Low-dose IL-2 therapy — a complex scenario that remains to be further explored

Humrich, Jens Y; Riemekasten, Gabriela

doi:10.1038/nrrheum.2017.71

Cited by 8 publications

(6 citation statements)

References 6 publications

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“…The association of high ab levels with signs of lung fibrosis and reduced progression of lung fibrosis seems to be a contradiction at first glance. A similar observation was found for regulatory T cells (Treg), which strongly correlate with disease activity in lupus [ 31 ]. This could be suggestive for their pathogenic role.…”

Section: Discussionsupporting

confidence: 74%

“…This could be suggestive for their pathogenic role. Nevertheless, enrichment of Treg improved lupus activity illustrating that high Treg numbers do not necessarily indicate a pathogenic role of the Treg [ 31 ]. Similar to the beneficial role of Treg, the prediction of progressive deterioration of FVC values by low anti-CXCR3/4 levels suggests a protective effect of the antibodies, which needs to be further evaluated.…”

Section: Discussionmentioning

confidence: 99%

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Antibodies against chemokine receptors CXCR3 and CXCR4 predict progressive deterioration of lung function in patients with systemic sclerosis

et al. 2018

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BackgroundThe chemokine receptors CXCR3 and CXCR4 are involved in the pathogenesis of fibrosis, a key feature of systemic sclerosis (SSc). It is hypothesized that immunoglobulin (Ig)G antibodies (abs) against these two receptors are present in patients with SSc and are associated with clinical findings.MethodsAnti-CXCR3 and anti-CXCR4 ab levels were measured in 449 sera from 327 SSc patients and in 234 sera from healthy donors (HD) by enzyme-linked immunosorbent assay (ELISA). In SSc, ab levels were compared with clinical data in a cross-sectional and longitudinal setting. Protein expression of CXCR3 and CXCR4 on peripheral blood mononuclear cells (PBMCs) was analyzed in 17 SSc patients and 8 HD by flow cytometry.ResultsAnti-CXCR3 and anti-CXCR4 ab levels were different among SSc subgroups compared with HD and were highest in diffuse SSc patients. The ab levels strongly correlated with each other (r = 0.85). Patients with SSc-related interstitial lung disease (SSc-ILD) exhibited higher ab levels which negatively correlated with lung function parameters (e.g., r = −0.5 and r = −0.43 for predicted vital capacity, respectively). However, patients with deterioration of lung function showed lower anti-CXCR3/4 ab levels compared with those with stable disease. Frequencies and median fluorescence intensities (MFI) of CXCR3+ and CXCR4+ PBMCs were lower in SSc patients compared with HD and correlated with the severity of skin and lung fibrosis. They correlated with the severity of skin and lung fibrosis.ConclusionsAnti-CXCR3/4 abs and their corresponding receptors are linked with the severity of SSc-ILD. Antibody levels discriminate patients with stable or decreasing lung function and could be used for risk stratification.Electronic supplementary materialThe online version of this article (10.1186/s13075-018-1545-8) contains supplementary material, which is available to authorized users.

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Section: Discussionsupporting

confidence: 74%

Section: Discussionmentioning

confidence: 99%

Antibodies against chemokine receptors CXCR3 and CXCR4 predict progressive deterioration of lung function in patients with systemic sclerosis

et al. 2018

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“…Low-dose IL-2 therapy intends to restore Treg homeostasis and early phase clinical trials suggest that this treatment is efficacious in large variety of autoimmune diseases including SLE [17,18,25,27,28]. Although it is undisputable that low-dose IL-2 therapy is capable to expand the Treg population very efficiently and also quite selectively in virtually every treated patient, the mechanisms of action of low-dose IL-2 therapy beyond Treg expansion are still not well understood [18,28,29]. In particular, deeper insights into the IL-2 induced immunological changes in the inflamed tissues are necessary for a better understanding of the modes of action of low-dose IL-2 therapy.…”

Section: Discussionmentioning

confidence: 99%

IL-2 Therapy Diminishes Renal Inflammation and the Activity of Kidney-Infiltrating CD4+ T Cells in Murine Lupus Nephritis

Rose

Spee-Mayer

Kloke³

et al. 2019

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An acquired deficiency of interleukin-2 (IL-2) and related disturbances in regulatory T cell (Treg) homeostasis play an important role in the pathogenesis of systemic lupus erythematosus (SLE). Low-dose IL-2 therapy was shown to restore Treg homeostasis in patients with active SLE and its clinical efficacy is currently evaluated in clinical trials. Lupus nephritis (LN), a challenging organ manifestation in SLE, is characterized by the infiltration of pathogenic CD4+ T cells into the inflamed kidney. However, the role of the Treg-IL-2 axis in the pathogenesis of LN and the mode of action of IL-2 therapy in the inflamed kidneys are still poorly understood. Using the (NZB × NZW) F1 mouse model of SLE we studied whether intrarenal Treg are affected by a shortage of IL-2 in comparison with lymphatic organs and whether and how intrarenal T cells and renal inflammation can be influenced by IL-2 therapy. We found that intrarenal Treg show phenotypic signs that are reminiscent of IL-2 deprivation in parallel to a progressive hyperactivity of intrarenal conventional CD4+ T cells (Tcon). Short-term IL-2 treatment of mice with active LN induced an expansion the intrarenal Treg population whereas long-term IL-2 treatment reduced the activity and proliferation of intrarenal Tcon, which was accompanied by a clinical and histological amelioration of LN. The association of these immune pathologies with IL-2 deficiency and their reversibility by IL-2 therapy provides important rationales for an IL-2-based immunotherapy of LN.

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“…In the absence of CD25, CD122, and CD132 form a lower affinity receptor for this cytokine, which is predominantly expressed by effector CD8+ T cells and natural killer (NK) cells (30,31). Accordingly, application of low doses of IL-2 is believed to selectively expand Treg populations, and has demonstrated therapeutic potential against some autoimmune disorders in clinical trials (32)(33)(34)(35). Interestingly, it was reported that this treatment inhibits allergic symptoms, but does not impair IgE production in a murine model of food allergy to OVA (36).…”

Section: Introductionmentioning

confidence: 99%

IL-2-Agonist-Induced IFN-γ Exacerbates Systemic Anaphylaxis in Food Allergen-Sensitized Mice

et al. 2020

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Food allergies are common, costly and potentially life-threatening disorders. They are driven by Th2, but inhibited by Th1 reactions. There is also evidence indicating that IL-2 agonist treatment inhibits allergic sensitization through expansion of regulatory T cells. Here, we tested the impact of an IL-2 agonist in a novel model for food allergy to hen´s egg in mice sensitized without artificial adjuvants. Prophylactic IL-2 agonist treatment expanded Treg populations and inhibited allergen-specific sensitization. However, IL-2 agonist treatment of already sensitized mice increased mast cell responses and allergic anaphylaxis upon allergen re-challenge. These effects depended on allergen-specific IgE and were mediated through IFN-γ, as shown by IgE transfer and blockade of IFN-γ with monoclonal antibodies. These results suggest that although shifting the allergic reaction toward a Treg/Th1 response inhibits allergic sensitization, the prototypic Th1 cytokine IFN-γ promotes mast cell activation and allergen-induced anaphylaxis in individuals that are already IgE-sensitized. Hence, while a Th1 response can prevent the development of food allergy, IFN-γ has the ability to exacerbate already established food allergy.

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Low-dose IL-2 therapy — a complex scenario that remains to be further explored

Cited by 8 publications

References 6 publications

Antibodies against chemokine receptors CXCR3 and CXCR4 predict progressive deterioration of lung function in patients with systemic sclerosis

Antibodies against chemokine receptors CXCR3 and CXCR4 predict progressive deterioration of lung function in patients with systemic sclerosis

IL-2 Therapy Diminishes Renal Inflammation and the Activity of Kidney-Infiltrating CD4+ T Cells in Murine Lupus Nephritis

IL-2-Agonist-Induced IFN-γ Exacerbates Systemic Anaphylaxis in Food Allergen-Sensitized Mice

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