach to boost immune responses in patients with invasive cancer or advanced HIV disease.
OBJECTIVES
The purpose of the review is to refer the mechanism of autoimmune disease caused by IL-2 deletion and the application of IL-2 in curing autoimmune disease.
STATE OF THE ART
IL-2 signal plays a key role in promoting the development, homeostasis and the function of the regulatory T cells. The deletion of IL-2 in vivo causes T cell-mediated autoimmune diseases. Now it is being considered as a kind of medicine inhibiting immune responses.
PERSPECTIVES
Further studies with controlled clinical trials will be needed to prove the potential of IL-2 as a therapeutic strategy for autoimmune diseases.
CONCLUSIONS
The decreased production of IL-2 in patients with autoimmune disease leads to immune defects, such as decreased production of Treg cells, decreased AICD and cytotoxicity. Combination therapy based on IL-2 may prove to be beneficial in curing the immunological disorders.
Topics: Animals; Autoimmune Diseases; Humans; Interleukin-2; Lymphocyte Transfusion; T-Lymphocytes, Regulatory
PubMed: 23111957
DOI: No ID Found -
Scientific Reports Mar 2022Interleukin-2 (IL-2) is an important cytokine in survival, expansion, function of CD8+ T cells and natural killer cells in immunotherapy of melanoma and renal cell...
Interleukin-2 (IL-2) is an important cytokine in survival, expansion, function of CD8+ T cells and natural killer cells in immunotherapy of melanoma and renal cell carcinomas. Its severe toxicity following binding to its high affinity IL-2 receptor alpha (IL-2Rα) has restricted its application in cancer patients. In the present study, we investigated the antitumor efficacy and cytotoxicity of a mutated human IL-2 previously designed by selective amino acid substitutions, and its reduced affinity towards high-affinity IL-2Rα (CD25) was approved compared to the wild type IL-2 (wtIL-2). Furthermore, their ability to induce PBMC cell proliferation, and interferon-gamma secretion was compared. The mutant IL-2 also represented higher antitumor activity and more efficient cytotoxicity than wild type hIL-2. The developed mutant IL-2 can be an alternative tool in IL-2 associated immunotherapy of various cancers.
Topics: Humans; Interleukin-2; Killer Cells, Natural; Leukocytes, Mononuclear; Melanoma; Receptors, Interleukin-2
PubMed: 35354847
DOI: 10.1038/s41598-022-09278-7 -
Frontiers in Immunology 2023The Interleukin-2 Family contains six kinds of cytokines, namely IL-2, IL-15, IL-4, IL-7, IL-9, and IL-21, all of which share a common γ chain. Many cytokines of the... (Review)
Review
The Interleukin-2 Family contains six kinds of cytokines, namely IL-2, IL-15, IL-4, IL-7, IL-9, and IL-21, all of which share a common γ chain. Many cytokines of the IL-2 family have been reported to be a driving force in immune cells activation. Therefore, researchers have tried various methods to study the anti-tumor effect of cytokines for a long time. However, due to the short half-life, poor stability, easy to lead to inflammatory storms and narrow safety treatment window of cytokines, this field has been tepid. In recent years, with the rapid development of protein engineering technology, some engineered cytokines have a significant effect in tumor immunotherapy, showing an irresistible trend of development. In this review, we will discuss the current researches of the IL-2 family and mainly focus on the application and achievements of engineered cytokines in tumor immunotherapy.
Topics: Humans; Cytokines; Interleukin-2; Immunotherapy; Neoplasms
PubMed: 36936961
DOI: 10.3389/fimmu.2023.1090311 -
Oncoimmunology 2022A major challenge in natural killer (NK) cell immunotherapy is the limited persistence of NK cells . However, the proliferation of NK cells is dependent on cytokines...
A major challenge in natural killer (NK) cell immunotherapy is the limited persistence of NK cells . However, the proliferation of NK cells is dependent on cytokines such as interleukin-2 (IL-2). Although IL-2 is a critical cytokine for NK cell activation and survival, IL-2 administration in adoptive NK cell therapy can induce adverse toxicities. To improve the persistence of NK cells and attenuate the systemic toxicity of IL-2, we constructed a cell-restricted artificial IL-2, named membrane-bound IL-2 (mbIL-2), comprising human IL-2 and human IL-2Rα joined by a classic linker. We found that mbIL-2-activated NK-92 cells can survive and proliferate and , independent of exogenous IL-2, while mbIL-2-expressing NK-92 cells do not support bystander cell survival or proliferation. Additionally, mbIL-2 enhanced NK-92 cell-mediated antitumor activity by tuning the IL-2 receptor downstream signals and NK cell receptor repertoire expression. To conclude, our novel mbIL-2 improves NK-92 cell persistence and enhances NK-92 cell-mediated antitumor activity. NK-92 cells genetically modified to express the novel mbIL-2 with potential significance for clinical development.
Topics: Cytokines; Humans; Interleukin-2; Interleukin-2 Receptor alpha Subunit; Killer Cells, Natural; Receptors, Interleukin-2; Receptors, Natural Killer Cell
PubMed: 36185809
DOI: 10.1080/2162402X.2022.2127282 -
Cytokine & Growth Factor Reviews Oct 2022Interleukin 2 (IL-2) is a pleiotropic cytokine that elicits both immunogenic and tolerogenic immune response essential for homeostasis. Initial clinical application of... (Review)
Review
Interleukin 2 (IL-2) is a pleiotropic cytokine that elicits both immunogenic and tolerogenic immune response essential for homeostasis. Initial clinical application of IL-2 based therapy was hampered by its function on broad spectrum of cells expressing corresponding receptors, which exerts uncontrolled side effects in clinical trials. While recent progress on structural modification or adjusted regimen of IL-2, revolutionized the use of IL-2 in immunomodulation process that requires stringent selection of effector cells, such as promotion of T cells for tolerance or invigoration of CD8 T cells against infection and cancer. Low-dose IL-2 therapy is amongst these succuss and is proved to be a promising immunotherapy to treat a broad range of autoimmune and inflammatory diseases. This article will review major recent advances in fundamental research on IL-2 as well as significant progress made in clinical trials where patients received low-dose IL-2 therapy. This knowledge also helps design further optimized IL-2 therapies for a broader application in treating human disease.
Topics: Autoimmune Diseases; Autoimmunity; CD8-Positive T-Lymphocytes; Humans; Immunotherapy; Interleukin-2; T-Lymphocytes, Regulatory
PubMed: 35803833
DOI: 10.1016/j.cytogfr.2022.06.003