Effect Of Low-dose IL-2 Research Articles

The effects of low-dose IL-2 on Th17/Treg cell imbalance in primary biliary cholangitis mouse models

Background/aimsPrimary biliary cholangitis (PBC) is a chronic cholestatic liver disease. The imbalance of Th17/Treg cells has been reported in PBC patients. Low-dose IL-2 can alleviate disease severity through modulating CD4 + T cell subsets in patients with autoimmune diseases. Hence, the present study aimed to examine the effects and mechanism of low-dose IL-2 in PBC mouse models.MethodsPBC models were induced in female C57BL/6 mice by two immunizations with 2OA-BSA at two-week intervals, and poly I: C every three days. PBC mouse models were divided into the IL-2 treated and untreated groups and low-dose IL-2 was injected at three different time points. Th17 and Tregs were analyzed by flow cytometry, and the related cytokines were analyzed by ELISA. Liver histopathology was examined by H&E and immunohistochemical staining.ResultsTwelve weeks after modeling, the serum AMA was positive and the ALP was significantly increased in PBC mouse models (P<0.05). The pathology showed lymphocyte infiltration in the portal area, damage, and reactive proliferation of the small bile duct (P<0.05). The flow cytometric showed the imbalance of Th17/Treg cells in the liver of PBC mouse models, with decreased Treg cells, increased Th17 cells, and Th17/Treg ratio (P < 0.05). After the low-dose IL-2 intervention, biochemical index and liver pathologies showed improvement at 12 weeks. Besides, the imbalance of Th17 and Treg cells recovered. Public database mining showed that Th17 cell differentiation may contribute to poor response in PBC patients.ConclusionLow-dose IL-2 can significantly improve liver biochemistry and pathology by reversing the imbalance of Th17 and Treg cells, suggesting that it may be a potential therapeutic target for PBC.

Modification of Intestinal Microbiota Dysbiosis by Low-Dose Interleukin-2 in Dermatomyositis: A Post Hoc Analysis From a Clinical Trial Study.

The microbiota has been observed altered in autoimmune diseases, including idiopathic inflammatory myopathies (IIMs), and associated with different treatments. Low-dose IL-2 treatment emerges as a new option for active IIMs. This study aims to explore the role of low-dose IL-2 in regulating intestinal dysbiosis involved in the IIMs. In this study, 13 patients with active IIMs were enrolled and received 1 ×106 IU of IL-2 subcutaneously every other day for 12 weeks plus standard care. The clinical response and immune response were assessed. Stool samples were obtained to explore the structural and functional alterations of the fecal microbiota targeting the V3–V4 region of the 16S rRNA gene and analyze their associations with clinical and immunological characteristics. Our study demonstrated that diversity of microbiota decreased remarkably in patients with IIMs, compared to healthy controls. The inflammatory-related bacteria, such as Prevotellaceae increased, while some butyrate-producing bacteria, such as Pseudobutyrivibrio, Lachnospiraceae, Roseburia, and Blautia, decreased significantly. The alteration associated with disease activities in patients with IIMs. After low-dose IL-2 treatment, 92.31% (12/13) of patients achieved IMACS DOI at week 12. Proportion of Treg cells significantly increased at week 12 compared with that in baseline (15.9% [7.73, 19.4%] vs. 9.89% [6.02, 11.8%], P = 0.015). Interestingly, certain butyrate-producing bacteria increase significantly after IL-2 treatment, like Lachnospiraceae, Pseudobutyrivibrio, etc., and are associated with a rise in L-Asparagine and L-Leucine. The effects of low-dose IL-2 on gut microbiota were more apparent in NOD mice. Together, the data presented demonstrated that low-dose IL-2 was effective in active IIMs and highlighted the potential for modifying the intestinal microbiomes of dysbiosis to treat IIMs.

T Cells, Interleukin-2 and Systemic Lupus Erythematosus-From Pathophysiology to Therapy.

The phenotypic and functional complexities of T cells engender complicated and often confusing concepts as to how T cells ignite, accelerate and brake the inflammatory processes involved in systemic lupus erythematosus (SLE), let alone the plasticity of T cells that takes place under different immunological contexts. Nevertheless, being one of the prime survival factors of T cells, interleukin (IL)-2 plays a potentially critical role in many immunological scenarios during the pathophysiological process of SLE. Here, the pathophysiology of lupus T cells and current, as well as ongoing, therapeutic approaches of SLE that involve low-dose IL-2 administration will be highlighted. The mechanisms of IL-2 deficiency in SLE pathophysiology, the effects of low-dose IL-2 on T cells and restoration of lupus manifestations in murine SLE models, as well as the efficacy and safety of clinical trials that evaluated low-dose IL-2-containing regimens in patients with SLE will be discussed.

Low-dose IL-2 effectively restored decreased regulatory T cells in patients with Behçet's disease

Although Behçet's disease (BD) is associated with immune mechanisms, the changes in circulating lymphocytes, especially regulatory T (Treg) cells remain unclear. Furthermore, low dose IL-2 has been reported to promote the expansion of Treg cells. This study aimed to investigate the significance of these subsets in the pathogenesis and the effect of low dose IL-2 on BD.Lymphocyte subsets and cytokines from 177 BD patients and 160 healthy controls (HCs) were characterised. Then the efficacy and safety of low dose IL-2 for refractory BD patients were explored.There was a decrease in the absolute number of Treg cells and IL-10 in patients, while no difference in Th1, Th2, Th17 cells or their related cytokines. Accordingly, the ratio of Th17/Treg cells in patients was greatly higher than those of healthy controls. Furthermore, circulating Treg levels were negatively correlated with erythrocyte sedimentation rate (ESR), C-reactive protein (CRP) and Behçet's disease current activity form (BDCAF), respectively. Lastly, after IL-2 treatment, all subsets were increased to some degree, while only Treg cells were amplified more dramatically, with a four-fold increase. Meanwhile, we found that the symptoms were mitigated without observed side effects.BD might be triggered by the defect of immunotolerance with decreased Treg. Moreover, low-dose IL-2 proposes a potential treatment by restoring Treg and promoting rapidly remission.

IL-6 Receptor Blockade but Not IL-2 Treatment Contributes to Long Term NHP Cardiac Allograft Survival in Transient Mixed Chimeras

Long term tolerance of cardiac allografts has been achieved in non-human primates (NHPs) using a mixed chimerism protocol and by co-transplanting a kidney from the same heart and bone marrow donor. In stark contrast, heart alone recipients rejected in 150-180 days. T cell subset analyses showed a greater expansion of regulatory T cells (Treg) in heart/kidney recipients compared to heart alone controls. To achieve tolerance of isolated heart allografts, we added IL-2 and/or anti-IL6R therapy to enhance host Treg activity. Twelve cynomolgus heart alone transplant recipients underwent donor bone marrow transplantation with mixed chimerism conditioning that included non-myeloablative total body irradiation, thymic irradiation, horse anti-thymocyte globulin, anti-CD154 mAb, and cyclosporine until POD 28. Five animals in Group A received low dose IL-2 (1MIU/m2 SC from POD -6 to 5) and IL-6 receptor blockade with tocilizumab (10 mg/kg IV on POD 0, 7, 14, 21, 28, 56, 84, and 112). Seven recipients in Group B, received tocilizumab alone (10 mg/kg IV on POD 0, 7, 14, 21, 28, 56, and 84). In Group A, 3/5 animals rejected their allografts at days 127, 198, and 254 post-transplant with evidence of acute cellular rejection (ACR), antibody mediated rejection (AMR), and donor specific antibodies (DSA). Two animals died on days 7 and 11 post-transplant from sepsis and pancytopenia, respectively. In Group B, 3/7 recipients are ongoing (POD 111 and 62) with one animal over 509 days with no evidence of ACR. 1/7 rejected at day 169 post-transplant with ACR 3R, pAMR3, and DSA and 3/7 animals died on days 5, 9, and 65 post-transplant from a technical failure, sedation complication, and pancytopenia, respectively. Recipients in Group A exhibited an average 15-fold expansion in the percent CD25+FoxP3+ of CD3+CD4+ cells in the periphery compared to an average 3-fold expansion in Group B recipients. Adding IL-6 receptor blockade to a mixed chimerism protocol has achieved tolerance of an isolated heart allograft for the first time. This protocol or a version thereof has the potential to be trialed in humans. The surprising deleterious effects of low dose IL-2 may be related to its ability to activate alloreactive T cells despite augmenting Tregs.

Low-dose IL-2 expands CD4+ regulatory T cells with a suppressive function in vitro via the STAT5-dependent pathway in patients with chronic kidney diseases

Background: Patients with chronic kidney disease (CKD) often have CD4+ regulatory T cells (Tregs) dysfunction and chronic inflammation. We aim to investigate the effect, function, and related mechanism of low-dose IL-2 on CD4+ regulatory T cells expansion in vitro from patients with CKD. Methods: A total of 148 newly diagnosed patients with CKD at Stage III and 35 healthy volunteer subjects were recruited into our studies. The number of peripheral Tregs in peripheral blood mononuclear cells isolated from CKD patients, which were characterized by FACS as CD4+CD25hi and CD4+CD25+FoxP3+. The effect of low-dose IL-2 on expansion of Tregs, and the suppressive function of expanded Tregs were also analyzed by FACS. The levels of FoxP3 mRNA were detected by qRT-PCR. The activation of IL-2 induced Stat5 and blocking experiments were assessed by Western Blotting and FACS. Results: We found that the frequency of peripheral Tregs from CKD patients was significantly lower than that in healthy volunteer subjects. We also showed that IL-2 selectively expanded CD4+CD25hi and CD4+CD25+FoxP3+ regulatory T cells, and also upregulated the expression of FoxP3 mRNA. Our in vitro studies demonstrated that expanded CD4+ regulatory T cells from CKD patients suppressed proinflammatory Th1 and Th17 cell response. Furthermore, STAT5 activation is required for IL-2-induced expansion of regulatory T cells and expression of FoxP3 mRNA from CKD patients. Conclusions: Our findings support the clinical Treg defects in CKD patients with glomerular diseases, and the rationale of evaluating low-dose IL-2 treatment for selectively modulating CD4+ Tregs.