Phase I trial of low-dose interleukin 2 therapy in patients with Wiskott-Aldrich syndrome

Jyonouchi, Soma; Gwafila, Brenda; Gwalani, Lavesh A.; Ahmad, Maria; Moertel, Chistopher; Holbert, Cecil; Kim, Ji Young; Kobrinsky, Nathan L.; Roy-Ghanta, Sumita; Orange, Jordan S.

doi:10.1016/j.clim.2017.02.001

Cited by 26 publications

(19 citation statements)

References 26 publications

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“…This opens a therapeutic window for the use of ultra-low doses of IL-2 to enhance selectively the Treg response in patients with T1D or other autoimmune and inflammatory diseases 12 . IL-2 therapy is currently being investigated in many diseases, including T1D [13][14][15][16][17][18][19][20][21][22][23][24][25][26][27][28][29][30] and our own investigations have established the doses of IL-2 in T1D patients that stimulate Tregs but not Teffs 23,24 .…”

Section: Introductionmentioning

confidence: 93%

Interleukin-2 Therapy of Autoimmunity in Diabetes (ITAD): a phase 2, multicentre, double-blind, randomized, placebo-controlled trial

Marcovecchio¹,

Wicker²,

Dutton³

et al. 2020

Wellcome Open Res

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Type 1 diabetes is a common autoimmune disease due to destruction of pancreatic β cells, resulting in lifelong need for insulin. Evidence suggest that maintaining residual β-cell function can improve glucose control and reduce risk of hypoglycaemia and vascular complications. Non-clinical, preclinical and some preliminary clinical data suggest that low-dose interleukin-2 (IL-2) therapy could block pancreatic β cells destruction by increasing the number of functional regulatory T cells (Tregs) that inhibit islet-specific autoreactive effector T cells (Teffs). However, there is lack of data on the effect of low-dose IL-2 in newly diagnosed children and adolescents with T1D as well as lack of specific data on its potential effect on β-cell function. The ‘Interleukin-2 Therapy of Autoimmunity in Diabetes (ITAD)’ is a phase 2, multicentre, double-blind, randomised, placebo-controlled trial in children and adolescents (6-18 years; having detectable C-peptide) initiated within 6 weeks of T1D diagnosis. A total of 45 participants will be randomised in a 2:1 ratio to receive either ultra-low dose IL-2 (aldesleukin), at a dose of 0.2 x 106 IU/m2 twice-weekly, given subcutaneously, or placebo, for 6 months. The primary objective is to assess the effects of ultra-low dose aldesleukin administration on endogenous β-cell function as measured by frequent home dried blood spot (DBS) fasting and post-prandial C-peptide in children and adolescents with newly diagnosed T1D. The secondary objectives are: 1) to assess the efficacy of regular dosing of aldesleukin in increasing Treg levels; 2) to confirm the clinical safety and tolerability of ultra-low dose aldesleukin; 3) to assess changes in the immune system indicating benefit or potential risk for future gains/loss in β-cell function and immune function; 4) to assess treatment effect on glycaemic control. Trial registration: EudraCT 2017-002126-20 (06/02/2019)

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Section: Introductionmentioning

confidence: 93%

Interleukin-2 Therapy of Autoimmunity in Diabetes (ITAD): a phase 2, multicentre, double-blind, randomized, placebo-controlled trial

Marcovecchio¹,

Wicker²,

Dutton³

et al. 2020

Wellcome Open Res

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“…PBMCs (1×10 6 cells/mL) were cultured in 96-well plates (100 μL/ well) with different concentrations of rIL-2 (5,10,15,20,25,30 and 35 μg/mL) for 72 hours at 37°C in 5% CO 2 . The absorbance of the cells at 450 nm was then measured.…”

Section: Parasites Animals and Cellsmentioning

confidence: 99%

“…Interleukin 2 (IL‐2 ) is produced by helper T cells stimulated by antigens or mitogens, and it is one of the most indispensable immune regulatory factors in terms of immune regulation . IL‐2 stimulates the proliferation of T cells and induces the differentiation and effector functions of many kinds of killer cells, such as CTL, NK and LAK, as well as the production of cytokines produced by these killer cells, including IFN‐γ and TGF‐α . Apart from this, the expression level of IL‐2 can also be reflected at the cellular level.…”

Section: Introductionmentioning

confidence: 99%

“…D, Lane 4: purification of rHC8 by SDS-PAGE F I G U R E 4 Cell proliferation assay. PBMCs were co-cultured with IL-2 and HCGB (A) or rHC8 (B) at different concentrations(10,20, and 40 μg/mL), respectively. PBMCs (blank), PBMCs cultured with HCGB or rHC8, with recombinant protein from E coli transferred with only pET32a (pET32a), and with ConA and IL-2 set as the negative and positive controls.…”

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confidence: 99%

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Y75B8A.8 (HC8) protein of Haemonchus contortus: A functional inhibitor of host IL‐2

Wang

Tian

et al. 2019

Parasite Immunology

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Summary Interleukin 2 (IL‐2) is an important immune regulatory factor in the immune response of the host. However, little is known about the inhibitor of host IL‐2 in Haemonchus contortus infection. In this study, we found that globin domain‐containing protein (HCGB) and Protein Y75B8A.8 (HC8) from H contortus excretory and secretory products are two binding proteins of IL‐2 in goats. The yeast two‐hybrid screening further validated the positive interactions of IL‐2 with HCGB and HC8. Meanwhile, we found that HC8 had inhibitory effects on IL‐2‐induced peripheral blood mononuclear cell (PBMC) proliferation, while HCGB did not. Furthermore, transcriptional analysis revealed that HC8 could block the IL‐2‐activated signalling pathway. Our results showed that HC8 was a functional inhibitor of goat IL‐2.

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“…Although WAVE2 has baseline function in T cells, in NK cells this function is induced following cytokine stimulation. As such, IL-2 therapy can alleviate low NK cell function in WAS patients, with promising results in a clinical trial (53). Finally, although WAS remains the most common PID as a result of mutations in this family of proteins, a patient with features of WAS has subsequently been identified with deleterious homozygous mutations in WASPinteracting protein (WIPF1) (54).…”

Section: Discovering the Cause Of Wiskott-aldrich Syndrome And Layingmentioning

confidence: 99%

Phase I trial of low-dose interleukin 2 therapy in patients with Wiskott-Aldrich syndrome

Cited by 26 publications

References 26 publications

Interleukin-2 Therapy of Autoimmunity in Diabetes (ITAD): a phase 2, multicentre, double-blind, randomized, placebo-controlled trial

Interleukin-2 Therapy of Autoimmunity in Diabetes (ITAD): a phase 2, multicentre, double-blind, randomized, placebo-controlled trial

Y75B8A.8 (HC8) protein of Haemonchus contortus: A functional inhibitor of host IL‐2

Discovering the Cause of Wiskott–Aldrich Syndrome and Laying the Foundation for Understanding Immune Cell Structuring

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