New therapeutic strategies based on IL-2 to modulate Treg cells for autoimmune diseases

Xu, Le; Song, Xiaolei; Su, Lili; Zheng, Yong; Li, Ru; Sun, Jian

doi:10.1016/j.intimp.2019.03.064

Cited by 31 publications

(14 citation statements)

References 96 publications

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“…The precedents established in animal models and preliminary clinical trials support further investigation of lowdose recombinant IL-2 therapy in autoimmune hepatitis, and investigations that are actively evaluating methods to improve Treg targeting and patient tolerance by engineering molecules of IL-2 that have sustained action and preferred Treg binding [274][275][276]278] or delivery systems that allow slow continuous release [277] strengthen these prospects.…”

Section: Overviewmentioning

confidence: 99%

Exploring the Pathogenic Role and Therapeutic Implications of Interleukin 2 in Autoimmune Hepatitis

Czaja

2020

Dig Dis Sci

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Interleukin 2 is essential for the expansion of regulatory T cells, and low-dose recombinant interleukin 2 has improved the clinical manifestations of diverse autoimmune diseases in preliminary studies. The goals of this review are to describe the actions of interleukin 2 and its receptor, present preliminary experiences with low-dose interleukin 2 in the treatment of diverse autoimmune diseases, and evaluate its potential as a therapeutic intervention in autoimmune hepatitis. English abstracts were identified in PubMed by multiple search terms. Full-length articles were selected for review, and secondary and tertiary bibliographies were developed. Interleukin 2 is critical for the thymic selection, peripheral expansion, induction, and survival of regulatory T cells, and it is also a growth factor for activated T cells and natural killer cells. Interleukin 2 activates the signal transducer and activator of transcription 5 after binding with its trimeric receptor on regulatory T cells. Immune suppressor activity is increased; anti-inflammatory interleukin 10 is released; pro-inflammatory interferon-gamma is inhibited; and activation-induced apoptosis of CD8 + T cells is upregulated. Preliminary experiences with cyclic injections of low-dose recombinant interleukin 2 in diverse autoimmune diseases have demonstrated increased numbers of circulating regulatory T cells, preserved regulatory function, improved clinical manifestations, and excellent tolerance. Similar improvements have been recognized in one of two patients with refractory autoimmune hepatitis. In conclusion, interferon 2 has biological actions that favor the immune suppressor functions of regulatory T cells, and low-dose regimens in preliminary studies encourage its rigorous investigation in autoimmune hepatitis.

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Section: Overviewmentioning

confidence: 99%

Exploring the Pathogenic Role and Therapeutic Implications of Interleukin 2 in Autoimmune Hepatitis

Czaja

2020

Dig Dis Sci

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“…The cytokine IL-2 is predominantly secreted from activated T cells and is critical in regulating the balance between immune tolerance and autoimmunity [13]. The secretion of IL-2 is driven by a rise of [Ca 2+ ] i [14].…”

Section: Resultsmentioning

confidence: 99%

Immunosuppressive effects of a novel potassium channel toxin Ktx-Sp2 from Scorpiops Pocoki

Zhang

Shi

et al. 2019

Cell Biosci

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BackgroundThe cDNA Library of venomous animals could provide abundant bioactive peptides coding information and is an important resource for screening bioactive peptides that target and regulate disease-related ion channels. To further explore the potential medicinal usage of the transcriptome database of Scorpiops Pocoki’s venom gland, this research identified the function of a new potassium channel toxin Ktx-Sp2, whose gene was screened from the database by sequence alignment.ResultsThe mature peptide of Ktx-Sp2 was obtained by genetic engineering. Whole-cell patch-clamp experiment showed that Ktx-Sp2 peptide could effectively block three types of exogenous voltage-gated potassium channels—Kv1.1, Kv1.2 and Kv1.3, among which, the blocking activity for Kv1.3 was relatively high, showing selectivity to some extent. Taking Jurkat T cells as the cell model, this study found that Ktx-Sp2 peptide could also effectively block endogenous Kv1.3, significantly reduce the free calcium concentration in Jurkat T cells, inhibit the activation of Jurkat T cells and reduce the release of inflammatory cytokines IL-2, showing a strong immunosuppressant effect.ConclusionsThis study further proves that the transcriptome database of the Scorpiops Pocoki venom gland is an important resource for discovery of novel bioactive polypeptide coding genes. The newly screened Kv1.3 channel blocker Ktx-Sp2 expanded the range of leading compounds for the treatment of autoimmune diseases and promoted the development and application of scorpion toxin peptides in the field of biomedicine.

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“…Early work focused on IL-2 muteins with attenuated binding to IL-2Rβ to mitigate IL-2-induced toxicity. Although these agents did not demonstrate decreased toxicity in clinical trials, they showed significant selectivity for high-affinity IL-2Rs and Tregs (86,87), which prompted further refinement of this approach. NKTR-358 is a PEGylated IL-2 molecule that selectively induces the proliferation and activation of Tregs.…”

Section: Il-2 Conjugates and Fusion Proteinsmentioning

confidence: 99%

Engineering IL-2 to Give New Life to T Cell Immunotherapy

2021

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Interleukin-2 (IL-2) is integral to immune system regulation. Its opposing immunostimulatory and immunosuppressive actions make it an attractive therapeutic target for cancer and autoimmune diseases. A challenge in developing IL-2-directed anticancer therapies has been how to stimulate effector T cells (Teffs) without inducing regulatory T cells (Tregs) in the tumor microenvironment; conversely, IL-2 therapy for autoimmune diseases requires Treg induction without further stimulation of Teffs. High-dose IL-2 is approved for melanoma and renal cell carcinoma, but its therapeutic value is limited by a need for frequent dosing at specialist centers, its short half-life, severe toxicity, and a lack of efficacy in most patients. Re-engineered IL-2 therapeutics are designed to have longer in vivo half-lives, target specific IL-2 receptor conformations to stimulate specific T cell subsets, or localize to target tissues to optimize efficacy and reduce toxicity. We discuss recent studies that elucidate the potential of newly engineered IL-2-based therapeutics for cancer and autoimmune diseases. Expected final online publication date for the Annual Review of Medicine, Volume 72 is January 27, 2021. Please see http://www.annualreviews.org/page/journal/pubdates for revised estimates.

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New therapeutic strategies based on IL-2 to modulate Treg cells for autoimmune diseases

Cited by 31 publications

References 96 publications

Exploring the Pathogenic Role and Therapeutic Implications of Interleukin 2 in Autoimmune Hepatitis

Exploring the Pathogenic Role and Therapeutic Implications of Interleukin 2 in Autoimmune Hepatitis

Immunosuppressive effects of a novel potassium channel toxin Ktx-Sp2 from Scorpiops Pocoki

Engineering IL-2 to Give New Life to T Cell Immunotherapy

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