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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. [ABSTRACT FROM AUTHOR]

Abstract: Interleukin 2 (IL2) is the key cytokine supporting survival and function of regulatory T cells (Tregs). We recently reported that low-dose IL2 safely expands/stimulates Tregs and improves autoimmune conditions in humans. Further development of IL2 in autoimmune diseases will require chronic IL2 administration, which could affect beneficial effector immune responses regulated by Tregs. We used recombinant adeno-associated viral vector (rAAV)-mediated gene transfer to continuously release IL2 in mice and assessed its long-term effects on immune responses. A single rAAV-IL2 injection enabled sustained stimulation and expansion of Tregs without inducing Teff activation and prevented diabetes in NOD mice. After several weeks of IL2 production, mice responded normally to a viral challenge and to vaccination, and had pregnancies with offspring that developed normally. They showed no change in the occurrence and growth of chemically-induced tumors. Altogether, chronic low-dose IL2 treatment does not affect beneficial effector immune responses at doses that prevent autoimmune diabetes. [Copyright &y& Elsevier]

Molecular mechanisms underlying large-vessel involvement in giant cell arteritis (LV-GCA) are largely unknown. Herein, we explore the critical involvement of pro-inflammatory signaling pathways in both aorta and T cells from patients with LV-GCA. We analyzed transcriptome and interferon gene signature in inflamed aortas from LV-GCA patients and compared them to non-inflammatory control aorta. Differential transcriptomic analyses of circulating CD4+ and CD8+ T cells were also performed between patients with active GCA (not under any immunosuppressants or corticosteroid doses higher than 10 mg/day by the time of blood collection) and healthy donors. Interferon-alpha serum levels were measured using ultra-sensitive technique (HD-X Simoa Planar Technology) in GCA patients according to disease activity status. Transcriptomic analyses revealed 1042, 1479 and 2075 significantly dysregulated genes for aortas, CD4+ and CD8+ cells from LV-GCA patients, respectively, as compared to controls. A great enrichment for pathways linked to interferons (type I, II and III), JAK/STAT signaling, cytokines and chemokines was seen across aortas and circulating T cells. A type I interferon signature was identified as significantly upregulated in the aorta of patients with LV-GCA, notably regarding EPSTI1 and IFI44L genes. STAT3 was significantly upregulated in both aorta and T cells and appeared as central in related gene networks from LV-GCA patients. Interferon-alpha serum levels were higher in patients with active GCA when compared to those in remission (0.024 vs. 0.011 pg/mL; p = 0.028). LV-GCA presents a clear type I interferon signature in aortas, which paves the way for tailored therapeutical targeting. • Aortas from LV-GCA patients are enriched with type I interferon signature. • JAK/STAT pathway seems key in disease mechanisms, notably regarding STAT3. • Interferon-alpha serum levels may be associated with disease activity. • Upregulated signaling pathways in LV-GCA paves the way for therapeutical targeting. [ABSTRACT FROM AUTHOR]

Background: Adjuvant treatment could be helpful in prevent recurrence after partial hepatectomy for liver metastases. The purpose of this study was to assess the benefit of in vivo injection of irradiated autologous cancer cells expressing cytokines after partial hepatectomy in rats. Methods: Fifty-four BDIX rats were injected with 3 × 106 DHD-K12 cancer cells into the portal vein to induce multiple hepatic metastases. A 70% hepatectomy was carried out 3 days after the injection. The rats were then randomized into three groups of 18 rats each. Rats were given three injections at days 8, 15, and 21 of 5 × 106 irradiated DHD-K12 cancer cells expressing either interleukin 12 (IL-12) (group 1), granulocyte monocyte colony stimulating factor (GM-CSF) (group 2), or only saline solution (control group). At day 30, animals of each group were divided into two subgroups: 10 rats of each group were killed for pathological examination and cytofluorimetric analysis and 8 rats of each group were maintained for survival follow-up. Results: At day 30, mean number of tumors on liver surface was lower in rats treated by irradiated cancer cells expressing IL-12 than those in GM-CSF group or in the control group. Furthermore, peritoneal carcinomatosis was significantly more frequent in the control group: 3/9 (33%) than in pooled IL-12 and GM-CSF groups: 1/19 (5%) (P < 0.05). In the survival study, we observed a significant increased survival in treated rats compared with the control group (P = 0.0008). Conclusion: Our results suggest that vaccination with autologous irradiated cancer cells expressing either IL-12 or GM-CSF induced a systemic immune antitumoral response that may be useful as an adjuvant therapy after surgical resection for liver metastases. [Copyright &y& Elsevier]