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

Churlaud, Guillaume; Jiménez, Verónica; Ruberte, Jesús; Zin, Martin Amadoudji; Fourcade, Gwladys; Gottrand, Gaëlle; Casana, Estefanía; Lambrecht, Bénédicte; Bellier, Bertrand; Piaggio, Eliane; Bosch, Fátima; Klatzmann, David

doi:10.1016/j.clim.2014.02.003

Cited by 46 publications

(48 citation statements)

References 49 publications

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“…Alternatively, specific IL-2 treatment regimens to maintain a high level of Tregs over a long-term period could be proposed. Importantly, we previously demonstrated that sustained stimulation and expansion of Tregs does not induce general immunosuppression because we showed that long-term IL-2 treatments control immune disorders in mice without impairing immune responses to infection, vaccination, and cancer (47). Alternative and more convenient routes of ld-IL-2 administration can be proposed.…”

Section: Foxp3mentioning

confidence: 99%

Low-Dose IL-2 Induces Regulatory T Cell–Mediated Control of Experimental Food Allergy

Bonnet¹,

Vigneron

Levacher

et al. 2016

The Journal of Immunology

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Section: Foxp3mentioning

confidence: 99%

Low-Dose IL-2 Induces Regulatory T Cell–Mediated Control of Experimental Food Allergy

Bonnet¹,

Vigneron

Levacher

et al. 2016

The Journal of Immunology

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“…Until recently, the latter purpose was achieved by long-term repeated systemic administration of IL-2, thereby boosting the risk of unwanted pleiotropic and systemic activity of IL-2. Yet, a very recent study has shown that sustained stimulation and local expansion of Tregs, achieved by using recombinant adeno-associated virus (rAAV) vectors expressing IL-2 at low doses, was able to improve autoimmunity without impairing immune responses to infection, vaccination, cancer development, and pregnancy [82,83]. Recent studies have also shown that rAAV-IL-2 injection resulted in achievement of different levels of IL-2 to boost tissue-resident Tregs, while avoiding the potential toxic effects of systemic IL-2 [21,57,82].…”

Section: Il-2 Immunotherapy In An Animal Model Of Autoimmunitymentioning

confidence: 99%

“…Yet, a very recent study has shown that sustained stimulation and local expansion of Tregs, achieved by using recombinant adeno-associated virus (rAAV) vectors expressing IL-2 at low doses, was able to improve autoimmunity without impairing immune responses to infection, vaccination, cancer development, and pregnancy [82,83]. Recent studies have also shown that rAAV-IL-2 injection resulted in achievement of different levels of IL-2 to boost tissue-resident Tregs, while avoiding the potential toxic effects of systemic IL-2 [21,57,82]. Recombinant adeno-associated virus (rAAV) is a non-integrative vector used for gene delivery to localize IL-2 long-term expression to the islets of NOD mice [68].…”

Section: Il-2 Immunotherapy In An Animal Model Of Autoimmunitymentioning

confidence: 99%

Low-Dose Interleukin-2 Therapy: A Driver of an Imbalance between Immune Tolerance and Autoimmunity

Kosmaczewska

2014

IJMS

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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.

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“…Furthermore, since FoxP3 expression is intracellular, purification of viable Tregs for adoptive transfer without Teff contamination is virtually impossible. Studies performed in the past few years indicate that the administration of low doses of recombinant IL-2 (rIL2) selectively targets Treg expansion [32,86,87] and has therapeutic benefits in the treatment of several forms of autoimmune disease [31,88,89] and graft rejection after transplantation [32,87]. Thus, low-dose IL-2-based immunotherapies may represent a good alternative to Treg-adoptive transfer approaches in order to boost Treg-mediated immunosuppression in vivo and to treat autoimmune disease.…”

Section: Il-2 and Treg Homeostasismentioning

confidence: 99%

Beyond Regulatory T Cells: The Potential Role for IL-2 to Deplete T-Follicular Helper Cells and Treat Autoimmune Diseases

Ballesteros-Tato¹

2014

Immunotherapy

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Low-dose IL-2 administration suppresses unwanted immune responses in mice and humans, thus evidencing the potential of IL-2 to treat autoimmune disorders. Increased Tregs activity is one of the potential mechanisms by which low-dose IL-2 immunotherapy induces immunosuppression. In addition, recent data indicate that IL-2 may contribute to prevent unwanted self-reactive responses by preventing the developing of T-follicular helper cells, a CD4+ T-cell subset that expands in autoimmune disease patients and promotes long-term effector B-cell responses. Here we discuss the mechanisms underlying the clinical benefits of low-dose IL-2 administration, focusing on the role of this cytokine in promoting Treg-mediated suppression and preventing self-reactive T-follicular helper cell responses.

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

Cited by 46 publications

References 49 publications

Low-Dose IL-2 Induces Regulatory T Cell–Mediated Control of Experimental Food Allergy

Low-Dose IL-2 Induces Regulatory T Cell–Mediated Control of Experimental Food Allergy

Low-Dose Interleukin-2 Therapy: A Driver of an Imbalance between Immune Tolerance and Autoimmunity

Beyond Regulatory T Cells: The Potential Role for IL-2 to Deplete T-Follicular Helper Cells and Treat Autoimmune Diseases

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