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.

Regulatory T cell therapy for type 1 diabetes: May the force be with you

“…A clinical trial with IL-2 plus rapamycin showed transient worsening in beta cell function [42], likely due to either the relatively higher dose of IL-2 employed and/or the rapamycin, with a dramatic increase in natural killer cells and eosinophils. However, early T1D studies with lower IL-2 doses have shown no acute worsening in b-cell function [66,67], and several studies are underway now to further assess safety and efficacy. In an upcoming phase I trial with autologous ex vivo expanded Tregs followed by low dose IL-2, we will evaluate if low dose IL-2 enhances the survival and function of the infused Tregs in vivo.…”

Calpains Released by T Lymphocytes Cleave TLR2 To Control IL-17 Expression

“…They were randomly assigned to placebo or IL-2 (0.33, 1, or 3 MIU/d) for a 5-d course and were followed on days 0, 6, and 15. On these days, blood samples were obtained, and ABCA1 gene expression was analyzed in PBMCs using the SurePrint G3 Human GE v2 8360K Microarray (Agilent Technologies; ID: 039494), according to the manufacturer's protocol, as reported (17). ABCA1 gene expression is the average expression measured by two probes (A_24_P235429, A_33_P3422897).…”

Le renouveau de l’interleukine 2

“…Dans le diabète de type 1, des études préliminaires d'efficacité ont permis de déterminer, chez les patients, la dose d'IL-2 induisant une augmentation des lymphocytes Treg sans que ne soient affectées les cellules effectrices T ou NK. Elle a de plus permis de montrer une réduction de la composante T spécifique des cellules β du pancréas [31,32]. L'ensemble de ces premières études indique donc l'intérêt des thérapies fondées sur des faibles doses d'IL-2 pour le traitement des maladies auto-immunes et inflammatoires.…”