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Low-dose interleukin-2 fosters a dose-dependent regulatory T cell tuned milieu in T1D patients.

Abstract：

:Most autoimmune diseases (AID) are linked to an imbalance between autoreactive effector T cells (Teffs) and regulatory T cells (Tregs). While blocking Teffs with immunosuppression has long been the only therapeutic option, activating/expanding Tregs may achieve the same objective without the toxicity of immunosuppression. We showed that low-dose interleukin-2 (ld-IL-2) safely expands/activates Tregs in patients with AID, such HCV-induced vasculitis and Type 1 Diabetes (T1D). Here we analyzed the kinetics and dose-relationship of IL-2 effects on immune responses in T1D patients. Ld-IL-2 therapy induced a dose-dependent increase in CD4(+)Foxp3(+) and CD8(+)Foxp3(+) Treg numbers and proportions, the duration of which was markedly dose-dependent. Tregs expressed enhanced levels of activation markers, including CD25, GITR, CTLA-4 and basal pSTAT5, and retained a 20-fold higher sensitivity to IL-2 than Teff and NK cells. Plasma levels of regulatory cytokines were increased in a dose-dependent manner, while cytokines linked to Teff and Th17 inflammatory cells were mostly unchanged. Global transcriptome analyses showed a dose-dependent decrease in immune response signatures. At the highest dose, Teff responses against beta-cell antigens were suppressed in all 4 patients tested. These results inform of broader changes induced by ld-IL-2 beyond direct effects on Tregs, and relevant for further development of ld-IL-2 for therapy and prevention of T1D, and other autoimmune and inflammatory diseases.

journal_name

J Autoimmun

journal_title

Journal of autoimmunity

authors

Rosenzwajg M,Churlaud G,Mallone R,Six A,Dérian N,Chaara W,Lorenzon R,Long SA,Buckner JH,Afonso G,Pham HP,Hartemann A,Yu A,Pugliese A,Malek TR,Klatzmann D

doi

10.1016/j.jaut.2015.01.001

subject

Has Abstract

pub_date

2015-04-01 00:00:00

pages

48-58

eissn

0896-8411

issn

1095-9157

pii

S0896-8411(15)00002-5

journal_volume

58

pub_type

杂志文章,随机对照试验

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