Serum sCD25 Research Articles

The effectiveness of the doxorubicin-etoposide-methylprednisolone regimen for adult HLH secondary to rheumatic disease.

To investigate the efficacy of the doxorubicin-etoposide-methylprednisolone, DEP) regimen as an effective treatment for adult Hemophagocytic Lymphohistiocytosis secondary to rheumatic disease and analyze prognosis in these patients. Fifty-eight adult patients diagnosed with Hemophagocytic Lymphohistiocytosis secondary to rheumatic disease admitted to Beijing Friendship Hospital from 1st Jan. 2018 to 31st Dec. 2022 were retrospectively included in this study. Patients were grouped according to previous treatment. Clinical data and laboratory characteristics of patients were retrospectively analyzed. The efficacy was evaluated every 2weeks after initiating the first course of the DEP regimen and until the last inpatient or 31st Dec. 2023. 26 patients were included in Group A and 32 patients were included in Group B due to the previous treatment. After the first course of the DEP regimen, the overall response rate of all patients was 82.8%, with 13.8% in complete response and 69% in partial response. There was no significant statistical objective response rate between the two groups after the DEP regimen, except at 2-week. Serum ferritin, sCD25, ALT, AST, and DBIL concentrations were significantly lower at 2, 4 and 6-week than pre-treatment (P < 0.05). The overall mortality rate is 20.7% (12/58). Importantly, advanced age, initial level of HB and PLT, and central nervous system (CNS) involvement were independent poor risk factors affecting OS in bivariate analysis. The DEP regimen is effective for adult HLH secondary rheumatic disease with a high overall rate and accepted side effects.

Abstract A002: Serum levels of immune markers associated with pathological complete response (pCR) and immune-related adverse events (irAEs) in early-stage breast cancer patients receiving immune checkpoint inhibitor plus chemotherapy in the I-SPY 2 trial

Abstract Background: Surrogate biomarkers of efficacy and AEs are needed for therapy with immune checkpoint inhibitors (ICI). Although ICI treatments have demonstrated effectiveness in combating early-stage breast cancer (BC), predicting early response and the associated risk of irAEs are important considerations. In this study, we evaluated pre-treatment, early on-treatment, and early changes of serum immune markers in women with BC treated with neoadjuvant chemotherapy plus an ICI. Methods: Serum samples were obtained from 49 women with early stage HER2-negative BC enrolled in the I-SPY 2 trial who received paclitaxel plus an ICI (anti-PD-1) followed by anthracycline/cyclophosphamide. Serum was collected at baseline (T0) and 3 weeks after the first dose (T1). Serum samples were assayed by Ella multiplex immunoassays for 18 pre-selected immune markers, including soluble immune checkpoint molecules (sPD-L1, LAG-3), cytokines (IL-6, IL-8, IFNg, TNFa, IL-10, G-CSF, MCP-1), chemokines (CXCL9, CXCL10, CXCL11, CXCL13), molecules associated with angiogenesis/lymphangiogenesis (VEGF-C), and other markers reflecting immune inflammation/activation (C-Reactive Protein [CRP], CD163, sCD25, GranzymeB). Serum markers showing significant changes from T0 to T1 were identified with the Wilcoxon test. Associations between absolute levels or changes in serum markers and response to therapy (pCR) and/or irAEs were assessed with the Mann–Whitney test. Results: Serum IFNg, G-CSF, IL-10, LAG-3, CCL2, CXCL-10, sCD25, CXCL-9 and CXCL-11 significantly increased between T0 and T1 (P &amp;lt;0.0001, 0.014, &amp;lt;0.001, 0.043, &amp;lt;0.0001, 0.032, &amp;lt;0.0001, &amp;lt;0.0001, &amp;lt;0.0001, respectively). In hormone-receptor positive (HR+)/HER2- patients (N=29), low baseline IFNg serum levels were associated with response to therapy (P = 0.04). In addition, a decrease in sCD25 serum levels from T0 to T1 was strongly associated with response (P = 0.0047) in all HER2- patients. Immune-related AEs were reported for a small number of patients (N=9/49). Increases in serum levels of VEGF-C from T0 to T1 were significantly associated with irAEs (P = 0.0055). In addition, patients who developed irAEs had significantly higher T0 and T1 levels of CD163 (P = 0.022 and 0.024, respectively). Conclusions: Baseline serum level of IFNg and early changes in serum sCD25 levels could be used to monitor and predict clinical benefit from anti-PD-1 agents. This study also suggests that VEGF-C and CD163 may serve as possible candidate prognostic biomarkers for irAEs in patients receiving anti-PD-1 therapy in the early-stage BC setting. While our preliminary results are promising, additional validation in a larger sample size is crucial to confirm the observed trends. Therefore, candidate biomarkers from additional I-SPY 2 arms containing ICIs will be analyzed. Citation Format: Silver Alkhafaji, Denise M. Wolf, Amrita Basu, Lamorna Brown-Swigart, Rita Nanda, Minneta Liu, Gillian L. Hirst, Laura J. Esserman, Laura van 't Veer, Michael Campbell. Serum levels of immune markers associated with pathological complete response (pCR) and immune-related adverse events (irAEs) in early-stage breast cancer patients receiving immune checkpoint inhibitor plus chemotherapy in the I-SPY 2 trial [abstract]. In: Proceedings of the AACR Special Conference in Cancer Research: Advances in Breast Cancer Research; 2023 Oct 19-22; San Diego, California. Philadelphia (PA): AACR; Cancer Res 2024;84(3 Suppl_1):Abstract nr A002.

Serum sCD25 is an indicator for rheumatoid arthritis-associated interstitial lung disease.

CD25 (IL-2Rα) is one of IL-2 receptor's polypeptide subunits, and its soluble form is increased in patients with various inflammatory or autoimmune diseases. This study aimed to evaluate the clinical correlation of serum soluble CD25 (sCD25) with interstitial lung disease (ILD) in rheumatoid arthritis (RA) patients. 294 RA patients, including 72 in the discovery cohort (15 patients with ILD, 57 patients without ILD), 222 in the validation cohort (41 patients with ILD and 181 patients without ILD), and 58 healthy controls (HCs) were recruited. High-resolution computed tomography (HRCT) scan provided evidence and patterns of RA-ILD. Serum sCD25 concentrations were measured by enzyme-linked immunosorbent assay (ELISA). Clinical and laboratory data were recorded and the association with sCD25 was also analysed. In the discovery cohort, 16 RA-related molecules including cytokines, chemokines and functional soluble cell surface proteins were investigated. The results showed that sCD25 was significantly higher in RA-ILD than in RA-no-ILD group (p=0.004). ROC analysis also showed RA-ILD was discriminated with RA-no-ILD by sCD25 (AUC=0.695, 95% CI=0.541-0.849). Logistics regression demonstrated that sCD25 was one of the risk factors of RA-ILD. This result was further confirmed in validation cohort (p<0.001). According to the cut-off value in the discovery cohort, the sensitivity and specificity of sCD25 in RA-ILD were 51.2%, 77.3%, respectively. Compared with RA-no-ILD, serum level of sCD25 was also higher in different HRCT patterns including UIP, NSIP and RA-ILA. The ROC curves revealed sCD25 as diagnostic marker in UIP, NSIP and RA-ILA (with AUCs of 0.730, 0.761, and 0. 694, respectively, p<0.05). The result indicated that sCD25 was a biomarker for RA-ILD subtypes. Although sCD25 was not correlated with HRCT scores, it was significantly higher in consolidation pattern by HRCT. sCD25 was significantly elevated in RA-ILD (including UIP, NSIP and RA-ILA) compared to RA-no-ILD and HCs, which supports their value as a potential biomarker in RA-ILD screening and assessment.

Reticuloendothelial activation and phenotypic alteration of peripheral monocytes with enhanced liver recruitment drive liver injury secondary to yellow phosphorus.

Monocytes and macrophages play a crucial role in the pathogenesis of acute liver failure (ALF). We aimed to study reticuloendothelial activation and its correlation with disease severity in commonly encountered yellow phosphorus (rodenticide)-induced hepatotoxicity patients. We also studied peripheral monocyte phenotype in a subset of patients. Reticuloendothelial activation markers were analyzed and correlated with disease severity score in a prospectively collected database of yellow phosphorus-related hepatoxicity patients between 2018 and 2021. In a prospective cohort of these patients and age-matched healthy controls, peripheral blood monocyte phenotyping was performed. Reticuloendothelial activation markers were analyzed in 67 patients [Age: 23(12-64) years; median (range), men: 25, acute liver injury (ALI): 38, ALF: 29, model for end-stage liver disease (MELD) score: 28 (7-40)] of yellow phosphorus-induced hepatotoxicity. Serum ferritin (927; 10.3-34807ng/mL), sCD163 (4.59; 0.11-12.7μg/mL), sCD25 (3050; 5.6-17300pg/mL) and plasma von Willebrand factor (423.5, 103-1106IU/dL) were increased and showed significant correlation with liver disease severity assessed by MELD score (ρ=0.29, ρ=0.6, ρ=0.56 and ρ=0.46 respectively). Phenotyping and serum immune markers were performed in seven patients (M: 4; age: 27, 15-37years; median, range; MELD score: 36, 21-40) and compared with eight healthy controls. Increase in classical monocytes and decrease in patrolling and intermediate monocyte subsets were observed in ALF cohort. HLA-DRlow CD163hi (immune exhaustion), CD64hi (immune complex-mediated response), and CCR2hi (liver homing) monocyte phenotype was noted. Altered peripheral monocyte phenotype with enhanced liver homing and macrophage activation, suggests important role of innate immune activation, and provides a potential therapeutic target, in yellow phosphorus-induced hepatotoxicity.

509 AMG487, A CXCR3 Antagonist, changes the Inflammatory Milieu in Familial Hemophagocytic Lymphohistiocytosis (FHL) Hepatitis

OBJECTIVES/GOALS: Familial Hemophagocytic Lymphohistiocytosis (FHL) is a systemic inflammatory disease, causing acute liver failure (ALF). Elevated Interferon gamma (IFN-γ) results in increased hepatic transcription of the chemokines CXCL9 and CXCL10. Inhibition of their receptor CXCR3 may reduce leukocyte recruitment and ameliorate hepatitis. METHODS/STUDY POPULATION: To determine the functional role of the IFN-γ-induced ligands, CXCL9 and CXCL10, in hepatic leukocyte recruitment via CXCR3 we used a prf-/- mouse infected with Lymphocytic Choriomeningitis Virus (LCMV) in our well-established model mimicking human FHL. We used AMG487, a small molecule CXCR3 antagonist, while maintaining intact IFN-γ signaling. Mice were sacrificed 10 days after infection when mice developed features of FHL: cytopenias, organomegaly, elevated serum ferritin and sCD25, and hepatic inflammation. Hepatic inflammation was characterized using flow cytometry, liver histology and noninvasive markers of hepatitis (ALT, liver size). RESULTS/ANTICIPATED RESULTS: AMG487 did not ameliorate the overall disease phenotype with mice developing similar FHL characteristics compared to control, including weight loss, elevation of ALT and sIL-2r as well as degree of thrombocytopenia and anemia. There was significant reduction of recruitment of CXCR3+CD4+ T cells and B cells in mice treated with AMG487. This indicates the importance of CXCR3 receptor in humoral response in FHL hepatitis. In addition, treatment with AMG487 resulted in reduction of CXCR3 expression in hepatic inflammatory monocyte (iMonos) measured by mean fluorescence intensity (MFI). DISCUSSION/SIGNIFICANCE: This is the first pre-clinical experience using AMG487, a small molecule CXCR3 antagonist, to treat FHL hepatitis. AMG487 changed the hepatic inflammatory milieu, reducing CD4 T-cell and B-cell recruitment, as well as CXCR3 expression on iMonos. However, it did not ameliorate FHL hepatitis and other therapeutic approaches should be pursued.

CD25, Soluble CD25, and CCL17 As Potential Predictors of Clinical Response to Camidanlumab Tesirine in Patients with Relapsed/Refractory Classical Hodgkin Lymphoma

Introduction: Camidanlumab tesirine (Cami), an antibody-drug conjugate targeting CD25, has shown single-agent anti-tumor activity and manageable toxicity in a phase 2 trial in relapsed/refractory (R/R) classical Hodgkin lymphoma (cHL; Carlo-Stella, et al. 2022). In the phase 1 cHL trial, biopsy tumor cell CD25 histoscores (H-scores) were significantly higher in responders vs nonresponders and low baseline soluble CD25 (sCD25) was possibly related to response (Hamadani, et al. 2021). Separately, circulating CCL17 has been correlated with response to therapies for cHL (Plattel, et al. 2016). Objective: To assess CD25, sCD25, and CCL17 as predictive biomarkers of clinical response to Cami in patients (pts) with R/R cHL. Methods: This analysis was based on the open-label, multicenter, phase 2 study in pts with R/R cHL after ≥3 prior lines of therapy (or ≥2 in pts ineligible for SCT; NCT04052997). CD25 expression was assessed by immunohistochemistry (IHC) and H-score in all archival tumor biopsies and a subset of recent biopsies (archival biopsies taken after the last systemic anticancer treatment, including SCT if applicable); serum sCD25 and CCL17 were assessed by qualified immunoassays prior to Cami infusion on day 1 of each cycle. Cami may interfere with the sCD25 assay, underestimating post-baseline (BL) sCD25. CD25 IHC, BL sCD25 and CCL17, and changes in sCD25 and CCL17 from BL were compared between responders and nonresponders. Receiver operating characteristic (ROC) analyses were performed to evaluate the predictive potential of these measures as response biomarkers. Results: Assessments of CD25, sCD25, and CCL17 in pts with a best overall response (BOR) of complete or partial response (responders) and stable disease or PD (nonresponders) were performed for 111 of 117 pts treated with Cami (6 pts were not evaluable for BOR). No significant difference in tumor cell CD25 H-score was observed between responders and nonresponders in all (n=99) or recent biopsies (n=23; p>0.05 for both), despite higher median levels in responders. BL sCD25 (n=108) was significantly higher in nonresponders than responders (p=0.018; Fig 1); though, overlapping values were observed in a substantial number of pts. There was also a significantly greater decrease in sCD25 in nonresponders vs responders from BL to C3D1 (n=79; median 0.53 vs 1.02; p=0.018). While there was no significant difference in BL CCL17 levels (n=106), there was a significantly greater decrease in BL CCL17 in responders vs nonresponders at C2D1 (n=97; median 0.50 vs 0.81; p<0.01 log10 change). In ROC analyses in a subset of 96 pts with CD25 IHC and BL sCD25 results available, sCD25 alone showed a modest predictive potential (area under curve [AUC]=0.65) that was not improved with the addition of tumor cell CD25 H-score (AUC=0.67). In a subset of 76 pts with results available for sCD25 and CCL17 at BL and C2D1, ROC curves of BL sCD25, BL sCD25 plus BL CCL17, sCD25 change from BL, and CCL17 change from BL showed modest predictive potential (AUC<0.7 for all). A better AUC was found in a model including change from BL at C2D1 of sCD25 and CCL17 (AUC=0.74). This AUC was further increased in a model of BL sCD25 and CCL17 plus their change from BL at C2D1 and a model of BL sCD25 plus sCD25 and CCL17 change from BL at C2D1 (AUC=0.76 for both; Fig 2). The latter model had a higher Youden index. Conclusions: Higher median tumor cell CD25 H-score was seen in responders vs nonresponders in all and recent biopsies but the differences did not reach significance. These data warrant further investigations as phase 1 data showed significantly higher tumor CD25 expression in responders (Hamadani, et al. 2021). Nonresponders had significantly higher BL sCD25; however, this parameter alone has insufficient predictive potential for Cami efficacy. Predictive models including BL sCD25 plus sCD25 and CCL17 change from BL at C2D1 (± BL CCL17) showed the best ROC AUCs but need further refining to be clinically relevant. However, given the high overall and early responses in most pts treated with Cami, biomarkers predicting response at C2D1 are suboptimal unless reaching a higher sensitivity and specificity. Investigation of sCD25 in the context of the Cami mode of action and exposure-response and the potential value of sCD25 and CCL17 changes as early indicators of Cami's effect and as biomarkers for disease monitoring and response are ongoing. Funding: ADC Therapeutics SA; writing: CiTRUS Health Group. Figure 1View largeDownload PPTFigure 1View largeDownload PPT Close modal

SCD40L Is Increased and Associated with the Risk of Gestational Diabetes Mellitus in Pregnant Women with Isolated TPOAb Positivity.

Background Autoimmune disorders are associated with gestational diabetes mellitus (GDM) in pregnant women who were positive for thyroid peroxidase antibody (TPOAb). Soluble CD40 ligand (sCD40L) and soluble interleukin-2 receptor (sCD25) are abnormally expressed in autoimmune diseases and are reliable markers of inflammation. The purpose of this study was to evaluate sCD40L and sCD25 in early pregnancy and investigate their correlation with GDM and TPOAb. Methods A total of 126 pregnant women in the first trimester were enrolled for analysis: 93 were positive for TPOAb and 33 were negative for TPOAb. Demographical and clinical data in early pregnancy were collected. A total of 123 participants underwent a 75 g oral glucose tolerance test in the second trimester. Serum sCD40L and sCD25 levels were measured by ELISA. Results The incidence of GDM was 24.4% in pregnant women with isolated TPOAb positivity in our study. Both sCD40L and sCD25 were positively correlated with TPOAb (r = 0.476, P < 0.001; r = 0.188, P < 0.05). sCD40L was highest in (P < 0.001) Ab-positive women with GDM group (P < 0.05). After adjusting for TPOAb, age, TSH, FT4, triglycerides, and low-density lipoprotein cholesterol, multivariate logistic regression analysis showed that sCD40L was an independent risk factor for GDM in pregnant women with TPOAb positivity (odds ratio = 3.235, 95% confidence interval 1.024–10.218, P < 0.05). Conclusions About a quarter of pregnant women with isolated positive TPOAb might have GDM. sCD40L was an independent risk factor for GDM in women with isolated TPOAb positivity.

Up-regulated serum levels of soluble CD25 and soluble CD163 in pediatric patients with SARS-CoV-2

Similar to hemophagocytic lymphohistiocytosis (HLH), some patients with SARS-CoV-2 have cytokine storm. Serum soluble interleukin-2 receptor (sCD25) and soluble CD163 (sCD163) are potential diagnostic biomarkers for HLH that help in guiding its treatment. This study was the first to investigate serum sCD25 and sCD163 levels in SARS-CoV-2. Serum sCD25 and sCD163 were measured by ELISA in 29 patients with SARS-CoV-2, aged between 2 months and 16 years (13 had COVID-19 and 16 had multisystem inflammatory syndrome in children (MIS-C)), in comparison to 30 age- and sex-matched healthy control children and 10 patients with HLH. Levels of these markers were re-measured in 21 patients with SARS-CoV-2 who were followed up 3 months after recovery. Patients with SARS-CoV-2 had significantly higher serum sCD25 and sCD163 than healthy control children (P < 0.001). SARS-CoV-2 patients had significantly higher sCD25 than patients with HLH (P < 0.05). Serum sCD25 was a good differentiating marker between patients with SARS-CoV-2 and HLH. Although there was a significant decrease of serum sCD25 and sCD163 of the 21 SARS-CoV-2 patients who were followed up, these levels were still significantly higher than the healthy controls levels (P < 0.001). Conclusion: Serum sCD25 and sCD163 levels were up-regulated in SARS-CoV-2 patients. Serum sCD25 was a good differentiating marker between SARS-CoV-2 and HLH. This initial report requires further studies, on large scales, to investigate the relationship between SARS-CoV-2 and both sCD25 and sCD163, including the disease severity and outcome. The therapeutic role of sCD25 and sCD163 antagonists should also be studied in SARS-CoV-2 patients.What is Known:• Similar to hemophagocytic lymphohistiocytosis (HLH), some patients with COVID-19 have cytokine storm due to excessive pro-inflammatory host response.• Serum soluble interleukin-2 receptor (sCD25) and soluble CD163 (sCD163) are potential diagnostic biomarkers for HLH. Monitoring of serum sCD25 and sCD163 levels can also help in guiding the treatment.What is New:• Serum sCD25 and sCD163 levels are up-regulated in patients with COVID-19, including patients presenting with multisystem inflammatory syndrome in children (MIS-C).• Serum sCD25 is a good differentiating marker between SARS-CoV-2 and HLH.

Serum sCD25 Protein as a Predictor of Lack of Long-Term Benefits from Immunotherapy in Non-Small Cell Lung Cancer: A Pilot Study.

Simple SummaryThe prognosis of advanced lung cancer is poor. Even though it can improve with immunotherapy, most patients do not respond to treatment. Identifying patients who would not benefit from therapy is an unmet goal. We hypothesized that one of the molecules present in human serum (namely, the soluble form of the unit α of the interleukin-2 receptor, sCD25) could be used as a predictor of successful immunotherapy in patients with lung cancer. Our study showed that patients who presented high sCD25 levels before treatment (≥5.99 ng/mL) and/or about three months from the start of treatment (≥7.73 ng/mL) progressed faster and lived shorter without the disease progression and serious toxicity. Serum levels of sCD25 could easily indicate patients with lung cancer who would not achieve long-term benefits from immunotherapy. Therefore, other more effective therapies could be implemented.Prognosis of advanced non-small cell lung carcinoma (NSCLC) is poor. Even though it can improve with anti-PD-1/PD-L1 agents, most patients do not respond to treatment. We hypothesized that the serum soluble form of the unit α of the interleukin-2 receptor (sCD25) could be used as a biomarker of successful immunotherapy in NSCLC. We recruited patients dosed with atezolizumab (n = 42) or pembrolizumab (n = 20) and collected samples at baseline and during the treatment. Levels of sCD25 were quantified with the ELISA kits. Patients with a high sCD25 at baseline (sCD25.0 ≥ 5.99 ng/mL) or/and at the end of the fourth treatment cycle (sCD25.4 ≥ 7.73 ng/mL) progressed faster and lived shorter without the disease progression and serious toxicity. None of the patients with high sCD25 at both time points continued therapy longer than 9.3 months, while almost 40% of patients with low sCD25 were treated for ≥12.3 months. There was a 6.3-times higher incidence of treatment failure (HR = 6.33, 95% CI: 2.10–19.06, p = 0.001) and a 6.5-times higher incidence of progression (HR = 6.50, 95% CI: 2.04–20.73, p = 0.002) in patients with high compared with low sCD25.0 and sCD25.4. Serum levels of sCD25 may serve as a non-invasive biomarker of long-term benefits from the anti-PD-1/PD-L1s in NSCLC.

Elevated ferritin and soluble CD25 in critically ill patients are associated with parameters of (hyper) inflammation and lymphocyte cytotoxicity.

Critically ill patients may develop a potentially fatal hyperinflammatory condition known as secondary (acquired) hemophagocytic lymphohistiocytosis (sHLH), the cause of which is unclear. We evaluated serum ferritin and soluble CD25 (sCD25) in critically ill patients, and their association with other parameters of inflammation and critical illness. Moreover, aiming to better understand the pathogenesis of sHLH, we also evaluated lymphocyte cytotoxicity parameters and correlations with the inflammatory markers ferritin and sCD25. In a prospective observational study, 32 patients with ferritin ≥500 µg/L (24 with sepsis) were studied on admission to an intensive care unit (ICU) with regard to ferritin and corresponding clinical and laboratory features including sCD25, and detailed lymphocyte cytotoxicity and genetic analyses whenever possible. Critically ill patients had elevated, positively correlated levels of serum ferritin and sCD25 (rs=0.465, P=0.008); both associated with other risk factors of poor outcome in critically ill, such as thrombocytopenia (rs=-0.534, P=0.002 and rs=-0.421, P=0.018, respectively), and sCD25 with hypoalbuminemia (rs=-0.678, P<0.001) and life support treatments (rs=0.479, P=0.006). Interestingly, ferritin levels were inversely associated with natural killer (NK)-cell cytotoxicity (rs=-0.462, P=0.047) and degranulation (rs=-0.504, P=0.030). Moreover, of four patients with abnormally low cytotoxicity, three (75%) had <5% circulating NK-cells. Our study suggests that hyperferritinemia and sCD25 correlate with other laboratory parameters indicative of severe hyperinflammation and organ dysfunction in critically ill ICU-patients, indicating their value in identifying hyperinflammatory critically ill patients for early intervention. Furthermore, it suggests that hyperferritinemia and hyperinflammation may partly be associated with a low percentage circulating NK-cells, and hence, the associated low lymphocyte cytotoxicity.

Development, analytical validation, and initial clinical evaluation of a radioimmunoassay for the measurement of soluble CD25 concentrations in canine serum

During immune activation, CD25 is expressed by T cells, and its soluble form (sCD25) is released into the extracellular matrix and the bloodstream. In humans, serum sCD25 concentrations are used as a surrogate marker for autoimmune diseases, malignancies, and transplant rejection. However, a canine-specific assay for the measurement of sCD25 in dog serum has not previously been described. Therefore, the aims of this study were to develop and analytically validate a radioimmunoassay to measure sCD25 in canine serum, to establish a reference interval for canine sCD25, and to test the clinical utility of this assay with serum samples for dogs with various diseases. A competitive radioimmunoassay (RIA) was developed and analytically validated. Analytical validation consisted of lower limit of detection (LLOD), dilutional parallelism, spiking recovery, and intra- and inter-assay variability using pooled surplus canine serum samples. A reference interval was established in healthy dogs and serum samples from dogs with various types of neoplasia, IBD, liver disease, suspected pancreatitis, or suspected small intestinal disease and serum samples with an increased C-reactive protein concentration (CRP) were analyzed to test the clinical utility of the assay. LLOD was calculated to be 0.5 ng/mL. The mean (±SD) observed-to-expected ratio (O/E) for serial dilutions was 101.7 ± 14.0%, and the mean (± SD) O/E for spiking recovery was 93.2 ± 4.2%. Coefficients of variation (CVs) for intra-assay variability were ≤12.5% (mean ± SD: 7.5 ± 4.2%), and inter-assay CVs were ≤15.7% (mean ± SD: 11 ± 4.4%). A reference interval (RI) for canine sCD25 of 1.2–4.2 ng/mL was established from a population of 112 clinically healthy dogs. Dogs with neoplasia and dogs with suspected small intestinal disease had decreased concentrations of serum sCD25 when compared to healthy dogs (p < 0.0001, respectively). However, the majority of clinical samples used in this study were within the reference interval. Median concentrations of serum sCD25 were 1.9 ng/mL for healthy dogs. Dogs with cancer, IBD, liver disease, suspected pancreatitis, or suspected small intestinal disease, as well as sera with an increased serum CRP concentration, had median serum sCD25 concentrations of 1.6 ng/mL, 2.1 ng/mL, 2.2 ng/mL, 1.7 ng/mL, 1.5 ng/mL, and 1.8 ng/mL, respectively.Thus, the RIA described here is linear, accurate, precise, and reproducible for measuring sCD25 in canine serum. However, this assay shows little clinical utility of sCD25 as a biomarker for dogs with inflammatory, autoimmune, and/or neoplastic conditions.

Retracted article: The clinical significance of serum sCD25 as a sensitive disease activity marker for rheumatoid arthritis

(2019). Retracted article: The clinical significance of serum sCD25 as a sensitive disease activity marker for rheumatoid arthritis. Scandinavian Journal of Rheumatology: Vol. 48, No. 6, pp. iii-vii.

Prognostic Impact of Gastrointestinal Involvement in Newly Diagnosed Diffuse Large B-Cell Lymphoma

Introduction: Involvement of >1 extranodal site is regarded as a poor prognostic factor for patients with diffuse large B-cell lymphoma (DLBCL). It is necessary to clarify the prognostic impact of specific extranodal sites. Gastrointestinal (GI) involvement is one of the most frequently involved extranodal sites.Methods: Patients with newly diagnosed DLBCL treated at the University of Heidelberg between 06/2001 and 07/2015 were identified and included in this retrospective analysis. Data on clinical characteristics and treatment modalities were obtained by review of medical charts. Progression-free survival (PFS) and overall survival (OS) were estimated using the Kaplan-Meier method. The impact of variables on PFS and OS was evaluated by univariate log-rank tests and by multivariate analysis using the Cox proportional hazards model.Results: A total of 1001 patients were identified of whom 119 (11.9%) presented with GI involvement. Median age of patients with GI involvement was 63.3 years [range 19.1-86.7], 71 (59.7%) were male. 92 patients had an available international prognostic index (IPI) score, 36 (39.1%) IPI 0-1, 33 (35.9%) IPI 2-3, and 23 (25%) IPI 4-5. The most frequently involved organs of GI were stomach (51.3%), small intestine (39.5%), colon (20.2%), and esophagus (2.5%).107 (89.9%) patients were treated in curative intent and were further analyzed regarding the prognostic impact of several factors on outcome. 80.4% of them received CHOP-like therapies, 17.8% received chemotherapy more aggressive than CHOP, typically addition of etoposide or treatment with high-dose methotrexate in case of CNS involvement, 87.9% received additional rituximab, and 22.4% additional radiotherapyIn DLBCL patients with GI involvement, we identified factors associated with worse OS (P<.05) by univariate analysis: B symptoms, elevated serum LDH, and involvement of more than two extranodal sites. On the contrary, age (>60 years), sex, Ann Arbor Stage (AAS) III/IV, and Performance Status of Eastern Cooperative Oncology Group(ECOG) more than one, and elevated serum sCD25 did not have any significant impact on OS. B symptoms were as well associated with decreased PFS (P<.05) by univariate analysis.Multivariate Cox Regression analysis revealed that patients with elevated serum LDH at diagnosis had significantly worse OS (P<.05), and patients with B symptoms had significantly worse PFS (P<.05).Regarding first-line treatment modalities, escalation of chemotherapy to more aggressive regimes than CHOP was associated with a prolonged OS and PFS in univariate analysis, not in multivariate analysis. Radiotherapy did not have any significant impact on OS or PFS.Regarding all DLBCL patients treated with curative intent, GI involvement did not have any significant prognostic impact on OS or PFS.Conclusions: In this retrospective registry analysis of patients with newly diagnosed DLBCL with GI involvement, B symptoms, elevated serum LDH, and involvement of more than two extranodal sites were identified as risk factors for inferior OS. Escalation of chemotherapy to more aggressive regimes than CHOP was associated with a prolonged OS and PFS.Further analyses are required as toward which treatment modalities might be best suited to improve prognosis of GI involvement. DisclosuresKriegsmann:Celgene: Research Funding; BMS: Research Funding.

Establishment of a protein biochip to detect serum IgG antibodies against IL-2 and soluble CD25 in hemophagocytic lymphohistiocytosis

BackgroundInterleukin-2 (IL-2) and soluble CD25 (sCD25) are among the most important cytokines and diagnostic biomarkers in hemophagocytic lymphohistiocytosis (HLH). Detecting serum level of IL-2 and sCD25 is valuable for making clinical diagnosis and treatment decision in HLH. MethodsSince tests showing serum IgG antibody against IL-2 or sCD25 have never been carried out, a new protein biochip, which was modified with cysteine and activated sophorolipid (Cys-SL), was developed. ResultsLimits of detection on the biochip were 78 pg/ml for IL-2 and 39 pg/ml for sCD25, respectively. The data showed that on-chip seroimmunological responses to IL-2 and sCD25 proteins were 20.8% and 83.1% and the seroprevalence of IL-2 and sCD25 IgG antibodies were 45.5% and 57.2%, respectively. Data collection for the seroprevalence of serum antigen-antibody complex of sCD25 was 68.8%. The new biochip model shared similar sensitivity and specificity to chemiluminescent immunoassay (CLIA) in its measuring capacity of serum sCD25. ConclusionsWe addressed and confirmed the involvement of serum IgG antibodies against IL-2 and sCD25 as well as Ag-Ab complex of sCD25 in HLH patients. Therefore, this biochip platform would offer a new technological substitution for clinical serological diagnosis of HLH.

Serum soluble CD25 as a risk factor of renal impairment in systemic lupus erythematosus - a prospective cohort study.

Objective Serum soluble CD25 (sCD25) could be used as a biomarker for disease activity in conditions associated with T-cell activation including various autoimmune diseases. This study aimed to explore the role of sCD25 as an indicator of disease activity and organ involvement in patients with systemic lupus erythematosus (SLE). Methods Serum samples were collected from 107 SLE patients and 92 age-matched healthy controls (HCs). All patients were followed up for 24 weeks, and sCD25 was measured by enzyme-linked immunosorbent assay. Clinical and laboratory data were recorded at baseline and then every two weeks until week 24. The Systemic Lupus Erythematosus Disease Activity Index-2000 (SLEDAI)-2K was adopted for assessing disease activity at all visits. Results Serum sCD25 levels were significantly increased in SLE patients compared to those in HCs ( p < 0.001). More patients in the high-sCD25 group had lupus nephritis, arthritis and vasculitis ( p = 0.010, p = 0.023 and p = 0.042, respectively). SLEDAI-2K, erythrocyte sedimentation rate, C-reactive protein and 24-hour urinary protein excretion were all associated with high levels of sCD25 ( p < 0.001, p = 0.002, p = 0.038 and p = 0.029, respectively). During the 24-week follow-up, more patients in the high-sCD25 group developed renal impairment (48% vs 6.2%, p = 0.005), and higher levels of sCD25 ( p = 0.033) were found at the time of onset of renal disease. Conclusions Serum sCD25 is a hallmark of disease activity and a predictor of renal disease in patients with SLE.

Clinical Significance of Soluble Interleukin-2 Receptor in Patients with Acute Leukemia

Objective: Investigate the expression level and clinical significance of serum soluble interleukin-2 receptor (sIL-2R, sCD25) in patients with acute leukemia.Methods: Serum sCD25 level were measured using enzyme linked immunosorbent assays (ELISA) in 97 acute leukemia patients and 10 healthy contrlols. Clinical and laboratory features, including bone marrow cellularity, white blood cell count (WBC), platelets (PLT), lactate dehydrogenase (LDH), serum ferritin (SF), erythrocyte sedimentation rate (ESR), as well as overall survival (OS) data were collected.Results: (1) Serum sCD25 level of the newly diagnosed leukemia group was significantly higher than that of the control group (P<0.0001). (2) Among the newly diagnosed AML patients, serum sCD25 level of the M3 group was significantly lower than that of the M2 or non-M2/M3 group (P<0.05). In addition, serum sCD25 level of the low/intermediate risk (AML) or standard risk (ALL) group was lower than that of the high risk group (P<0.05). (3) Serum sCD25 level of the complete remission (CR) group was significantly lower than that of the newly diagnosed group (P<0.002). However, no significant decrease was found in serum sCD25 level of the relapsed/refractory group compared to that of the newly diagnosed group. (4) Serum sCD25 level in newly diagnosed patients was positively correlated with peripheral WBC, LDH and SF. (5) Furthermore, although OS of the low sCD25 level group (sCD25<2000pg/ml) was not significantly different compared to the intermediate sCD25 level group (2000≤sCD25≤4000pg/ml) (P =0.532), both that of the low or intermediate sCD25 level group were significantly superior to that of the high sCD25 level group (sCD25>4000pg/ml) (P<0.05).Conclusion: Serum sCD25 levels have important clinical significance in evaluating disease activity, treatment outcomes and prognosis in patients with acute leukemia. DisclosuresNo relevant conflicts of interest to declare.

Anticancer immunotherapy by CTLA-4 blockade: obligatory contribution of IL-2 receptors and negative prognostic impact of soluble CD25.

The cytotoxic T lymphocyte antigen-4 (CTLA-4)-blocking antibody ipilimumab induces immune-mediated long-term control of metastatic melanoma in a fraction of patients. Although ipilimumab undoubtedly exerts its therapeutic effects via immunostimulation, thus far clinically useful, immunologically relevant biomarkers that predict treatment efficiency have been elusive. Here, we show that neutralization of IL-2 or blocking the α and β subunits of the IL-2 receptor (CD25 and CD122, respectively) abolished the antitumor effects and the accompanying improvement of the ratio of intratumoral T effector versus regulatory cells (Tregs), which were otherwise induced by CTLA-4 blockade in preclinical mouse models. CTLA-4 blockade led to the reduction of a suppressive CD4(+) T cell subset expressing Lag3, ICOS, IL-10 and Egr2 with a concomitant rise in IL-2-producing effector cells that lost FoxP3 expression and accumulated in regressing tumors. While recombinant IL-2 improved the therapeutic efficacy of CTLA-4 blockade, the decoy IL-2 receptor α (IL-2Rα, sCD25) inhibited the anticancer effects of CTLA-4 blockade. In 262 metastatic melanoma patients receiving ipilimumab, baseline serum concentrations of sCD25 represented an independent indicator of overall survival, with high levels predicting resistance to therapy. Altogether, these results unravel a role for IL-2 and IL-2 receptors in the anticancer activity of CTLA-4 blockade. Importantly, our study provides the first immunologically relevant biomarker, namely elevated serum sCD25, that predicts resistance to CTLA-4 blockade in patients with melanoma.

Soluble CD25 is increased in patients with sepsis‐induced acute kidney injury

Sepsis has been shown to induce the expansion of CD4+CD25+ regulatory T cells (Tregs), and this paradoxical immune suppression has been suggested to be closely associated with the development of sepsis-induced organ dysfunction. In the present study, we aimed to investigate the possible link between immune suppression and the development of septic acute kidney injury (AKI). We prospectively enrolled patients with a diagnosis of sepsis, with or without AKI and as well as patients with AKI but without sepsis. Serum and urine samples at the time of the diagnosis were collected to measure neutrophil gelatinase-associated lipocalin (NGAL), cytokines, and soluble CD25 (sCD25). Of the 82 patients enrolled, 44, 18, and 20 patients were classified into septic-AKI, sepsis-non AKI and non-septic AKI groups. There were no differences in the baseline characteristics in all three groups and the severity of infection in the two sepsis groups. Serum levels of interleukin (IL)-10 were significantly elevated in patients with septic-AKI compared to the other two groups. Serum and urine NGAL levels and the level of serum sCD25, a marker of regulatory T cells, were significantly elevated in patients with septic AKI group, indicating the potential association of paradoxical immune suppression and the development of septic-AKI. These results suggest that immune suppression in sepsis may be closely linked to the development of AKI and that sCD25 or IL-10 may be useful as novel biomarkers for the development of septic AKI.

Significance of serum sCD25 level in diagnosis of hepatocellular carcinoma

Significance of serum sCD25 level in diagnosis of hepatocellular carcinoma

Polyendocrinopathie endocrinienne multiple associant une insuffisance surrénale primitive, une maladie de Basedow et un diabète type 1 : à propos d’un cas

During immune activation, CD25 is expressed by T cells, and its soluble form (sCD25) is released into the extracellular matrix and the bloodstream. In humans, serum sCD25 concentrations are used as a surrogate marker for autoimmune diseases, malignancies, and transplant rejection. However, a canine-specific assay for the measurement of sCD25 in dog serum has not previously been described. Therefore, the aims of this study were to develop and analytically validate a radioimmunoassay to measure sCD25 in canine serum, to establish a reference interval for canine sCD25, and to test the clinical utility of this assay with serum samples for dogs with various diseases. A competitive radioimmunoassay (RIA) was developed and analytically validated. Analytical validation consisted of lower limit of detection (LLOD), dilutional parallelism, spiking recovery, and intra- and inter-assay variability using pooled surplus canine serum samples. A reference interval was established in healthy dogs and serum samples from dogs with various types of neoplasia, IBD, liver disease, suspected pancreatitis, or suspected small intestinal disease and serum samples with an increased C-reactive protein concentration (CRP) were analyzed to test the clinical utility of the assay. LLOD was calculated to be 0.5 ng/mL. The mean (±SD) observed-to-expected ratio (O/E) for serial dilutions was 101.7 ± 14.0%, and the mean (± SD) O/E for spiking recovery was 93.2 ± 4.2%. Coefficients of variation (CVs) for intra-assay variability were ≤12.5% (mean ± SD: 7.5 ± 4.2%), and inter-assay CVs were ≤15.7% (mean ± SD: 11 ± 4.4%). A reference interval (RI) for canine sCD25 of 1.2–4.2 ng/mL was established from a population of 112 clinically healthy dogs. Dogs with neoplasia and dogs with suspected small intestinal disease had decreased concentrations of serum sCD25 when compared to healthy dogs (p < 0.0001, respectively). However, the majority of clinical samples used in this study were within the reference interval. Median concentrations of serum sCD25 were 1.9 ng/mL for healthy dogs. Dogs with cancer, IBD, liver disease, suspected pancreatitis, or suspected small intestinal disease, as well as sera with an increased serum CRP concentration, had median serum sCD25 concentrations of 1.6 ng/mL, 2.1 ng/mL, 2.2 ng/mL, 1.7 ng/mL, 1.5 ng/mL, and 1.8 ng/mL, respectively.Thus, the RIA described here is linear, accurate, precise, and reproducible for measuring sCD25 in canine serum. However, this assay shows little clinical utility of sCD25 as a biomarker for dogs with inflammatory, autoimmune, and/or neoplastic conditions.