Serum Concentrations Of sIL-2R Research Articles

Increased serum soluble interleukin-2 receptor levels in dermatomyositis are associated with Th17/Treg immune imbalance.

Dermatomyositis (DM) represents a multifaceted chronic inflammatory myopathy, primarily manifesting as progressive deterioration of muscular and cutaneous tissues. Despite an incomplete comprehension of DM's etiology and pathogenesis, current evidence implicates the involvement of T lymphocyte infiltration, extensive cytokine release, myositis-specific antibodies, and myositis-associated antibodies in disease development. Serum soluble interleukin-2 receptor (sIL-2R) frequently serves as a marker for T cell activation; however, its role remains elusive. Consequently, this investigation sought to elucidate the association between sIL-2R levels, peripheral blood lymphocyte subset counts, and related cytokines in DM patients, with the aim of uncovering the intricate mechanisms underlying DM and establishing a theoretical foundation for the implementation of precise, targeted, individualized immunomodulatory therapy. In this study, a cohort of 60 dermatomyositis (DM) patients, comprising 32 with inactive DM and 28 with active DM, was enrolled and stratified into inactive and active groups based on the Myositis Disease Activity Visual Analogue Scale (MYOACT). Flow cytometry was employed to quantify the absolute counts of peripheral lymphocyte subsets and CD4+T cell subsets in each group, while a flow cytometry bead array was utilized to measure serum cytokine levels. In a comparative analysis between healthy individuals and patients diagnosed with DM, we observed a marked elevation in serum sIL-2R concentrations (P < 0.001) and T-helper 17 cell/regulatory T cell (Th17/Treg) ratios (P < 0.01) within the latter group. A positive correlation was identified between serum sIL-2R levels and various parameters, including ESR, CRP, VAS, AST, CKMB, LDH, HBDH, PT, APTT, DDi, IL-6, IL-10, and IFN-γlevels (P < 0.05). In contrast, serum sIL-2R levels demonstrated a negative correlation with LY, HGB, ALB, Th17 cell populations, and Th17/Treg cell ratios (P < 0.05). Employing multivariate logistic regression, we identified serum sIL-2R concentrations as an independent risk factor for both disease activity and hepatic involvement in DM patients. Moreover, receiver operating characteristic (ROC) curve analyses revealed that serum sIL-2R levels significantly contributed to the differentiation of disease activity and the detection of liver involvement in DM patients, with areas under the ROC curve (AUC) of 0.757 (95% CI 0.630-0.884, P = 0.001) and 0.826 (95% CI 0.717-0.935, P < 0.001), respectively. This study highlights the potential utility of serum sIL-2R levels as a valuable biomarker for assessing disease activity and liver involvement in dermatomyositis. Elevated serum concentrations of sIL-2R were observed in patients with DM, exhibiting significant associations with Th17 cell populations and Th17/ Treg ratios. These findings indicate that sIL-2R may be implicated in the immunopathogenesis of DM, thereby warranting further investigation to elucidate its role in the disease process.

Clinical diagnostic value of serum soluble IL-2 receptor for stage I sarcoidosis in benign isolated mediastinal and hilar lymphadenopathy

BackgroundSerum soluble interleukin-2 receptor (sIL-2R) is recognized as a marker of T-cell activation and is abnormally elevated in sarcoidosis. However, its value for stage I sarcoidosis in benign granulomatous diseases is unclear. MethodsWe enrolled 33 stage I sarcoidosis patients, 17 lymph node tuberculosis patients, 15 reactive lymphadenopathy patients, and 11 healthy controls. Serum biomarkers concentrations were collected and collated. ResultsSerum sIL-2R concentrations were the highest in stage I sarcoidosis. The AUC of serum sIL-2R for stage I sarcoidosis was 0.7452 in all subjects and 0.6861 in granulomatous diseases. The AUCs of two combined diagnostic forms, sIL-2R with angiotensin-converting enzyme (ACE) and sIL-2R with ACE, erythrocyte sedimentation rate (ESR), and lactate dehydrogenase (LDH) were 0.7994 and 0.891 in all subjects, respectively. In granulomatous disease groups for ROC analysis, the best cut-off value of sIL-2R was 745.00 U/ml with 48.50% sensitivity and 84.40% specificity. The combination of four parameters increased the diagnostic accuracy for stage I sarcoidosis in granulomatous diseases (74.10% sensitivity and 100% specificity). Serum sIL-2R concentrations were positively correlated with serum ACE (r = 0.4652, P = 0.0126). ConclusionSerum sIL-2R appeared to be valuable in identifying stage I sarcoidosis in a group of benign granulomatous disorders.

Factors influencing serum concentrations of soluble interleukin-2 receptor: a general adult population study

Introduction: Measuring soluble interleukin-2 receptor (sIL-2R) might be useful for diagnosis and monitoring of immune-mediated diseases. The study investigated factors associated with serum sIL-2R concentrations in adults. Methods: Serum sIL-2R concentrations were measured in 1499 randomly selected individuals (44.6% male, median age 52 years, range 18–91 years). Lifestyle factors (alcohol consumption, smoking, and physical activity) were assessed by questionnaire. Body mass index and data defining metabolic syndrome were measured in all participants. Atopy was defined by skin tests to aeroallergens. Results: Serum sIL-2R concentrations displayed wide variation (2.5–97.5 percentile range, 209–950 U/mL). A total of 230 (15.3%) individuals showed values higher than the standard reference range (158–623 U/mL). After adjusting for covariates, sIL-2R concentrations increased with age, particularly after 65 years. Serum sIL-2R concentrations were higher in males than in females, were higher in smokers than in never smokers, and were higher in atopic than in non-atopic individuals. Serum sIL-2R concentrations were positively associated with metabolic syndrome, particularly with abdominal obesity, and with a history of ischemic heart disease. Light alcohol drinkers showed lower sIL-2R concentrations than abstainers. Conclusion: Aging, sex, lifestyle factors, atopy, metabolic abnormalities, and ischemic heart disease might influence serum sIL-2R concentrations in adults.

The Predicting Role of Serum TSGF and sIL-2R for the Lymph Node Metastasis of Papillary Thyroid Carcinoma.

Objective To explore the clinical utility of tumor-specific growth factor (TSGF) and the soluble interleukin-2 (IL-2) receptor (sIL-2R) as immune-related factors for predicting lymph node metastases (LNM) of papillary thyroid carcinoma (PTC). Methods A total of 206 patients with PTC subjected to curative surgery were enrolled. All patients had complete medical records. Serum levels of TSGF were detected using Automatic Biochemistry Analyzer and the serum sIL-2R concentration was detected by enzyme-linked immunosorbent assay (ELISA). Furthermore, we analyzed the relationship between the two indicators and the clinicopathological characteristics and assessed their effect on lymphatic metastasis in patients with PTC by logistic regression analysis. Results Receiver operating characteristic (ROC) analysis revealed that the determined cut-off value of serum TSGF and sIL-2R was 63.35 U/mL and 507 U/mL, respectively. Serum TSGF was associated with focality (χ2 = 4.97, P = 0.026) and lymphatic metastasis (χ2 = 4.154, P = 0.042), while serum sIL-2R was remarkably related to gender (χ2 = 4.464, P = 0.035). Univariate logistic regression analysis indicated that age, tumor size, serum TSGF level, capsule invasion, and nodular goiter were the lymphatic metastasis-related factor of PTC. Multivariate regression analysis revealed that age > 45 years was a protective factor (OR: 0.4, 95% CI: 0.206-0.777, P = 0.007). Conversely, larger tumor size (OR: 4.594, 95% CI: 2.127-9.921, P = 0.000), higher serum TSGF levels (OR: 1.888, 95% CI: 1.009-3.533, P = 0.047), and capsule invasion (OR: 1.939, 95% CI: 1.009-3.726, P = 0.047) were associated with an increased risk of LNM. Conclusion Serum TSGF levels were identified as an independent factor for LNM in patients with PTC.

Increased Serum Soluble Interleukin-2 Receptor Associated with Severity of Acute Exacerbation of Chronic Obstructive Pulmonary Disease.

BackgroundThis study aimed to reveal the correlation between serum soluble interleukin-2 receptor (sIL-2R) and prognosis in patients with acute exacerbation of chronic obstructive pulmonary disease (AECOPD).MethodsA total of 315 patients diagnosed with AECOPD between December 2017 and June 2020 were enrolled. The patients were divided into the good and adverse groups based on the outcomes. An adverse outcome in COPD exacerbation was defined by the presence of at least one of the following: (1) death from a respiratory cause during hospitalisation or within 1 month of follow-up; (2) intensive care unit admission; (3) invasive or non-invasive mechanical ventilation; and (4) COPD-related emergency visit or readmission within 1 month of follow-up. A good outcome was considered as the absence of all the aforementioned issues. The patients underwent lung function (spirometry) assessment, and clinical and inflammatory profiles were collected. Univariate and multivariate analyses were performed to identify the correlation between serum sIL-2R concentration and other variables related to adverse outcomes of AECOPD. The receiver operating characteristic curve was used to show the predictive ability of sIL-2R for adverse outcomes of AECOPD.ResultsWe enrolled 315 patients, of whom 161 and 154 had good and adverse outcomes, respectively. We demonstrated that patients with adverse outcomes of AECOPD had a higher concentration of serum sIL-2R than patients with good outcomes (p < 0.001). The increased serum sIL-2R was positively associated with mMRC scores (p < 0.001), GLOD grades (p < 0.001), frequent exacerbation (p < 0.001), and smoking (p < 0.001) in patients with AECOPD and negatively correlated with pulmonary function (p < 0.001). An elevated sIL-2R level was a predictor for the risk of adverse outcomes in AECOPD with a cut-off value of 860 U/mL.ConclusionIncreased serum sIL-2R concentration correlated with the risk of the adverse outcomes in AECOPD, indicating that it can be a predictive factor contributing to the diagnosis and assessment of adverse outcomes in patients with AECOPD.

Measurement of the concentration of serum soluble interleukin-2 receptor alpha chain in dogs with lymphoma

Soluble interleukin-2 receptor (sIL-2r) is released directly from the surface of lymphocytes expressing interleukin-2 receptor alpha chain (CD25), and its serum concentration has been found to reflect the prognosis of human lymphoproliferative malignancies. In this study, we demonstrated the presence of sIL-2r in canine serum and developed a specific sandwich enzyme-linked immunosorbent assay (ELISA) to quantify the concentration of canine serum sIL-2r. In the immunoprecipitation (IP) assay, CD25 protein weighing approximately 45 kDa was detected in canine serum, smaller than the membrane-bound CD25 (approximately 55 kDa). To measure the concentration of serum sIL-2r in dogs, an ELISA system was developed. Serum sIL-2r levels were significantly higher in dogs with multicentric high-grade B-cell lymphoma before therapy than that in healthy dogs. Serum sIL-2r concentration was also found to be elevated in a proportion of dogs with other types of lymphoma. Changes in serum sIL-2r levels generally paralleled the changes in mass and lymph node size in dogs with high-grade B-cell lymphoma. This study demonstrated that serum sIL-2r level would be a marker to monitor tumour growth and regression in canine lymphoma.

The significance of serum levels of soluble interleukin-2 receptor in patients undergoing maintenance hemodialysis

Background Elevated serum levels of sIL-2R are commonly observed in patients undergoing maintenance hemodialysis (MHD). However, the clinical implications in these subjects are unclear. This study is aimed to assess the significance of elevated sIL-2R levels in MHD patients. Methods A total of 382 MHD patients were followed-up from September 2016 to December 2019. Patients were divided into two groups: high sIL-2R, with sIL-2R levels ≥2-fold of the upper limit of normal (710 U/ml); and low sIL-2R, with sIL-2R levels < 2-fold the upper limit of normal. The relationships between sIL-2R levels and other clinical parameters, as well as patient prognosis were both assessed. Results The median concentration of sIL-2R was 1268 U/mL. A total of 372 (97.38%) patients exhibited sIL-2R levels higher than the upper limit of the normal range. Multiple linear regression analysis revealed that monocyte count (β = 0.1571, p = 0.01), and β2-MG (β = 0.2635, p < 0.0001), hemoglobin (β = −0.1610, p = 0.001), SCr (β = −0.3471, p < 0.0001), and HDL-C (β = −0.1091, p = 0.029) levels were independent factors influencing serum concentrations of sIL-2R. High sIL-2R was significantly correlated with non-cardiovascular-related mortality (OR 2.97 [95% CI 1.59–5.56; p = 0.001), of which 39 (82.98%) were attributed to infection and/or cancer. Conclusions Elevated sIL-2R is prevalent in MHD patients and related with several unfavorable parameters. sIL-2R appears to have no ability to predict cardiovascular mortality, which accounts for approximately one-half of all deaths. However, sIL-2R may be beneficial in predicting noncardiovascular mortality.

YKL-40, Soluble IL-2 Receptor, Angiotensin Converting Enzyme and C-Reactive Protein: Comparison of Markers of Sarcoidosis Activity

The aims of this study were to describe the clinical, radiological and immunological features of a population of sarcoidosis patients and to analyse chitinase-3-like protein 1 (YKL-40), soluble interleukin-2 receptor (sIL-2R), neopterin concentrations and adenosine deaminase (ADA) activity in serum of these patients in order to understand their potential as disease markers. Fifty-nine patients affected by chronic sarcoidosis, in active (20 patients) and inactive (39 patients) phase according to the clinical, radiological and laboratory criteria were studied. Serum YKL-40, sIL-2R, high-sensitive C-reactive protein (hs-CRP), neopterin levels and ADA activities were evaluated and compared with those of 25 healthy controls. Individuals with chronic sarcoidosis were significantly higher serum YKL-40, sIL-2R, neopterin, hs-CRP concentrations, angiotensin converting enzyme (ACE) and ADA activity than those of control subjects. Sarcoidosis patients in the active phase of the disease were significantly higher YKL-40, sIL-2R, hs-CRP levels and ACE activity than those in the inactive phase, while ADA activities and neopterin levels did not display any significant difference between the active and inactive disease groups. In comparison to the other parameters, as panel measurement of the serum YKL-40, sIL-2R, ACE and hs-CRP indicate a greater discrimination between active and inactive disease. The results indicate that serum YKL-40, sIL-2R, ACE and hs-CRP concentrations may be useful marker for monitoring sarcoidosis disease activity.

Soluble interleukin-6 receptor mediated fatigue highlights immunological heterogeneity of patients with early breast cancer who undergo radiation therapy

PurposeThis study aimed to explore the associations between dose-volume parameters of localized breast irradiation, longitudinal interleukin-6 soluble receptor (sIL-6R), and leukocyte counts as markers of an immune-mediated response and fatigue as a centrally-driven behavior. Methods and MaterialsThis prospective cohort study recruited 100 women who were diagnosed with stage 0-IIIa breast cancer, prescribed 40 Gy in 15 fractions over 3 weeks adjuvant radiation therapy, and had no prior or concurrent chemotherapy. Dose-volume parameters were derived from treatment plans and related to serum sIL-6R concentrations, leukocyte counts, and a validated measure of self-reported fatigue at baseline, after 10 and 15 fractions, and 4 weeks after radiation therapy. ResultssIL-6R concertation was significantly higher in patients with a total volume of tissue irradiated within the 50% isodose >2040 cm3 (P = .003). When controlling for body mass index, this result only remained significant after treatment. The volume of liver irradiated within the 10% isodose correlated with the sIL-6R concentration during and after radiation therapy (ρ = .3-.4; P = .03-.007). The 38% of the cohort that was classified as fatigued had a higher mean sIL-6sR concentration at all observation points, but the differences were only statistically significant during radiation therapy: Mean (standard deviation [SD]) after 15 fractions for fatigued patients was 47.6 ng/dL (11.2 SD) versus 41.6 ng/dL (11.4 SD) for nonfatigued patients (P = .01). Cohort leukocyte counts and leukocyte subsets decreased consistently from baseline and the values for the fatigued group were 4% lower at baseline and between 7% and 9% lower during and after treatment compared with those of the nonfatigued group but the differences were not statistically significant. ConclusionsThis is the first study to show that localized irradiation induces increased systemic sIL-6R during treatment in participants who reported elevated levels of fatigue before, during, and after treatment. This behavioral response appears to reflect a variation in innate host immunity, which then mediates the cellular and/or psychological stress of radiation therapy.

Clinical possibility of baseline FDG-PET SUVmax as a prognostic factor in patients with head and neck non-Hodgkin’s lymphoma: A preliminary study

ObjectiveFDG-PET has been shown useful in the staging of malignant lymphoma (ML) and in evaluating treatment outcomes. Serum concentration of soluble interleukin-2 receptor (sIL-2R) has also been shown prognostic in patients with MLs. This study analyzed the clinical possibility of baseline FDG-PET parameters, such as maximum standardized uptake values (SUVmax), metabolic tumor volume (MTV), total lesion glycolysis (TLG), and serum sIL-2R and lactate dehydrogenase (LDH) concentrations, as prognostic variables in patients with oral and neck non-Hodgkin’s lymphoma (NHL). MethodsBaseline FDG-PET parameters and serum protein concentrations were correlated with 2-year prognosis in 12 patients with oral and neck NHL. The optimal cutoff values for FDG SUVmax, serum sIL-2R and LDH were determined by receiver operating characteristics analyses. ResultsAt 2-year follow up, seven patients remained alive (good prognosis), and five had died (poor prognosis). The median FDG SUVmax was significantly higher in the poor than in the good prognosis groups (P = 0.04), but serum sIL-2R concentrations did not differ significantly between the two groups (P = 0.09). Baseline MTV and TLG were significantly higher in patients with poor than with good prognosis (P = 0.02 each). Serum LDH levels was significantly higher in patients with poor than with good prognosis (P = 0.01). Univariate logistic regression analysis showed significant correlations between FDG SUVmax and patient prognosis (P = 0.04, odds ratio, 23.4). ConclusionComprehensive evaluation of baseline FDG SUVmax may have possibility for predicting the prognosis of patients with oral and neck NHLs.

The clinical characteristics of patients with IgG4-related disease with infiltration of the labial salivary gland by IgG4-positive cells

Objectives. Mikulicz's disease (MD) is an immunoglobulin (Ig) G4-related disease with systemic symptoms. Submandibular gland (SMG) biopsy is recommended for patients with possible IgG4-related MD for accurate differential diagnosis; however, it is difficult for certain patients to undergo this procedure. In contrast, labial salivary gland (LSG) biopsy is more convenient. Here we present an analysis of patients with IgG4-related MD whose LSG specimens were infiltrated with abundant IgG4-positive plasma cells.Methods. Sixteen patients diagnosed with IgG4-related MD underwent simultaneous SMG and LSG biopsies. We evaluated patients’ serological and 18F-fluoro-2-deoxyglucose-positron emission tomography/computed tomography (18F-FDG-PET/CT) and grouped them as LSG+ (LSG specimens with > 40% IgG4-positive plasma cells/IgG-positive plasma cells, 11 patients) or LSG− (LSG specimens with < 40% IgG4-positive plasma cells/IgG-positive plasma cells, 6 patients).Results. There were not significant differences in serum IgG and IgG4 levels between the two groups; however, serum concentrations of soluble interleuikin-2 receptor (sIL-2R) were significantly higher in the LSG+ group. All patients with increased 18F-FDG uptake in their parotid glands were a part of the LSG+ group.Conclusions. When a SMG biopsy is not possible, the serum concentration of sIL-2R and 18F-FDG-PET/CT findings may predict whether LSG biopsy will facilitate the diagnosis of IgG4-related MD.

Circulating LR11 is a novel soluble-receptor marker for early-stage clinical conditions in patients with non-Hodgkin's lymphoma

BackgroundWe reported that the soluble LDL receptor relative with 11 ligand-binding repeats (sLR11) is a promising biomarker for follicular lymphoma (FL). In this study, we evaluated the fluctuations in serum sLR11 levels compared with those of serum soluble urokinase-type plasminogen activator receptor (suPAR) and soluble interleukin-2 receptor (sIL-2R) in patients with non-Hodgkin's lymphoma (NHL). MethodsSerum sLR11, suPAR, and sIL-2R levels were measured using ELISA in 175 NHL patients and 57 healthy controls. The levels at diagnosis and at remission were evaluated in 64 paired samples. ResultsSerum sLR11 levels were significantly increased in FL, diffuse large B-cell lymphoma (DLBCL), and peripheral T-cell lymphoma patients compared with healthy controls. Serum sLR11 levels revealed significant positive correlations with serum suPAR and sIL-2R levels. Serum sLR11 levels at remission were decreased compared with those at diagnosis, and the declines at remission expressed a slope of approximately −1 with an intercept near that of controls. The receiver operating characteristic–area under the curve of serum sLR11 concentrations was equivalent to that of serum suPAR and sIL-2R concentrations in an early-stage DLBCL and FL. ConclusionssLR11 may be a novel soluble receptor indicative of early-stage NHL, with potential use for evaluating therapeutic efficacy.

THU0301 Neopterin (NPT) and soluble interleukin 2 receptor (SIL-2R) as useful markers of disease activity in juvenile idiopathic arthritis (JIA)

BackgroundJIA is the common chronic rheumatic disease in children that may continue to be active in adulthood. The new laboratory markers are needed to adjust therapy of JIA to the...

Elevated circulating soluble interleukin-2 receptor in patients with chronic liver diseases is associated with non-classical monocytes

BackgroundThe soluble interleukin-2 receptor (sIL-2R, sIL2R, sTAC, sCD25) is a reliable biomarker for disease activity in inflammatory disorders such as sarcoidosis. Based on the essential pathogenic role of inflammation for progression of liver diseases, we hypothesized that sIL-2R might be an indicator of inflammatory cell activation and disease severity in patients with chronic liver diseases (CLD).MethodsWe measured sIL-2R serum levels in 71 patients with different stages and etiologies of CLD in comparison to 41 healthy controls. Serum sIL-2R concentrations were correlated with laboratory markers of liver diseases, cytokine / chemokine levels and circulating immune cell subpopulations as simultaneously assessed by FACS analysis from peripheral leukocytes.ResultsCLD patients showed significantly elevated serum sIL-2R levels compared with controls. sIL-2R was significantly higher in patients with compared to patients without established liver cirrhosis and increased with the Child-Pugh stage of cirrhosis, independent of the underlying etiology. sIL-2R levels correlated inversely with parameters indicating the hepatic biosynthetic capacity, such as albumin or international normalized ratio, and positively with non-invasive markers of liver fibrosis such as hyaluronic acid or procollagen-III-peptide. Circulating immune cells might represent a major source of sIL-2R. In fact, sIL2-R levels correlated closely with circulating monocytes, especially non-classical CD14+ CD16+ monocytes, which were found to express high levels of CD25 by FACS. Pro-inflammatory cytokines, including IL-2, IFNγ or IL-6, and chemokines were also associated with sIL2-R. In addition, renal failure was an important confounder of sIL-2R levels independent of liver dysfunction and inflammation.ConclusionssIL-2R is elevated in patients with liver diseases and cirrhosis, is associated with circulating inflammatory cells and is increased in concomitant renal failure. These data indicate that sIL-2R might be a potential marker for immune cell activation in CLD, especially for proinflammatory and profibrogenic non-classical CD14 + CD16+ monocytes.

CD8+CD28− Lymphocytes in Peripheral Blood and Serum Concentrations of Soluble Interleukin 6 Receptor are Increased in Patients with Graves’ Orbitopathy and Correlate with Disease Activity

Background. The extrathyroid, orbital manifestation of Graves’ disease (GD)—Graves’ orbitopathy (GO)—presents a difficult clinical problem. The immunological status of GO patients is still under investigation. The aim of this study was to assess the serum concentration of interleukin 6 (IL-6), soluble interleukin 6 receptor (sIL-6R), and CD8+CD28− lymphocytes in GO patients and to evaluate if these parameters were associated with disease activity. Patients. Thirty-nine patients (29 women and 10 men, aged 24–71, mean 50.18) with newly diagnosed GD were enrolled in the study. Active GO was diagnosed in 20 patients. The control group included 12 healthy individuals. Methods. Serum concentrations of IL-6 and sIL-6R were estimated by ELISA. Percentages of CD8+CD28− lymphocytes in peripheral blood were assessed by flow cytometry. Results. Mean serum IL-6 and sIL-6R concentrations were significantly higher in all GD patients and in GO and non-GO patients than in normal controls. In all GD patients and the non-GO group, serum IL-6 and sIL-6R concentrations were significantly reduced after efficient treatment. In GO patients, only serum sIL-6R concentration was significantly lower after efficient treatment. In all GD patients, the mean percentage of CD8+CD28− lymphocytes was significantly lower after efficient treatment. In GO patients, the mean percentage of CD8+CD28− lymphocytes was significantly higher than in the non-GO group or in normals. Moreover, in the GO group, the mean percentage of CD8+CD28− lymphocytes was significantly lower after treatment. Conclusion. Our results have shown that CD8+CD28− lymphocyte percentage in peripheral blood and serum concentration of sIL-6R are increased in GO patients and correlate with disease activity.

Potent antitumor effects of bevacizumab in a microenvironment-dependent human lymphoma mouse model

We established a mouse model of microenvironment-dependent human lymphoma, and assessed the therapeutic potential of bevacizumab, an antitumor agent acting on the microenvironment. NOD/Shi-scid, IL-2Rγnull (NOG) mice were used as recipients of primary tumor cells from a patient with diffuse large B-cell lymphoma (DLBCL), which engraft and proliferate in a microenvironment-dependent manner. The lymphoma cells could be serially transplanted in NOG mice, but could not be maintained in in vitro cultures. Injection of bevacizumab together with CHOP (cyclophosphamide, doxorubicin, vincristine, prednisolone) significantly increased necrosis and decreased vascularization in the tumor, compared with CHOP alone. Levels of human soluble interleukin-2 receptor (sIL2R) in the serum of bevacizumab+CHOP-treated mice (reflecting the DLBCL tumor burden) were significantly lower than in CHOP recipients. Mice receiving bevacizumab monotherapy also showed significant benefit in terms of tumor necrosis and vascularization, as well as decreased serum sIL2R concentrations. The present DLBCL model reflects the human DLBCL in vivo environment more appropriately than current mouse models using established tumor cell lines. This is the first report to evaluate the efficacy of bevacizumab in such a tumor microenvironment-dependent model. Bevacizumab may be a potential treatment strategy for DLBCL patients.

Serum levels of IL‐18 and sIL‐2R in patients with alopecia areata receiving combined therapy with oral cyclosporine and steroids

This study was to determine which immunologic factors contribute to the prognosis of patients with alopecia areata (AA) who were receiving oral cyclosporine A and methylprednisolone. Patients with > 25% hair regrowth were defined as responders, and patients exhibiting < or = 25% regrowth were poor-responders. The serum levels of IL-18 and soluble IL-2 receptor (sIL-2R) were measured at baseline in 21 patients with AA and 22 control subjects. The mean serum level of IL-18 in the patients with extensive AA was significantly higher than that in the control subjects. The mean serum concentration of sIL-2R in the AA patients significantly decreased after 1 month of treatment. The mean basal serum level of IL-18 was highest in the responder, whereas the baseline level of sIL-2R was significantly higher in the poor-responder group than other groups. In conclusion, increased serum sIL-2R level and lower IL-18 level at baseline was associated with a poor prognosis in patients with AA.

The relationship between thyroid function, serum monokine induced by interferon gamma and soluble interleukin-2 receptor in thyroid autoimmune diseases

Interactions between cytokines play an important role in the development of thyroid autoimmunity. Using enzyme-linked immunosorbent assay we investigated serum concentrations of soluble interleukin-2 receptor (sIL-2R), interferon-gamma, tumour necrosis factor (TNF)-alpha, interleukin (IL)-10, CD30, monokine induced by interferon-gamma (MIG), cytotoxic T lymphocyte antigen-4 and markers of apoptosis decoy receptor 3 and Bcl-2 in 28 patients with hyperthyroid Graves' disease (GD), 24 patients with untreated Hashimoto's thyroiditis (HT) and 15 healthy controls. TNF-alpha, IL-10 and sIL-2R were higher in GD compared with HT and controls (TNF-alpha: 8.79 in GD versus 2.54 pg/ml in HT, P = 0.01; IL-10: 10.00 versus 3.10 versus 3.10 pg/ml, P(1) < 0.001, P(2) = 0.005; sIL-2R: 1.26 versus 0.64 versus 0.46 ng/ml, P < 0.001). MIG and CD30 were higher in HT compared with controls (649.22 +/- 262.55 versus 312.95 +/- 143.35 pg/ml, P = 0.037, 6.57 +/- 2.35 versus 3.03 +/- 1.04 U/ml, P = 0.036 respectively). In GD sIL-2R decreased when the euthyroid state was achieved (1.31 +/- 0.64 versus 0.260 +/- 0.11, n = 12, P < 0.001). sIL-2R correlated positively with free thyroxine (FT4) (R = 0.521, P = 0.000) and negatively with thyroid stimulating hormone (TSH) (R = -0.472, P = 0.00132). MIG correlated negatively with FT4 (R = -0.573, P = 0.00234) and positively with TSH (R = 0.462, P = 0.0179). The results suggest that serum concentrations of sIL-2R and MIG are related to thyroid function rather than to activation of autoimmunity.

Significance of Serum Soluble IL-2R in DLBCL and FL Is Different from That in ATL

Interleukin-2 receptor (IL2R) is usually expressed on activated T cells by antigen stimulation and on pre-B cells during B cell differentiation. Soluble IL-2R (sIL-2R) in serum is a truncated form of the 55-kDa chain of IL-2R, which is believed to be produced by cleavage by proteases. The concentration of sIL-2R in serum has been an index of tumor burden in adult T cell leukemia/lymphoma (ATL), in which CD4-positive T cells express IL-2R (CD25) on the cell surface. Subsequently, analysis of serum sIL-2R concentration has also been useful in predicting disease activity and response to treatment in B cell lymphoma. However, it is still unclear whether B cell lymphoma cells express IL-2R (CD25) or whether serum sIL-2R concentration is due to IL-2R on B cell lymphoma cells. Furthermore, it is unclear how sIL-2R is released from IL-2R in ATL. First, we examined whether serum sIL-2R concentration is a prognostic factor in previously untreated patients with DLBCL (n = 105, median age 67.0 (18–91 years)) or FL (n = 30, median age 60.0 (40–82 years)) diagnosed between January 2001 and December 2005, and who received six cycles of R + CHOP or R + THP-COP therapy. Patients who relapsed or had disease progression after R + CHOP or R + THP-COP received R + EDAP or R + ICE for DLBCL, and R + FND for FL. The 5-year OS rates for patients with sIL-2R levels of < 1500 U/ml and ⊠ 1500 U/ml were 76% and 62%, respectively (p < 0.05) in DLBCL, and 100% and 79.3%, respectively (p = 0.19) in FL. Next, we analyzed IL-2R (CD25) expression on lymphoma cells by flow cytometry. Nine of 25 patients with DLBCL and 4 of 11 patients with FL showed CD25 expression. Some T cells (CD3-positive cells) expressed CD25 in both lymphomas. On the other hand, 7 of 7 patients with MCL expressed CD25. There was no significant relationship between serum sIL-2R concentrations and CD25 expression on lymphoma cells or clinical stage in either DLBCL or FL. Metalloproteinase-9 (MMP-9) is reported to be an important protease for releasing sIL-2R from IL-2R. However, there was no significant relationship between MMP-9 and sIL-2R levels in sera from patients with DLBCL or FL. On the other hand, 7 of 7 patients with ATL showed high concentration of MMP-9 (> 128 ng/ml) irrespective of sIL-2R levels. We then confirmed MMP-9 expression in 3 ATL cell lines by Western blotting, and addition of MMP-9 inhibitor to culture media of these cell lines significantly decreased sIL-2R levels in supernatants. On immunohistochemical staining (IHC) using anti-MMP-9 antibody, macrophages not lymphoma cells or T cells were positive for MMP-9 in DLBCL and FL. These findings suggest that high serum sIL-2R concentrations in ATL are due to the cleavage of IL-2R by MMP-9 produced by ATL cells. On the other hand, the main source of sIL-2R may be due to release from activated T cells in DLBCL and FL. Therefore, serum sIL-2R levels may indicate activity of neoplastic cells in ATL; however, its levels may reflex the activity of microenviromental non-neoplastic cells in DLBCL and FL.

Serum soluble markers in the evaluation of treatment in human visceral leishmaniasis.

Visceral leishmaniasis (VL) has a fatal course if not properly treated. Recovery from VL is linked to cellular immune response. Unresponsiveness to antimonial therapy reinforces the importance of determining parameters for treatment assessment. We analysed the pre- and post-treatment serum levels of soluble CD4 (sCD4), sCD8, sIL-2R, soluble intercellular adhesion molecule-1 (sICAM-1) and neopterin in groups of VL patients either responsive or not to standard antimonial therapy. Pretreatment serum levels of all markers except for sICAM-1 were significantly higher in VL patients than in healthy subjects from the same area (P < 0.05). sICAM-1 levels were similar in healthy controls and in VL patients refractory to antimonial therapy (P = 0.25), but significantly higher in patients responsive to treatment (P = 0.02). The comparison of pre- and post-treatment concentrations showed that all markers, except sCD4 and sICAM-1, presented a significant fall (P < 0.05) in patients responsive to antimonial therapy. However, only neopterin presented with levels compatible with those of healthy subjects at the end of treatment (P = 0.30). In refractory patients sICAM-1 presented with post-treatment levels significantly higher than the pretreatment determinations (P = 0.03), while sCD4 experienced a significant drop (P = 0.01). All markers displayed clearly distinct behaviour according to the patient's response to therapy. This makes all soluble molecules studied suitable for use as indicators of antimonial therapy response. Additionally the comparison of pretreatment levels of the markers between responders and refractory patients to antimonial therapy showed that serum concentrations of sIL-2R and sICAM-1 significantly differed among these two groups (P = 0.02 in each case), suggesting that they may be used in future as predictors of antimonial therapy response.