IL-33 improves the suppressive potential of regulatory T cells in patients with type 1 diabetes

Ryba-Stanisławowska, Monika; Buksa, Laura; Brandt, Agnieszka; Juhas, Ulana; Myśliwiec, Małgorzata

doi:10.1016/j.diabres.2017.04.011

Cited by 12 publications

(9 citation statements)

References 32 publications

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“…Further, Yuan et al ( 16 ) recently showed that in prediabetic NOD mice a combination of CD122 and IL-33 promotes Tregs abundance and function in pancreatic islets. Finally Ryba-Stanislawowska et al ( 17 ) reported that in vitro IL-33 treatment of Tregs derived from patients with type 1 diabetes resulted in quantitative and qualitative enhancement of their suppressive activity.…”

Section: Introductionmentioning

confidence: 99%

IL-33 Prevents MLD-STZ Induction of Diabetes and Attenuate Insulitis in Prediabetic NOD Mice

et al. 2018

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Type 1 diabetes is an autoimmune disease caused by the immune-mediated destruction of pancreatic β-cells. Prevention of type 1 diabetes requires early intervention in the autoimmune process against beta-cells of the pancreatic islets of Langerhans, which is believed to result from disordered immunoregulation. CD4+Foxp3+ regulatory T cells (Tregs) participate as one of the most important cell types in limiting the autoimmune process. The aim of this study was to investigate the effect of exogenous IL-33 in multiple low dose streptozotocin (MLD-STZ) induced diabetes and to delineate its role in the induction of protective Tregs in an autoimmune attack. C57BL/6 mice were treated i. p. with five doses of 40 mg/kg STZ and 0.4 μg rIL-33 four times, starting from day 0, 6, or 12 every second day from the day of disease induction. 16 weeks old NOD mice were treated with 6 injections of 0.4 μg/mouse IL-33 (every second day). Glycemia and glycosuria were measured and histological parameters in pancreatic islets were evaluated at the end of experiments. Cellular make up of the pancreatic lymph nodes and islets were evaluated by flow cytometry. IL-33 given simultaneously with the application of STZ completely prevented the development of hyperglycemia, glycosuria and profoundly attenuated mononuclear cell infiltration. IL-33 treatment was accompanied by higher number of IL-13 and IL-5 producing CD4+ T cells and increased presence of ST2+Foxp3+ regulatory T cells in pancreatic lymph nodes and islets. Elimination of Tregs abrogated protective effect of IL-33. We provide evidence that exogenous IL-33 completely prevents the development of T cell mediated inflammation in pancreatic islets and consecutive development of diabetes in C57BL/6 mice by facilitating the induction Treg cells. To extend this finding for possible relevance in spontaneous diabetes, we showed that IL-33 attenuate insulitis in prediabetic NOD mice.

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Section: Introductionmentioning

confidence: 99%

IL-33 Prevents MLD-STZ Induction of Diabetes and Attenuate Insulitis in Prediabetic NOD Mice

et al. 2018

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“…Based on what has been described in transplantation clinical trials, the function and application of huTregs are quite promising. Until now, it has been possible to generate protocols for the purification and expansion of huTregs from healthy donors and patients, with the following infusion for treating conditions as transplant rejection, GvHD or autoimmune diseases [1,2,4,20].…”

Section: Discussionmentioning

confidence: 99%

“…For instance, the receptor for IL-33, or ST2, has served as a marker for highly activated murine Tregs with a Th2-like phenotype [25], and also for suppressive Tregs residing in the intestine [11]. Conversely, the treatment with IL-33 (for 24 hours) of freshly isolated huTregs from diabetic patients has been tested, resulting in an increased ST2 expression [26], no variation in Foxp3 levels, but greater capacity to block IFN-γ expression on effector T cells [20]. Comparing this last study with ours, it seems surprising that IL-33 only improves huTregs function from diabetic, and not healthy donors (as in this current report).…”

Section: Il-33 Boosts the Suppressive Function Of Hutregsmentioning

confidence: 99%

IL-33 improves the suppressive capacity of human regulatory T cells

Gajardo¹,

Campos‐Mora²,

Pino‐Lagos³

2017

Trends in Transplant

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One of the main problems that immunologists have not solved yet involves the immunosuppression of ongoing exacerbated responses, as in transplant rejection and autoimmune diseases. To overcome these difficulties, different approaches have been used including the administration of immunosuppressive drugs, monoclonal antibodies, and more recently, the utilization of cellular therapy. In this last strategy, huTregs have been proposed as a safe tool to control transplant rejection or collateral immune reactions such as GvHD. Tregs are a subtype of CD4+ T cells characterized by the expression of markers such as CD25, CD127, Foxp3, among others, and their capacity to induce immune tolerance. For this reason, huTregs have become an attractive target for their manipulation and application in the clinic. In this work, we used an established protocol for the expansion of peripheral blood-derived huTregs, adding IL-33 as a putative enhancer of huTregs function, due to its previously identified capacity for driving transplant tolerance. Here, we characterized the phenotype, expansion rate and suppressive function of huTregs 33 . Although IL-33 did not modify the expression of Tregs canonical markers nor their proliferative activity, it did potentiate their suppressive function. This remarkable observation may be driven in part by the up-regulation of the immune regulatory-related genes, Foxp3, Amphiregulin and ST2. Thus, huTregs 33 should be considered for pre-clinical and clinical studies.

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“…(7) IL-33 and sST2 have been implicated in the pathogenesis of autoimmune diseases. Elevated levels of IL-33 have subsequently been reported in many autoimmune diseases, including type 1 diabetes, (8) rheumatoid arthritis, (9) inflammatory bowel diseases, (10) and autoimmune pancreatitis. (11) IL-33 has been reported to correlate with liver injury in patients with primary biliary cirrhosis (PBC).…”

mentioning

confidence: 99%

“…IL‐33 and sST2 have been implicated in the pathogenesis of autoimmune diseases. Elevated levels of IL‐33 have subsequently been reported in many autoimmune diseases, including type 1 diabetes, rheumatoid arthritis, inflammatory bowel diseases, and autoimmune pancreatitis …”

mentioning

confidence: 99%

Interleukin‐33/ST2‐Mediated Inflammation Plays a Critical Role in the Pathogenesis and Severity of Type I Autoimmune Hepatitis

Abe¹,

Takahashi²,

Fujita³

et al. 2019

Hepatol Commun

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Interleukin (IL)‐33 was recently described as a new member of the IL‐1 family; members of this family have proinflammatory activity. IL‐33 and its soluble receptor ST2 (sST2) have been implicated in the pathogenesis of autoimmune diseases. This study investigated serum IL‐33 and sST2 in type I autoimmune hepatitis (AIH) and the relationship of these molecules with clinical and pathologic parameters. Subjects included 65 patients with AIH who were diagnosed in our hospital. The control population included 17 healthy individuals and 36 patients with primary biliary cholangitis (PBC). Mean age at AIH diagnosis was 55.5 years, and the male‐to‐female ratio was 6:59. Serum IL‐33 and sST2 levels were significantly higher in patients with AIH than in those with PBC or controls. Importantly, immunohistochemistry revealed high IL‐33 expression in liver sections from patients with AIH. In particular, serum IL‐33 and sST2 levels were significantly higher in acute‐onset AIH than in chronic‐onset AIH. Serum IL‐33 levels were positively correlated with serum total bilirubin (TB), alanine aminotransferase (ALT), and necroinflammatory activity in AIH. We performed multivariate logistic regression analysis and found serum IL‐33 levels to be independent factors for severe activity. Serum sST2 levels were positively correlated with serum TB and ALT and negatively correlated with serum albumin and prothrombin time in AIH. In particular, serum sST2 levels were significantly higher in severe symptoms of AIH. Serum IL‐33 and sST2 levels in patients with AIH responsive to treatment with prednisolone were significantly decreased after treatment. Interestingly, serum IL‐33 level was associated with a significantly increased risk of relapse. Conclusion: IL‐33/ST2 may play an important role in the pathogenesis and severity of AIH and may be a promising target for AIH therapy.

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IL-33 improves the suppressive potential of regulatory T cells in patients with type 1 diabetes

Cited by 12 publications

References 32 publications

IL-33 Prevents MLD-STZ Induction of Diabetes and Attenuate Insulitis in Prediabetic NOD Mice

IL-33 Prevents MLD-STZ Induction of Diabetes and Attenuate Insulitis in Prediabetic NOD Mice

IL-33 improves the suppressive capacity of human regulatory T cells

Interleukin‐33/ST2‐Mediated Inflammation Plays a Critical Role in the Pathogenesis and Severity of Type I Autoimmune Hepatitis

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