Effect of cyclosporin A on interleukin-6 and soluble interleukin-2 receptor in patients with rheumatoid arthritis.

OBJECTIVE--To investigate the effect of cyclosporin A (CyA) therapy on circulating concentrations of interleukin-6 (IL-6) and soluble interleukin-2 receptor (sIL-2R) in patients with rheumatoid arthritis (RA). METHODS--Twenty four RA patients with active disease were studied. Plasma was collected before and after 16 weeks of CyA treatment. IL-6 was measured by B9 bioassay and sIL-2R by enzyme linked immunosorbent assay (ELISA). RESULTS--The initial median IL-6 concentration of 165 IU/ml decreased significantly to 71 IU/ml after 16 weeks (p < 0.05). Similarly, the initial median plasma sIL-2R value of 665 U/ml decreased significantly to 570 U/ml (p < 0.05). This decrease was accompanied by an improvement in clinical parameters of disease activity. Some association between sIL-2R, IL-6, haemoglobin, and platelets was also observed. CONCLUSIONS--This study has demonstrated that, in vivo, CyA therapy in RA can significantly reduce circulating concentrations of IL-6 and sIL-2R. Modulation of both T and non-T cell derived cytokines may be one mechanism by which CyA improves rheumatoid disease. Whether this is a direct effect of CyA on the cells within the rheumatoid joint producing these cytokines or an indirect effect mediated by other cytokines which can influence IL-6 and Il-2R values remains to be determined.     

Plasma soluble interleukin-2 receptor in patients with primary myelofibrosis

Summary Using an enzyme-linked immunosorbant assay (ELISA) test, the level of soluble Tac peptide, one chain of the human interleukin-2 receptor, was measured in the plasma of 26 patients with primary myelofibrosis (MF), seven patients with polycythaemia vera and 11 normal controls. The plasma soluble interleukin-2 receptor (sIL-2R) was found to be significantly elevated in patients with primary MF compared to polycythaemia vera or controls ( P <0·01), while the plasma sIL-2R of patients with polycythaemia vera also was found to be significantly elevated compared to controls ( P <0·01). The significantly elevated value of sIL-2R seen in primary MF may be secondary to T cell activation resulting from autoimmune phenomena, and myeloblast activation with release of sIL-2R may also be a contributing factor. In primary MF, plasma sIL-2R levels were also found to be correlated to survival, circulating blast cell counts, and thrombocytopenia, but not to white blood cell counts, LDH levels, degree of marrow fibrosis, or degree of splenomegaly. Patients with primary MF with higher titre of plasma sIL-2R had a shorter survival. Further studies involving more patients and longer follow-up may substantiate that plasma sIL-2R is an important prognostic indicator in primary MF.     

Elevated serum levels of soluble interleukin-2 receptor in patients with Wegener's granulomatosis. Association with disease activity.

OBJECTIVE. To investigate whether soluble interleukin-2 receptor (sIL-2R), a marker of T cell activation, could be a useful marker of disease activity in Wegener's granulomatosis (WG). METHODS. Soluble IL-2R levels were determined by enzyme-linked immunosorbent assay. WG disease activity in 102 patients was assessed according to clinical features and levels of classic antineutrophil cytoplasmic antibody (c-ANCA) and C-reactive protein (CRP). RESULTS. Soluble IL-2R levels were higher in patients with generalized and active disease than in those with limited and inactive disease. In 25 patients with complete clinical remission, sIL-2R levels were significantly elevated, although levels of CRP and c-ANCA were normal. Eight of these 25 patients had disease relapses within 6 months. Levels of sIL-2R were significantly higher in patients who had relapses than in those who did not. Patients with clinically active WG but low c-ANCA or CRP levels had elevated levels of sIL-2R. CONCLUSION. Levels of sIL-2R correlate with disease activity in patients with WG, and may indicate imminent relapse.     

Elevated serum levels of soluble interleukin-2 receptor in patients with Wegener's granulomatosis. Association with disease activity

Objective. To investigate whether soluble interleukin-2 receptor (sIL-2R), a marker of T cell activation, could be a useful marker of disease activity in Wegener's granulomatosis (WG). Methods. Soluble IL-2R levels were determined by enzyme-linked immunosorbent assay. WG disease activity in 102 patients was assessed according to clinical features and levels of classic antineutrophil cytoplasmic antibody (c-ANCA) and C-reactive protein (CRP). Results. Soluble IL-2R levels were higher in patients with generalized and active disease than in those with limited and inactive disease. In 25 patients with complete clinical remission, sIL-2R levels were significantly elevated, although levels of CRP and c-ANCA were normal. Eight of these 25 patients had disease relapses within 6 months. Levels of sIL-2R were significantly higher in patients who had relapses than in those who did not. Patients with clinically active WG but low c-ANCA or CRP levels had elevated levels of sIL-2R. Conclusion. Levels of sIL-2R correlate with disease activity in patients with WG, and may indicate imminent relapse.     

Plasma soluble interleukin-2 receptor levels in patients with idiopathic thrombocytopenic purpura

Soluble interleukin-2 receptor (sIL-2R) was measured in the plasma of 31 patients with idiopathic thrombocytopenic purpura (ITP) and 22 normal controls. When thrombocytopenia persisted longer than 6 months, the diagnosis of chronic ITP was made. Twenty patients had acute ITP, 11 patients had chronic ITP, and all patients received high-dose methylprednisolone (HDMP) (30 mg/kg/d for 3 days, 20 mg/kg/d for 4 days). The sIL-2R levels of the patients were determined before being giving HDMP and 14 days after the end of HDMP therapy. Platelet counts were determined before administration of HDMP, one day after the end of HDMP therapy, and once every 28 days for 7 months thereafter. There was not a significant difference between the mean pre-treatment plasma sIL-2R levels of both acute and chronic ITP groups (P > 0.05), and these were higher than that of the control group (P < 0.001). The mean post-treatment sIL-2R level of the chronic ITP group was significantly higher than those of both the control and post-treatment acute ITP groups (P < 0.001). There were negative correlations between the plasma sIL-2R levels and platelet counts of both group patients in the pre-treatment period and between post-treatment sIL-2R levels and platelet counts in chronic ITP group (P < 0.05). We think that there was a good correlation between prognosis of ITP and sIL-2R levels after HDMP therapy, and platelet counts in patients with ITP are linked to sIL-2R levels. Am. J. Hematol. 57:119–123, 1998. © 1998 Wiley-Liss, Inc.     

阿尔茨海默病患者血清和脑脊液中白细胞介素-2及白细胞介素-2受体水平的研究

目的　探讨阿尔茨海默病 (AD)的病因及发病机制。方法　采用双抗体夹心酶联免疫吸附试验分别对AD患者血清和脑脊液中白细胞介素 2 (IL 2 )及白细胞介素 2受体 (sIL 2R)水平进行检测。结果　 (1)AD组脑脊液 (CSF)中sIL 2R阳性率明显高于脑血管性痴呆 (VD)组及对照组 (P <0 .0 5 ) ;(2 )AD组血清和CSF中IL 2和sIL 2R含量明显高于VD组和正常对照组 (P <0 .0 5 ,P <0 .0 1) ;(3)AD组IL 2与sIL 2R在血清或CSF中含量均呈正相关 ,与简易智力状态检查量表得分呈负相关。结论　AD组患者CSF中IL 2和sIL 2R可来源于外周免疫系统 ,还可能来源于中枢神经系统的自身合成。检测AD患者CSF中IL 2和sIL 2R水平可反映AD的病理改变程度     

Frequently relapsing Crohn's disease is characterized by persistent elevation in interleukin-6 and soluble interleukin-2 receptor serum levels during remission

We examined immune and inflammatory activation during remission in patients with Crohn's disease who presented with various clinical profiles (prolonged remission vs. relapsing disease). Thirty-six patients with at least 3 years' follow-up starting from a remission period were studied retrospectively. Relapses were defined by a retrospective calculation of the Crohn's disease activity index or by the clinical judgement of the physicians in charge of the patients. Disease course over the study period was assessed by the mean number of annual relapses. Analysis used measurements during remission of the following: erythrocytes sedimentation rate, relative lymphocytosis, acid alpha1-glycoprotein, interleukin-6 (IL-6), and soluble interleukin-2 receptor (sIL-2R) serum levels. During the study period 21 patients experienced at least one relapse and 15 did not. Mean serum levels of sIL-2R and mean relative lymphocytosis in remission significantly discriminated between relapsing and nonrelapsing patients. Only the mean sIL-2R serum level was selected by multivariate analysis, with a cutoff value of 82 pM/1 (sensitivity of 76% and specificity of 80%). The only features correlated with mean number of annual relapses in the relapsing patients were mean serum levels of sIL-2R (r=0.58, P=0.015) and IL-6 in remission (r=0.45, P=0.039). Multivariate analysis demonstrated statistical significance only for the mean serum level of IL-6 (P=0.014). In Crohn's disease the persistent elevation in sIL-2R serum levels during remission corresponds to chronic active disease, while high serum levels of IL-6 in these patients is associated with a high frequency of relapse.     

Soluble interleukin-2 receptor in Crohn's disease: relation of serum concentrations to disease activity.

Serum concentrations of soluble interleukin-2 receptor (sIL-2R) were measured as a marker of immune activation in a group of 30 patients with Crohn's disease. sIL-2R concentrations were determined by enzyme linked immunosorbent assay during periods of active and inactive disease and correlated with standard parameters of disease activity. Serum concentrations of sIL-2R were significantly raised in patients with active Crohn's disease compared with patients with inactive disease (p less than 0.001) and control subjects. There was a significant correlation between serum sIL-2R concentrations and disease activity as assessed by the Harvey-Bradshaw index (r = 0.42, p less than 0.01), platelet numbers (r = 0.49, p less than 0.01), and orosomucoid (r = 0.47, p less than 0.01), alpha 1 antitrypsin (r = 0.44, p less than 0.01), and C reactive protein concentrations (r = 0.48, p less than 0.001) but not with the erythrocyte sedimentation rate. Measurement of serum sIL-2R concentration is a simple and useful laboratory means of assessing disease activity. Raised concentrations in patients with active Crohn's disease is further evidence for in vivo immune activation occurring in this disease.     

Soluble interleukin-2 receptor in Crohn's disease

In Crohn's disease, the activity of the disease is sometimes difficult to evaluate and the evolution of the disease is difficult to predict. The soluble interleukin-2 receptor serum level has been reported to correlate with clinical activity of the disease and with mucosal immune activation. We compared serum soluble interleukin-2 receptor to classical inflammatory markers and other immune parameters in the assessment of clinical disease activity and prediction of relapse in patients with Crohn's disease. Soluble interleukin-2 receptor serum levels correlated well with the Crohn's disease activity index, and multivariate analysis showed that this correlation was independent of the other inflammatory and immune markers. The correlation was not greater, however, than that between some inflammatory markers, such as ESR, and Crohn's disease activity index. Longitudinal follow-up showed that a high soluble interleukin-2 receptor serum level was highly predictive of relapse. Multivariate analysis showed that the soluble interleukin-2 recepteur serum level was complementary to other inflammatory, and clinical markers in the prediction of relapse of disease. We conclude that soluble interleukin-2 receptor is of use in monitoring Crohn's disease, particularly in prediction of relapse.     

Plasma soluble interleukin-2 receptor level in patients with primary myelodysplastic syndromes: a relationship with disease subtype and clinical outcome

To assess the hypothesis that the plasma soluble interleukin-2 receptor (sIL-2R) level may have predictive value for morbidity/mortality in patients with myelodysplastic syndromes (MDS), we determined the plasma sIL-2R level of 80 MDS patients and examined their subsequent clinical course. Compared with low-risk MDS (refractory anaemia (RA) and RA with ringed sideroblasts) patients and normal subjects, the plasma sIL-2R level was significantly elevated in high-risk MDS (three other MDS subtypes and acute leukaemia following MDS) patients (high-risk MDS versus low-risk MDS, P  < 0.01; high-risk MDS versus normal subjects, P  < 0.01). 14/40 low-risk MDS patients developed at least one of the following during the follow-up period: erythrocyte transfusion dependence, infections requiring hospitalization, disease progression or MDS-related death. The plasma sIL-2R level was higher in these eventful subjects than in event-free low-risk subjects ( P  < 0.0001), and all of 10 low-risk subjects with a plasma sIL-2R level > 540 U/ml experienced at least one event. By logistic regression analysis of various parameters in these 40 low-risk subjects, the plasma sIL-2R level was identified as the strongest independent parameter for predicting eventful subjects ( P  < 0.0047). The plasma sIL-2R level did not show a predictive value in high-risk MDS. This study revealed that the plasma sIL-2R level is significantly elevated in high-risk MDS and suggested that the plasma sIL-2R level is a valuable predictive factor for the clinical outcome in low-risk MDS.     

Mononuclear cell activation in Crohn's disease. Evaluation using serum assay of neopterin and interleukin-2 soluble receptors

To determine the degree of mononuclear blood cell activation in Crohn's disease (CD), 65 patients were prospectively investigated (22 with mild, 26 with moderate and 17 with severe disease). Serum levels of soluble receptors for interleukin-2 (SR-IL-2) were measured by ELISA. In CD patients SR-IL-2 levels were significantly higher (m = 707 +/- 326 U/ml) than in three other groups: 70 controls (m = 258 +/- 87 U/ml, p less than 0.0001); 8 patients with acute infectious colitis (m = 405 +/- 216 U/ml, p less than 0.0001); 101 HIV seropositive subjects (m = 564 +/- 216 U/ml, p less than 0.002). There was a positive correlation between SR-IL-2 level and the Van Hees activity index (r = 0.595, p less than 0.0001). On the other hand, the numbers of activated T cells (CD 3+, HLA DR+), CD 4+, CD 8+ and NK cells did not differ according to the CD activity groups. Furthermore, CD patients treated with steroids (n = 39) did not differ from those without any medication. As a marker of monocyte activation, serum neopterin level was determined by RIA. All CD patients considered as a group, serum neopterin level was 2.89 +/- 1.44 ng/l (n less than 2.5 ng/l). Neopterin level increased with disease activity (1.97 +/- 0.92 vs 3.10 +/- 1.46 vs 3.74 +/- 1.36, p less than 0.01), and was positively correlated with SR-IL-2 (r = 0.609, p less than 0.0001). These results suggest a monocyte-macrophage activation in CD, which parallels disease activity.(ABSTRACT TRUNCATED AT 250 WORDS)     

T-cell activation in Crohn's disease. Increased levels of soluble interleukin-2 receptor in serum and in supernatants of stimulated peripheral blood mononuclear cells

Serum levels of soluble interleukin-2 receptor were determined in 29 patients with active and quiescent Crohn's disease. In addition, the ability of peripheral blood mononuclear cells of 23 of these patients to generate soluble interleukin-2 receptor following mitogenic stimulation was studied in vitro. Serum soluble interleukin-2 receptor concentrations of patients with active Crohn's disease (n = 19) were significantly elevated (757 +/- 438 U/ml) compared with levels in patients with inactive disease (n = 10; 412 +/- 120 U/ml) and healthy control individuals (n = 40; 375 +/- 102 U/ml; p less than 0.003 and p less than 0.0005, respectively). Serial determinations of serum soluble interleukin-2 receptor concentration in a follow-up of 11 hospitalized patients treated for highly active disease showed a decrease from 1252 +/- 494 U/ml to 527 +/- 193 U/ml (p less than 0.004) that corresponded to clinical improvement, as assessed by Crohn's disease activity index and a reduction of inflammatory parameters. In vitro phytohemagglutinin stimulation of peripheral blood mononuclear cells derived from patients with Crohn's disease resulted in elevated soluble interleukin-2 receptor production not only in patients with active disease (3987 +/- 2439 U/ml), but also in patients with inactive disease (3297 +/- 2282 U/ml), compared with the amount of soluble interleukin-2 receptor produced by mononuclear cells of healthy individuals (1523 +/- 1152 U/ml; p less than 0.005 and p less than 0.02, respectively). In addition, cultivation of mononuclear cells without mitogen resulted in higher soluble interleukin-2 receptor production in patients with active disease than in patients with inactive disease (p less than 0.02). However, patients suffering from active ulcerative colitis also had significantly increased serum levels of soluble interleukin-2 receptor (1080 +/- 400 U/ml) compared with the levels in patients with chronic disease (455 +/- 140 U/ml; p less than 0.0025). In addition, peripheral blood mononuclear cells derived from patients with ulcerative colitis produced significantly more soluble interleukin-2 receptor upon mitogenic stimulation with phytohemagglutinin (2314 +/- 936 U/ml), than cells from healthy controls (1523 +/- 1152 U/ml; p less than 0.05). The finding of elevated soluble interleukin-2 receptor serum levels in patients with active Crohn's disease and its increased production by mononuclear cells of patients with both active and inactive disease is a further example of an alteration of the immune system in this condition; however, this alteration can also be found in other inflammatory bowel diseases.     

Soluble interleukin-2 receptor, interleukin-6 and interleukin-1 beta in patients with Crohn's disease and ulcerative colitis: preoperative levels and postoperative changes of serum concentrations.

Crohn's disease (CD) and ulcerative colitis (UC) show an intestinal activation of T cells and macrophages within the inflamed lesions. The aim of the present prospective study was to determine whether circulating interleukins (IL) represent useful markers of immune activation in vivo and to characterize their respective roles in monitoring disease activity. Serum concentrations of the soluble IL-2 receptor (sIL-2R), IL-6 and IL-1 beta were measured in 10 patients with CD and 10 patients with UC before, at day 10 and 2 years after resection of inflamed bowel segments. The data were correlated with neopterin, C-reactive protein and other standard parameters of disease activity. Preoperatively, mean sIL-2R concentration was 495 +/- 62 U/ml (mean +/- SEM; healthy controls; 210 +/- 25 U/ml; p less than 0.02) in CD and 705 +/- 120 U/ml (p less than 0.00002) in UC. The corresponding IL-6 serum concentrations were 37 +/- 6 U/ml in CD (controls: 11 +/- 0.6 U/ml; p less than 0.0036) and 33 +/- 6 U/ml (p less than 0.04) in UC. Two years postoperatively, sIL-2R was still elevated in 6 out of 9 patients in both disease groups. These patients did not differ from the remaining group with respect to disease activity. Serum IL-6, elevated in 7 patients with CD and in 6 patients with UC at day 10 postoperatively, had returned to normal in all patients by this time.(ABSTRACT TRUNCATED AT 250 WORDS)     

Clinical significance of serum soluble interleukin-2 receptor level in patients with non-Hodgkin's lymphoma]

The aim of this study was to assess the clinical significance of serum soluble interleukin-2 receptors (sIL-2R) in non-Hodgkin's lymphoma (NHL). Using a sandwich ELISA method, serum sIL-2R levels were measured in 720 samples from 87 patients with NHL (including 65 untreated patients) and 36 patients with other diseases such as infectious mononucleosis. The mean serum sIL-2R level in NHL was 4,017 U/ml (mean +/- SD, 4017 +/- 6352 U/ml). Patients in clinical stages III/IV (5116 +/- 6629) had significantly higher sIL-2R levels than those in clinical stages I/II (813 +/- 611). Patients with sIL-2R levels exceeding 8,000 U/ml had significantly lower survival rates (2-year survival: 12.3%) than those with sIL-2R levels below 8,000 U/ml (2-year survival: 76.0%) (P < 0.01). Multivariate analysis of variables including age, clinical stage, LDH, CRP, performance status, number of extranodal diseases, and sIL-2R demonstrated that sIL-2R and LDH were significant prognostic indicators of overall survival. The upper limit of the 95% confidence interval for maximum sIL-2R level in follow-up of patients with complete remission was 2,014 U/ml. Although an increased sIL-2R level of around 2,000 U/ml in the remission stage did not necessarily suggest relapse of NHL, it did seem to warrant careful follow-up. The serum sIL-2R level appears to reflect tumor activity and may prove to be a useful prognostic indicator in patients with NHL.     

Plasma soluble triggering receptor expressed on myeloid cells-1 in Crohn's disease

BackgroundNo definite conclusions can be drawn from available data on the accuracy of soluble triggering receptor expressed on myeloid cells-1 (sTREM-1) to assess disease activity in Crohn's disease.AimsPlasma sTREM-1 levels were correlated with disease activity markers in Crohn's disease.Methods191 consecutive patients from a single referral centre (Nancy IBD cohort) were prospectively enrolled between June 1, 2005 and December 12, 2008. Plasma sTREM-1 levels were also assessed amongst 20 healthy controls.ResultsThe sTREM-1 was detectable in 87 Crohn's disease patients (46%). Plasma sTREM-1 level was higher in Crohn's disease patients (interquartile range, 0–356) than in healthy controls (interquartile range, 0–15.1; P = 0.01). It was neither correlated with Crohn's disease activity index (r = 0.05, P = 0.56), C-reactive protein (r = 0.06, P = 0.53), nor with albumin (r = −0.041, P = 0.66). Crohn's disease activity index, C-reactive protein and albumin median levels were similar between patients with positive sTREM-1 levels and those with undetectable sTREM-1 levels. Azathioprine (P = 0.06), infliximab (P = 0.68) and methotrexate (P = 0.56) did not influence sTREM-1 levels.ConclusionPlasma sTREM-1 does not appear to be an accurate marker of disease activity in Crohn's disease and cannot be recommended for assessing disease activity in these patients.     

Relationship between serum levels of soluble interleukin-2 receptor and various disease parameters in patients with squamous cell carcinoma of the esophagus.

BACKGROUND/AIMS: Soluble interleukin-2 receptor (sIL-2R) is a useful biomarker for the management of hematologic malignancies. We determined the significance of serum sIL-2R levels in patients with squamous cell carcinoma of the esophagus. METHODOLOGY: The correlation between serum sIL-2R levels and a variety of clinicopathologic factors in 51 patients with squamous cell carcinoma of the esophagus was evaluated. We also investigated the expression of IL-2R in the resected specimen using immunohistochemical staining. RESULTS: Expression of IL-2R was detected in primary esophageal carcinoma cells as well as infiltrating mononuclear cells. Serum sIL-2R levels in the 51 patients with esophageal cancer were significantly higher than those in the 18 healthy volunteers (p < 0.01). Multivariate analysis showed that pM, tumor size, and lymph node metastasis was significantly correlated with serum sIL-2R levels. Univariate analysis demonstrated that tumor size, pM, pTNM stage, and resectability were parameters which were significantly correlated with serum sIL-2R levels. There was no relationship between serum sIL-2 levels and tumor depth, lymph node metastasis, pT, histologic type, or curability. CONCLUSIONS: These results suggest that the serum sIL-2R levels may be an indicator of the extent of disease and resectability in patients with esophageal squamous cell carcinoma. Immunohistochemical staining suggests that esophageal cancer cells and infiltrating mononuclear cells may be the source of sIL-2R in the serum.     

川崎病患儿血清可溶性白细胞介素-2受体和白细胞介素-6的变化及意义

目的探讨血清可溶性白细胞介素-2受体(sIL-2R)和白细胞介素-6(IL-6)水平在川崎病(K D)患儿中的变化,及其在发病中的作用。方法采用酶联免疫吸附试验(ELISA)双抗夹心法测定血清sIL-2R和IL-6水平;利用德灵BN ProSpec特种蛋白分析仪检测血清超敏C反应蛋白(hs-CRP)水平。结果30例KD患儿大剂量丙种球蛋白静脉滴注前(静丙前)和滴注后(静丙后)血清slL-2R和hs-CRP水平与对照组比较差异均有统计学意义(P<0.01),静丙前和静丙后比较差异有统计学意义(P<0.01);静丙前KD患儿血清IL-6和对照组比较差异有统计学意义(P<0.01);KD患儿血清slL-2R与hs-CR P水平呈正相关(r=0.6,P<0.01),静丙前K D患儿血清IL-6和hs-CRP呈正相关(r=0.68,P<0.01)。结论血清IL-6和slL-2R参与了川崎病的发生,它们可作为判断预后、评估患儿免疫功能状况的参考指标。