The Association of Cytokines IL-2, IL-6, TNF-α, IFN-γ, and IL-10 With the Disease Severity of COVID-19: A Study From Bangladesh.

Introduction Clinically, the early prediction of the severity of COVID-19 is often challenging, as a dramatic change in severity can occur without warning. The severity of COVID-19 disease is associated with an increased level of inflammatory mediators, including cytokines. This study aimed to evaluate the association of the levels of cytokines interleukin (IL)-2, IL-6, tumor necrosis factor-alpha (TNF-α), interferon-gamma (IFN-γ), and IL-10 with the severity of COVID-19 in Bangladesh. Materials and methods This cross-sectional study included a total of 60 confirmed cases of COVID-19, comprising 30 severe cases (Group A) and 30 non-severe cases (Group B), and 10 healthy individuals (Group C) attending Bangabandhu Sheikh Mujib Medical University (BSMMU) from March 2021 to February 2022. The cytokine assay was performed using the human Th1/Th2/Th17 cytokine kit BD cytometric bead array (CBA) on the BD Accuri C6 Plus flow cytometer. Statistical analysis was conducted using IBM SPSS Statistics for Windows, Version 23 (Released 2015; IBM Corp., Armonk, New York). Results The mean ages of the patients in Groups A, B, and C were 60.73±5.97, 57.13±7.68, and 48.10±9.13 years, respectively, with a male predominance in all groups. The mean IL-2, IL-6, IL-10, and TNF-α levels had a positive correlation with the increased age group and male gender, although it was not statistically significant. The mean IL-6 and IFN-γ levels were significantly higher among severe cases (216.95±147.78 and 0.98±0.95 pg/mL, respectively) compared to non-severe cases (94.29±128.79 and 0.41±0.61 pg/mL, respectively) and healthy individuals (1.08±1.97 and 0.15±0.28 pg/mL, respectively). Furthermore, the anti-inflammatory cytokine IL-10 was also significantly higher among severe cases (17.92±21.87 pg/mL) compared to non-severe cases (5.38±6.73 pg/mL) and healthy individuals (1.62±1.65 pg/mL). Conclusion IL-6, IFN-γ, and IL-10 have a significant association with the severity of COVID-19 disease. Clinicians treating patients with COVID-19 can consider the level of these cytokines as biomarkers of severity.

Are single nucleotide polymorphisms in the IL-2 gene biomarkers for Hashimoto's thyroiditis?

Background and aims: Hashimoto's thyroiditis (HT) is an autoimmune disorder that can lead to hypothyroidism. The pathophysiology of HT involves the production of antithyroid antibodies that attack the thyroid tissue, causing inflammation and progressive fibrosis. Recent studies demonstrated a strong correlation between Interleukin-2 (IL-2) levels and the development of autoimmune diseases, suggesting that this cytokine may play a crucial role in the pathogenesis of HT. Methods: In this study, we determined the presence of the point mutation +114T/G in the IL-2 gene in patients with HT compared with a control group, and also the serum level of anti-thyroid peroxidase (TPOAbs) and anti-thyroglobulin (TgAbs) antibodies in HT patients with vs. without the mutation. The sequences of the IL-2 gene obtained from subjects were determined by the Sanger sequencing method. Results: Our study did not reveal that the +114T/G polymorphism of the IL-2 gene is a susceptibility or protective factor for HT. No significant correlations were observed between the reference genotype, hetero- and homozygous +114T/G polymorphism and TPOAbs, respectively TgAbs serum levels in HT patients. Conclusions: Further studies of more cases are needed to identify more polymorphisms in the IL-2 gene and study their correlations with HT.

The efficacy and safety of short-term and low-dose IL-2 combined with tocilizumab to treat rheumatoid arthritis.

Background: Immunotherapy targeting factors related to immune imbalance has been widely employed for RA treatment. This study aimed to evaluate the efficacy and safety of low-dose interleukin (IL)-2 combined with tocilizumab (TCZ), a biologics targeting IL-6, in RA patients. Methods: Fifty adults with active RA who met the criteria with complete clinical data were recruited, and divided into three groups: control group (n=15), IL-2 group (n=26), and IL-2+TCZ group (n=9). In addition to basic treatment, participants in the IL-2 group received IL-2 (0.5 MIU/day), while participants in the IL-2+TCZ group received IL-2 (0.5 MIU/day) along with one dose of TCZ (8 mg/kg, maximum dose: 800 mg). All subjects underwent condition assessment, laboratory indicators and safety indicators detection, and records before treatment and one week after treatment. Results: Compared with the baseline, all three groups showed significant improvement in disease conditions, as evidenced by significantly reduced disease activity indicators. The low-dose IL-2 and combination treatment groups demonstrated a violent proliferation of Tregs, while the absolute number of Th1, Th2, and Th17 cells in the latter group showed a decreasing trend. The decrease in the Th17/Treg ratio was more pronounced in the IL-2+TCZ groups. No significant adverse reactions were observed in any of the patients. Conclusion: Exogenous low doses of IL-2 combined TCZ were found to be safe and effective in reducing effector T cells and appropriately increasing Treg levels in RA patients with high effector T cell levels. This approach helps regulate immune homeostasis and contributes to the prevention of disease deterioration. Clinical trial registration: https://www.chictr.org.cn/showprojEN.html?proj=13909, identifier ChiCTR-INR-16009546.

Interleukin-2 is required for NKp30-dependent NK cell cytotoxicity by preferentially regulating NKp30 expression.

Natural killer (NK) cells are key effectors in cancer immunosurveillance, eliminating a broad spectrum of cancer cells without major histocompatibility complex (MHC) specificity and graft-versus-host diseases (GvHD) risk. The use of allogeneic NK cell therapies from healthy donors has demonstrated favorable clinical efficacies in treating diverse cancers, particularly hematologic malignancies, but it requires cytokines such as IL-2 to primarily support NK cell persistence and expansion. However, the role of IL-2 in the regulation of activating receptors and the function of NK cells expanded for clinical trials is poorly understood and needs clarification for the full engagement of NK cells in cancer immunotherapy. Here, we demonstrated that IL-2 deprivation significantly impaired the cytotoxicity of primary expanded NK cells by preferentially downregulating NKp30 but not NKp46 despite their common adaptor requirement for expression and function. Using NK92 and IL-2-producing NK92MI cells, we observed that NKp30-mediated cytotoxicity against myeloid leukemia cells such as K562 and THP-1 cells expressing B7-H6, a ligand for NKp30, was severely impaired by IL-2 deprivation. Furthermore, IL-2 deficiency-mediated NK cell dysfunction was overcome by the ectopic overexpression of an immunostimulatory NKp30 isoform such as NKp30a or NKp30b. In particular, NKp30a overexpression in NK92 cells improved the clearance of THP-1 cells in vivo without IL-2 supplementation. Collectively, our results highlight the distinct role of IL-2 in the regulation of NKp30 compared to that of NKp46 and suggest NKp30 upregulation, as shown here by ectopic overexpression, as a viable modality to harness NK cells in cancer immunotherapy, possibly in combination with IL-2 immunocytokines.

NOD/Scid IL2Rγnull Mice Reconstituted with PBMCs from Patients with Atopic Dermatitis or Psoriasis Vulgaris Reflect the Respective Phenotype.

NSG (NOD/Scid IL2Rγnull) mice reconstituted with PBMCs donated by patients with ulcerative colitis or Crohn's disease highly reflect the respective pathological phenotype. To determine whether these findings could be applicable to atopic dermatitis (AD) and psoriasis vulgaris (PV), PBMCs isolated from patients with AD and PV were first subjected to immunological profiling. Subsequently, NSG mice were reconstituted with these PBMCs. Hierarchical clustering and network analysis revealed a distinct profile of patients with AD and PV with activated CD4+ T cells (CD69, CD25) occupying a central position in the AD network and CD4+ CD134+ cells acting as the main hub in the PV network. After dermal application of DMSO, both NSG mice reconstituted with PBMCs from donors with AD (ie, NSG-AD mice) and NSG mice reconstituted with PBMCs from donors with PV (ie, NSG-PV mice) exhibited increased clinical, skin, and histological scores. Immunohistochemical analysis, frequencies of splenic human leukocytes, and cytokine expression levels indicated that CD4+ CD69+ cells, M1 and TSLP receptor-expressing monocytes, switched B cells, and monocyte chemoattractant protein 3 were the driving factors of inflammation in NSG-AD mice. In contrast, inflammation in NSG-PV mice was characterized by an increase in fibroblasts in the epidermis, frequencies of CD1a-expressing monocytes, and IL-17 levels. Therefore, the pathological phenotypes of NSG-AD mice and NSG-PV mice differ and partially reflect the respective human diseases.

Development of Biomarkers and Prognosis Model of Mortality Risk in Patients with COVID-19.

Background: As of 30 April 2023, the COVID-19 pandemic has resulted in over 6.9 million deaths worldwide. The virus continues to spread and mutate, leading to continuously evolving pathological and physiological processes. It is imperative to reevaluate predictive factors for identifying the risk of early disease progression. Methods: A retrospective study was conducted on a cohort of 1379 COVID-19 patients who were discharged from Xin Hua Hospital affiliated with Shanghai Jiao Tong University School of Medicine between 15 December 2022 and 15 February 2023. Patient symptoms, comorbidities, demographics, vital signs, and laboratory test results were systematically documented. The dataset was split into testing and training sets, and 15 different machine learning algorithms were employed to construct prediction models. These models were assessed for accuracy and area under the receiver operating characteristic curve (AUROC), and the best-performing model was selected for further analysis. Results: AUROC for models generated by 15 machine learning algorithms all exceeded 90%, and the accuracy of 10 of them also surpassed 90%. Light Gradient Boosting model emerged as the optimal choice, with accuracy of 0.928 ± 0.0006 and an AUROC of 0.976 ± 0.0028. Notably, the factors with the greatest impact on in-hospital mortality were growth stimulation expressed gene 2 (ST2,19.3%), interleukin-8 (IL-8,17.2%), interleukin-6 (IL-6,6.4%), age (6.1%), NT-proBNP (5.1%), interleukin-2 receptor (IL-2R, 5%), troponin I (TNI,4.6%), congestive heart failure (3.3%) in Light Gradient Boosting model. Conclusion: ST-2, IL-8, IL-6, NT-proBNP, IL-2R, TNI, age and congestive heart failure were significant predictors of in-hospital mortality among COVID-19 patients.

A novel dual mechanism-of-action bispecific PD-1-IL-2v armed by a "ßγ-only" interleukin-2 variant.

Introduction: Interleukin-2 (IL-2) is one of the first cytokines to be discovered as an immune agonist for cancer immunotherapy. Biased IL-2 variants had been discovered to eliminate Treg activation or enhance the tumor specific T cell cytotoxicity. However, all the biased IL-2 variants pose the risk to overstimulate immune response at a low-dose range. Here, we introduce a novel dual-MOA bispecific PD-1-IL-2v molecule with great anti-tumor efficacy in a high dosed manner. Methods: The novel IL-2 variant was designed by structural truncation and shuffling. The single armed bispecific PD-1-IL-2v molecule and IL-2v were studied by immune cell activations in vitro and in vivo and anti-tumor efficacy in mouse model. Results and discussion: The IL-2 variant in this bispecific antibody only binds to IL-2Rßγ complex in a fast-on/off manner without α, ß or γ single receptor binding. This IL-2v mildly activates T and NK cells without over stimulation, meanwhile it diminishes Treg activation compared to the wild type IL-2. This unique bispecific molecule with "ßγ-only" IL-2v can not only "in-cis" stimulate and expand CD8 T and NK cells moderately without Treg activation, but also block the PD-1/L1 interaction at a similar dose range with monoclonal antibody.

Comparison of Low-Dose Interleukin 2 Therapy in Conjunction With Standard Therapy in Patients With Systemic Lupus Erythematosus vs Rheumatoid Arthritis: A Systematic Review.

This systematic review aims to compare the efficacy and safety of a novel immunotherapy with low-dose interleukin 2 (IL2) across two of the most prevalent autoimmune diseases i.e. systemic lupus erythematosus (SLE) and rheumatoid arthritis (RA). Contemporary therapeutic practices have not been able to achieve complete remission from these autoimmune disorders. In contrast, low-dose IL2 has shown promise in achieving this therapeutic goal via inducing self-tolerance in patients with autoimmune diseases; however, due to variable irregularities among autoimmune processes of variable diseases, the benefit of low-dose IL2 could not be determined among different autoimmune diseases. Therefore, we conducted a study to compare low-dose IL2 therapy effects on SLE and RA. We systematically screened four databases: PubMed, Medical Literature Analysis and Retrieval System Online (MEDLINE), PubMed Central (PMC), and Google Scholar. Inclusion and exclusion criteria were implemented. Quality appraisal of studies chosen for the review was done using the Cochrane Risk-of-Bias (RoB) assessment tool for randomized controlled trials, and the Newcastle-Ottawa Scale (NOS) and JBI critical appraisal tool for non-randomized clinical trials. Information was gathered from seven articles: three randomized controlled trials and four non-randomized clinical trials. Our review concluded that low-dose IL2 therapy in conjunction with respective standard therapies for SLE and RA has a higher efficacy and safety profile as compared to standard therapy alone and the therapeutic effects were comparable in both SLE and RA patients treated with low-dose IL2; however, this novel intervention does not seem to have a significant corrective effect on the biomarkers of RA as it does for SLE biomarkers.

Association between peripheral plasma cytokine levels and suicidal ideation in first-episode, drug-naïve major depressive disorder.

BACKGROUND: Inflammatory processes could potentially impact both mood and suicide risk, however, the relationship between cytokines and suicidal ideation remains unclear. This study aimed to investigate the association between plasma levels of cytokines and suicidal ideation in population with major depressive disorders (MDD). METHODS: A cross-sectional study was performed to assess the peripheral plasma levels of interleukin-1ß (IL-1ß), IL-2, IL-6, IL-8, IL-10 and tumor necrosis factor-α (TNF-α) in 88 Chinese Han first-episode drug-naïve MDD patients. Suicidal ideation in the past week were identified using the Beck Scale for Suicide Ideation-Chinese Version (BSI-CV). The Hamilton Depression Rating Scale-17 (HAMD-17), the Hamilton Anxiety Rating Scale-14 (HAMA-14) and the Childhood Trauma Questionnaire (CTQ) was used to assess depression, anxiety and childhood trauma. Multivariable logistic regression models were used to estimate the association between cytokines and suicidal ideation. Interaction and stratified analyses were conducted according to age, sex, marital status, education, smoking status, BMI and physical activity. RESULTS: Among the 88 participants, 42 individuals (47.7%) reported suicidal ideation within the past week. In the fully adjusted model, a statistically significant trend was observed in the association between IL-2 level and suicidal ideation (OR: 1.40, 95% CI: 1.00-1.97). The stratified analysis showed a statistically significant association between IL-6 level and suicidal ideation among younger people (OR: 1.17, 95% CI: 1.01-1.36) and a significant positive association between IL-8 (OR: 1.59, 95% CI: 1.03-2.44) and IL-10 (OR: 2.51, 95% CI: 1.27-4.96) levels and suicide ideation among higher educated populations. LIMITATIONS: The cross-sectional design, residual confounding effects and small sample size CONCLUSION: Our findings indicate a significant positive association between plasma IL-2 level and suicidal ideation in MDD patients. IL-2 has the potential to be a biomarker of suicidal ideation in patients with depression.

Establishment of reference intervals for plasma IL-2, IL-4, IL-5, and IL-17A in healthy adults from the Jiangsu region of eastern China using flow cytometry: A single-center study.

BACKGROUND: Cytokines are of utmost importance in both the physiological and pathological immune responses of the human body. This study utilized flow cytometry to measure the levels of plasma interleukin-2 (IL-2), interleukin-4 (IL-4), interleukin-5 (IL-5) and interleukin-17A (IL-17A) and established their reference intervals, aiming to provide data support for the diagnosis and treatment of clinical diseases. METHODS: According to the inclusion and exclusion criteria, a total of 728 reference individuals were included in this study from January 2023 to June 2023. The Kolmogorov-Smirnov test was used to analyse the distributions of plasma IL-2, IL-4, IL-5 and IL-17A. The reference intervals of plasma IL-2, IL-4, IL-5 and IL-17A were established by the unilateral percentile method (95th percentile) based on the guidelines of C28-A 3 and WS/T 402-2012. RESULTS: In this study, the levels of plasma IL-2, IL-4, IL-5 and IL-17A were nonnormally distributed. The concentrations of plasma IL-2, IL-4, IL-5 and IL-17A in healthy adults were not significantly different by sex or age (all P > 0.05). Therefore, all the reference individuals were combined into one group, and the reference intervals of plasma IL-2, IL-4, IL-5 and IL-17 were established by flow cytometry (IL-2 ≤ 10.25 pg/mL, IL-4 ≤ 9.87 pg/mL, IL-5 ≤ 3.36 pg/mL and IL-17A ≤ 9.46 pg/mL). CONCLUSIONS: We first established the reference intervals of plasma IL-2, IL-4, IL-5 and IL-17A in healthy adults based on a single-center population in the Jiangsu region in eastern China, which will provide an important reference value for evaluating human immune status and the diagnosis and treatment of clinical diseases.

Mathematical model for IL-2-based cancer immunotherapy.

A basic mathematical model for IL-2-based cancer immunotherapy is proposed and studied. Our analysis shows that the outcome of therapy is mainly determined by three parameters, the relative death rate of CD4+ T cells, the relative death rate of CD8+ T cells, and the dose of IL-2 treatment. Minimal equilibrium tumor size can be reached with a large dose of IL-2 in the case that CD4+ T cells die out. However, in cases where CD4+ and CD8+ T cells persist, the final tumor size is independent of the IL-2 dose and is given by the relative death rate of CD4+ T cells. Two groups of in silico clinical trials show some short-term behaviors of IL-2 treatment. IL-2 administration can slow the proliferation of CD4+ T cells, while high doses for a short period of time over several days transiently increase the population of CD8+ T cells during treatment before it recedes to its equilibrium. IL-2 administration for a short period of time over many days suppresses the tumor population for a longer time before approaching its steady-state levels. This implies that intermittent administration of IL-2 may be a good strategy for controlling tumor size.

Modulatory effect of interleukin-2 loaded chitosan nano sphere on regulatory T cell activity in streptozotocin-induced diabetic mice.

OBJECTIVE: The current study aimed to assess the modulating effect of IL-2 encapsulated chitosan-nanoparticles (CSNPs) on the function of Treg cells through induction of type 1 diabetes (T1D). Treg cell function was monitored by the forkhead box P3 (FoxP3) and transforming growth factor beta (TGFß) levels, correlating them with blood glucose and serum insulin levels. MATERIALS AND METHODS: In this case-control study, a low dose of IL-2 (free and chitosan-loaded) was injected into a diabetic mice group. The levels of FoxP3 and TGF-ß 1 were assessed using Enzyme-Linked Immunosorbent Assay. In addition, blood glucose and serum insulin levels were determined. RESULTS: The mean glucose level decreased significantly after free rIL-2 or rIL-2 / CSNPs treatment. Meanwhile, the mean serum insulin level was significantly increased after treatment with free rIL-2 or rIL-2/CSNPs. The mean levels of FoxP3 and TGFß 1 were significantly increased with either free rIL-2 or rIL-2/CSNPs compared to the T1D untreated group (P < 0.001). In the treated mice group receiving free CSNPs, there was a significant negative correlation between glucose and insulin levels. Moreover, FoxP3 & TGFß 1 levels had a significant positive correlation. In treated mice groups with free rIL-2 and IL-2 CSNPs, there was a significant positive correlation between FoxP3 and glucose levels. A significant negative correlation was found after conducting a correlation between insulin level and FoxP3 in the T1D/ rIL-2 / CSNPs group. CONCLUSIONS: Low-dose IL-2 selectively modulates FoxP3 + Tregs, and TGFß 1 increases their levels. These results demonstrated that IL-2-free and chitosan-loaded nanoparticles can be therapeutic agents in T1D.

Impacts of cryopreservation on phenotype and functionality of mononuclear cells in peripheral blood and ascites.

Background: Mononuclear cells in peripheral blood and ascites are important clinical resources commonly used in translational and basic research. However, the impact of different cryopreservation durations and extra freeze-thaw cycles on the number and function of mononuclear cells is unknown. Methods: Peripheral blood samples (n = 21) and ascites samples (n = 8) were collected from healthy volunteers and ovarian cancer patients. Mononuclear cells were isolated, frozen, and thawed at 6 and 12 months. The impact of cryopreservation on cell viability, the phenotype, and the activation and proliferation of T cells were analyzed by flow cytometry. Single-cell sequencing was applied to investigate the underlying mechanism. Results: The cell number and viability of mononuclear cells in peripheral blood and ascites were significantly decreased after cryopreservation. The T lymphocytes, especially CD4+ T cells, were affected the most significantly. By contrast, monocytes, natural killer (NK) cells, natural killer T (NKT) cells, and B cells were more tolerant. Meanwhile, T cell proliferation and IL-2 secretion are significantly affected after long-term cryopreservation. Mechanistically, the cell death induced by elevated reactive oxygen species (ROS) was involved in the reduction of CD4+ T cells after cryopreservation. Conclusions: Our data indicates that different subtypes of mononuclear cells exhibit different tolerance capacities upon cryopreservation. Thus, our research can provide evidence and support for individuals who are conducting experiments using frozen clinical patient-derived mononuclear cells, for basic research or clinical trials. In addition, extra caution is worthwhile when researchers compare immune cell functionality from peripheral blood or ascites across datasets obtained in different cryopreservation conditions.

Cellular and molecular signaling towards T cell immunological self-tolerance.

The binding of a cognate antigen to T cell receptor (TCR) complex triggers a series of intracellular events controlling T cell activation, proliferation, and differentiation. Upon TCR engagement, different negative regulatory feedback mechanisms are rapidly activated to counterbalance T cell activation, thus preventing excessive signal propagation and promoting the induction of immunological self-tolerance. Both positive and negative regulatory processes are tightly controlled to ensure the effective elimination of foreign antigens while limiting surrounding tissue damage and autoimmunity. In this context, signals deriving from co-stimulatory molecules (i.e., CD80, CD86), co-inhibitory receptors (PD-1, CTLA-4), the tyrosine phosphatase CD45 and cytokines such as IL-2 synergize with TCR-derived signals to guide T cell fate and differentiation. The balance of these mechanisms is also crucial for the generation of CD4+ Foxp3+ regulatory T cells, a cellular subset involved in the control of immunological self-tolerance. This review provides an overview of the most relevant pathways induced by TCR activation combined with those derived from co-stimulatory and co-inhibitory molecules implicated in the cell-intrinsic modulation of T cell activation. In addition to the latter, we dissected mechanisms responsible for T cell-mediated suppression of immune cell activation through regulatory T cell generation, homeostasis, and effector functions. We also discuss how imbalanced signaling derived from TCR and accessory molecules can contribute to autoimmune disease pathogenesis.

Interleukin-2-induced skin inflammation.

Recombinant human IL-2 has been used to treat inflammatory diseases and cancer; however, side effects like skin rashes limit the use of this therapeutic. To identify key molecules and cells inducing this side effect, we characterized IL-2-induced cutaneous immune reactions and investigated the relevance of CD25 (IL-2 receptor α) in the process. We injected IL-2 intradermally into WT mice and observed increases in immune cell subsets in the skin with preferential increases in frequencies of IL-4- and IL-13-producing group 2 innate lymphoid cells and IL-17-producing dermal γδ T cells. This overall led to a shift toward type 2/type 17 immune responses. In addition, using a novel topical genetic deletion approach, we reduced CD25 on skin, specifically on all cutaneous cells, and found that IL-2-dependent effects were reduced, hinting that CD25 - at least partly - induces this skin inflammation. Reduction of CD25 specifically on skin Tregs further augmented IL-2-induced immune cell infiltration, hinting that CD25 on skin Tregs is crucial to restrain IL-2-induced inflammation. Overall, our data support that innate lymphoid immune cells are key cells inducing side effects during IL-2 therapy and underline the significance of CD25 in this process.

Correlation of serum IL-2 and IFN-γ levels with clinical prognosis of nasopharyngeal carcinoma patients and analysis of risk factors.

Background: This study aims to investigate the correlation between serum levels of interleukin-2 (IL-2) and interferong (IFN-g) and the clinical prognosis of patients with nasopharyngeal carcinoma (NPC). Additionally, the study aims to analyse the risk factors associated with this correlation. Methods: The clinical data of 195 NPC patients admitted to our hospital from October 2020 to October 2022 were selected for a retrospective study. Based on the Glasgow score, patients were divided into two groups: the good prognosis group (group g), consisting of patients who scored 0 points, and the poor prognosis group (group p), consisting of patients who scored 1-2 points. The levels of serum IL-2 and IFN-g were compared between the two groups, and the clinical values of serum IL-2 and IFN-g in the prognosis of patients were analysed. The clinical parameters of the patients were collected, and the risk factors affecting the prognosis of NPC were analysed by univariate and multivariate logistic regression.

Interleukin-2/anti-interleukin-2 immune complex attenuates cold ischemia-reperfusion injury after kidney transplantation by increasing renal regulatory T cells.

BACKGROUND: Cold ischemia-reperfusion injury (IRI) is an unavoidable complication of kidney transplantation. We investigated the role of regulatory T cells (Treg) in cold IRI and whether the interleukin (IL)-2/anti-IL-2 antibody complex (IL-2C) can ameliorate cold IRI. METHODS: We developed a cold IRI mouse model using kidney transplantation and analyzed the IL-2C impact on cold IRI in acute, subacute and chronic phases. RESULTS: Treg transfer attenuated cold IRI, while Treg depletion aggravated cold IRI. Next, IL-2C administration prior to IRI mitigated acute renal function decline, renal tissue damage and apoptosis and inhibited infiltration of effector cells into kidneys and pro-inflammatory cytokine expression on day 1 after IRI. On day 7 after IRI, IL-2C promoted renal regeneration and reduced subacute renal damage. Furthermore, on day 28 following IRI, IL-2C inhibited chronic fibrosis. IL-2C decreased reactive oxygen species-mediated injury and improved antioxidant function. When IL-2C was administered following IRI, it also increased renal regeneration with Treg infiltration and suppressed renal fibrosis. In contrast, Treg depletion in the presence of IL-2C eliminated the positive effects of IL-2C on IRI. CONCLUSION: Tregs protect kidneys from cold IRI and IL-2C inhibited cold IRI by increasing the renal Tregs, suggesting a potential of IL-2C in treating cold IRI. KEY POINTS: Interleukin (IL)-2/anti-IL-2 antibody complex attenuated acute renal injury, facilitated subacute renal regeneration and suppressed chronic renal fibrosis after cold ischemia-reperfusion injury (IRI) by increasing the renal Tregs. IL-2/anti-IL-2 antibody complex decreased reactive oxygen species-mediated injury and improved antioxidant function. This study suggests the therapeutic potential of the IL-2/anti-IL-2 antibody complex in kidney transplantation-associated cold IR.

Se Alleviated Pb-Caused Neurotoxicity in Chickens: SPS2-GPx1-GSH-IL-2/IL-17-NO Pathway, Selenoprotein Suppression, Oxidative Stress, and Inflammatory Injury.

Lead (Pb), a heavy metal environmental pollutant, poses a threat to the health of humans and birds. Inflammation is one of the most common pathological phenomena in the case of illness and poisoning. However, the underlying mechanisms of inflammation remain unclear. The cerebellum and the thalamus are important parts of the nervous system. To date, there have been no reports of Pb inducing inflammation in animal cerebellums or thalami. Selenium (Se) can relieve Pb poisoning. Therefore, we aimed to explore the mechanism by which Se alleviates Pb toxicity to the cerebellums and thalami of chickens by establishing a chicken Pb or/and Se treatment model. Our results demonstrated that exposure to Pb caused inflammatory damage in cerebellums and thalami, evidenced by the characteristics of inflammation, the decrease in anti-inflammatory factors (interleukin (IL)-2 and interferon-γ (INF-γ)), and the increase in pro-inflammatory factors (IL-4, IL-6, IL-12ß, IL-17, and nitric oxide (NO)). Moreover, we found that the IL-2/IL-17-NO pathway took part in Pb-caused inflammatory injury. The above findings were reversed by the supplementation of dietary Se, meaning that Se relieved inflammatory damage caused by Pb via the IL-2/IL-17-NO pathway. In addition, an up-regulated oxidative index malondialdehyde (MDA) and two down-regulated antioxidant indices (glutathione (GSH) and total antioxidant capacity (TAC)) were recorded after the chickens received Pb stimulation, indicating that excess Pb caused an oxidant/antioxidant imbalance and oxidative stress, and the oxidative stress mediated inflammatory damage via the GSH-IL-2 axis. Interestingly, exposure to Pb inhibited four glutathione peroxidase (GPx) family members (GPx1, GPx2, GPx3, and GPx4), three deiodinase (Dio) family members (Dio1, Dio2, and Dio3), and fifteen other selenoproteins (selenophosphate synthetase 2 (SPS2), selenoprotein (Sel)H, SelI, SelK, SelM, SelO, SelP1, SelPb, SelS, SelT, SelU, and selenoprotein (Sep)n1, Sepw1, Sepx1, and Sep15), suggesting that Pb reduced antioxidant capacity and resulted in oxidative stress involving the SPS2-GPx1-GSH pathway. Se supplementation, as expected, reversed the changes mentioned above, indicating that Se supplementation improved antioxidant capacity and mitigated oxidative stress in chickens. For the first time, we discovered that the SPS2-GPx1-GSH-IL-2/IL-17-NO pathway is involved in the complex inflammatory damage mechanism caused by Pb in chickens. In conclusion, this study demonstrated that Se relieved Pb-induced oxidative stress and inflammatory damage via the SPS2-GPx1-GSH-IL-2/IL-17-NO pathway in the chicken nervous system. This study offers novel insights into environmental pollutant-caused animal poisoning and provides a novel theoretical basis for the detoxification effect of Se against oxidative stress and inflammation caused by toxic pollutants.

Suspension culture promoted the expansion of NK-92 cells ex vivo by enhancing the expression of IL-2 receptor.

Vigorous ex vivo expansion of NK-92 cells is a pivotal step for clinical adoptive immunotherapy. Interleukin-2 (IL-2) is identified as a key cytokine for NK-92 cells, and it can stimulate cell proliferation after binding to the IL-2 receptor (IL-2R). In this work, the differences in IL-2 consumption and IL-2R expression were investigated between the two culture modes. The results showed that suspension culture favored ex vivo expansion of NK-92 cells compared with static culture. The specific consumption rate of IL-2 in suspension culture was significantly higher than that in static culture. It was further found that the mRNA levels of the two IL-2R subunits remained unchanged in suspension culture, but the proportion of NK-92 cells expressing IL-2Rß was increased, and the fluorescence intensity of IL-2Rß was remarkably enhanced. Meanwhile, the proportion of cells expressing IL-2R receptor complex also increased significantly. Correspondingly, the phosphorylation of STAT5, a pivotal protein in the downstream signaling pathway of IL-2, was up-regulated. Notably, the expression level and colocalization coefficient of related endosomes during IL-2/IL-2R complex endocytosis were markedly elevated, suggesting the enhancement of IL-2 endocytosis. Taken together, these results implied that more IL-2 was needed to support cell growth in suspension culture. Therefore, the culture process was optimized from the perspective of cytokine utilization to further improve the NK-92 cell's expansion ability and function. This study provides valuable insight into the efficient ex vivo expansion of NK-92 cells.

Regulatory T Cells for Control of Autoimmunity.

Regulatory T (Treg) cells, which specifically express the master transcription factor FoxP3, are indispensable for the maintenance of immunological self-tolerance and homeostasis. Their functional or numerical anomalies can be causative of autoimmune and other inflammatory diseases. Recent advances in the research of the cellular and molecular basis of how Treg cells develop, exert suppression, and maintain their function have enabled devising various ways for controlling physiological and pathological immune responses by targeting Treg cells. It is now envisaged that Treg cells as a "living drug" are able to achieve antigen-specific immune suppression of various immune responses and reestablish immunological self-tolerance in the clinic.