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Objective: Treg cells modulate immune responses and can suppress the development of autoimmune diseases. Tumor necrosis factor receptor II (TNFRII) has been recognized as a key receptor on these cells that facilitates expansion and stabilization of CD4+ Treg cells. The purpose of the present study was to investigate the therapeutic activity of a novel TNFRII agonist in experimental arthritis as well as the role of different Treg cell subsets. Methods: A novel mouse TNFRII–selective fusion protein (EHD2‐sc‐mTNFR2) was generated by genetic engineering. Mouse T cells were incubated together with interleukin‐2 and/or EHD2‐sc‐mTNFR2, and the effects on Treg cells were analyzed by flow cytometry. Mice with collagen‐induced arthritis (CIA) were treated with EHD2‐sc‐mTNFR2 or saline, and the therapeutic effects were monitored and characterized. Results: Selective activation of TNFRII was found to expand both CD4+ and CD8+ Treg cells. Moreover, TNFRII activation elevated the number of CD4+CD25+ and CD8+CD25+ Treg cells and increased the number of FoxP3‐expressing cells in CD8+, but not CD4+, Treg cells, indicating different mechanisms of TNFRII‐induced expansion of diverse T cell subsets with suppressive activity. In the CIA model, we demonstrated that administration of the TNFRII agonist EHD2‐sc‐mTNFR2 led to the expansion of both CD4+ and CD8+ Treg cells in vivo and induced antiinflammatory responses that alleviated arthritis. Conclusion: Our findings support the use of TNFRII‐selective therapeutics as an effective approach to the treatment of arthritic disease and possibly other inflammatory and autoimmune diseases. [ABSTRACT FROM AUTHOR]

Background & Aims Norfloxacin exerts immunomodulatory effects in cirrhosis beyond its bactericidal activity. We aimed at identifying the role of regulatory T (Treg) cells in the norfloxacin mechanism that compensates the inflammatory environment in cirrhosis. Patients & Methods Consecutively admitted patients with cirrhosis and ascitic fluid ( AF) with: spontaneous bacterial peritonitis ( SBP), non-infected AF, and norfloxacin as secondary SBP prophylaxis ( SID group). Tregs were defined by flow-cytometry as CD4+ CD25+FoxP3+ cells. Dendritic cells ( DCs) were purified for co-stimulatory signalling evaluation and norfloxacin and IL-10 levels were measured in serum. Wildtype and recombination activating gene 1 (Rag1)-deficient mice with CCl4-induced cirrhosis were used for adoptive-transfer experiments using naïve CD4+ T cells and Tregs. Results Eighty-four patients were included. Treg percentage was significantly increased in SID patients compared with SBP or non-infected AF patients. A positive correlation was observed between Tregs and serum norfloxacin and IL-10 levels. DCs from SID patients showed a significantly decreased expression of CD80 and CD86 compared with SBP and non-infected AF patients and correlated with norfloxacin levels. Modulation of co-stimulatory signalling by norfloxacin was not detected in Rag1-deficient mice and Rag1-deficient mice reconstituted with naïve T-cells. However, reconstitution with naïve T-cells and Tregs was associated with significantly downregulated CD80 and CD86 expression in the presence of norfloxacin. Norfloxacin immunomodulatory effect on IL-2 and IFN-gamma reduction and on the increase of IL-10 was significantly achieved only when the Tregs were restored in Rag1-deficient mice. Conclusions These results provide a plausible mechanism for the immunomodulatory effects of norfloxacin in cirrhosis beyond its bactericidal effect. [ABSTRACT FROM AUTHOR]

Emerging T-helper type 2 (Th2) cytokine-based asthma therapies, such as tralokinumab, lebrikizumab (anti-interleukin (IL)-13), and mepolizumab (anti-IL-5), have shown differences in their blood eosinophil (EOS) response. To better understand these effects, we developed a mathematical model of EOS dynamics. For the anti-IL-13 therapies, lebrikizumab and tralokinumab, the model predicted an increase of 30% and 10% in total and activated EOS in the blood, respectively, and a decrease in the total and activated EOS in the airways. The model predicted a rapid decrease in total and activated EOS levels in blood and airways for the anti-IL-5 therapy mepolizumab. All model-based predictions were consistent with published clinical observations. The modeling approach provided insights into EOS response after treatment with Th2-targeted therapies, and supports the hypothesis that an increase in blood EOS after anti-IL-13 therapy is part of the pharmacological action of these therapies. [ABSTRACT FROM AUTHOR]

The treatment of human immunodeficiency virus (HIV) remains a major challenge, even if significant progress has been made in infection treatment by 'drug cocktails'. Nowadays, research trend is to minimize the number of pills taken when treating infection. In this paper, an HIV-1 within host model where healthy cells follow a simple logistic growth is considered. Basic reproduction number of the model is calculated using next generation matrix method, steady states are derived; their local, as well as global stability, is discussed using the Routh-Hurwitz criteria, Lyapunov functions and the Lozinskii measure approach. The optimal control policy is formulated and solved as an optimal control problem. Numerical simulations are performed to compare several cases, representing a treatment by Interleukin2 alone, classical treatment by multitherapy drugs alone, then both treatments at the same time. Objective functionals aim to (i) minimize infected cells quantity; (ii) minimize free virus particles number; and (iii) maximize healthy cells density in blood. Copyright © 2015 John Wiley & Sons, Ltd. [ABSTRACT FROM AUTHOR]

Extrapulmonary tuberculosis ( EPTB) remains a challenging diagnosis both for clinicians and microbiologists. We hypothesized that the profile of IFN-ɤ/ IL-2 ratio in clinically diagnosed cases of EPTB would be distinct from that of age- and sex-matched healthy controls. Therefore, in our study, we have assessed the ratio of serum levels of IFN-ɤ and IL-2 in clinically diagnosed cases of EPTB to assess their potential role as diagnostic biomarkers. Sixty-nine (69) clinically confirmed EPTB cases and 69 age- and sex-matched healthy controls were included in the study. All the extrapulmonary specimens were subjected to Ziehl-Neelsen staining for acid-fast bacilli and culture on Lowenstein-Jensen ( LJ) medium. Detection of serum levels of IFN-ɤ and IL-2 was carried out using commercially available ELISA kits following manufacturers' instructions. The ratio of serum levels of IFN-ɤ and IFN-ɤ/ IL-2 was discriminative for the diagnosis of EPTB cases (p < 0.001), although the same was not observed with IL-2 (p > 0.05). Distribution of all biomarkers significantly differed between culture-positive and culture-negative cases (p < 0.05). Among the smear-positive and smear-negative ones, only IFN-ɤ and IFN-ɤ/ IL-2 ratio could significantly differentiate (p < 0.05). Ratio of IFN-ɤ and IL-2 rather than the individual levels was the best discriminatory biomarker with the highest area under the ROC curve. Although IFN-ɤ and IFN-ɤ/ IL-2 ratio could aid in the diagnosis of EPTB, IL-2 has a limited utility in the diagnosis of EPTB. Further elaborate studies to validate these results are required. [ABSTRACT FROM AUTHOR]

Malignant ascites caused by peritoneal dissemination of gastric cancer is chemotherapy-resistant and associated with poor prognosis. We conducted a pilot study to evaluate the safety of weekly intraperitoneal injections of in vitro expanded V γ9V δ2 T cells together with zoledronate for the treatment of such malignant ascites. Patient peripheral blood mononuclear cells were stimulated with zoledronate (5 μmol/L) and interleukin-2 (1000 IU/mL). After 14 days culture, V γ9V δ2 T-cells were harvested and administered intraperitoneally in four weekly infusions. The day before T-cell injection, patients received zoledronate (1 mg) to sensitize their tumor cells to V γ9V δ2 T-cell recognition. Seven patients were enrolled in this study. The number of V γ9V δ2 T-cells in each injection ranged from 0.6 to 69.8 × 108 (median 59.0 × 108). There were no severe adverse events related to the therapy. Intraperitoneal injection of V γ9V δ2 T cells allows them access to the tumor cells in the peritoneal cavity. The number of tumor cells in the ascites was significantly reduced even after the first round of therapy and remained substantially lower over the course of treatment. IFN- γ was detected in the ascites on treatment. Computed tomography revealed a significant reduction in volume of ascites in two of seven patients. Thus, injection of these antitumor V γ9V δ2 T-cells can result in local control of malignant ascites in patients for whom no standard therapy apart from paracentesis is available. Adoptively transferred V γ9V δ2 T-cells do indeed recognize tumor cells and exert antitumor effector activity in vivo, when they access to the tumor cells. [ABSTRACT FROM AUTHOR]

Objectives Interleukin-2 ( IL-2) therapy increased CD4 cell counts and delayed antiretroviral therapy ( ART) initiation in HIV-infected patients in the Agence Nationale de Recherche sur le SIDA et les Hépatites Virales ( ANRS) 119 trial. However, four cases of lymphoma were reported. Epstein− Barr virus ( EBV) replication is associated with an increased risk of lymphoma in immunocompromised patients. We assessed whether IL-2 had an impact on EBV replication and the development of lymphoma. Methods A total of 130 ART-naïve patients were randomized to receive IL-2 therapy ( n = 66) or no treatment ( n = 64). Clinical data for patients with lymphomas were reviewed and tumours assessed for evidence of EBV infection and CD25 (the IL-2 receptor) expression. EBV DNA levels were measured in whole blood and plasma in both arms using real-time polymerase chain reaction ( PCR), up to 48 weeks after baseline ( BL). Results Four lymphomas occurred, a median of 61 weeks [range 40−94 weeks] after randomization at a median CD4 cell count of 396 cells/μL ( IQR 234-536 cells/μL). In the IL-2 arm, two patients developed EBV-positive Hodgkin's lymphoma, and one developed EBV-negative Burkitt-type lymphoma. One patient in the control group developed EBV-positive non-Hodgkin's lymphoma. CD25 was negative in all cases. Among the 41 of 55 (control arm) and 44 of 58 ( IL-2 arm) patients with detectable EBV DNA in whole blood at both BL and week 48, the median change in EBV DNA between BL and week 48 was +0.04 log10 copies/ml in both arms ( P = 0.7). In plasma, EBV was detected at least once in 22 of 52 controls and 21 of 54 IL-2-treated patients ( P = 0.8). Conclusions IL-2 therapy had no significant effect on EBV replication over 48 weeks in these ART-naïve patients. The occurrence of lymphomas did not seem to be associated with IL-2 therapy. [ABSTRACT FROM AUTHOR]

Background. Radiofrequency ablation (RFA) is a minimally invasive tumor destruction technique and can provide the antigen source initiating tumor immunity. However, induced immune response is weak and requires additional immunotherapy for optimized RFA treatment against cancer. Methods. A murine orthotopic model of head and neck squamous cell carcinoma (HNSCC) was established to investigate the efficacy and mechanism of an RFA + interleukin-2 (IL-2) combination adenoviral gene therapy among 6 groups. Tumor volume change, apoptosis, in situ macrophage recruitment, cytotoxic T lymphocyte (CTL) activity, migration of dendritic cells into the regional lymph nodes, and systemic antitumor immunity were examined. Results. RFA + IL-2 therapy induced the highest levels of macrophage recruitment and dendritic cell migration resulting in enhanced CTL activity, increased tumor apoptosis, enhanced systemic antitumor immunity, and the best inhibition of tumor growth among all groups. Conclusion. RFA + IL-2 combination therapy generates potent tumor immunity to suppress tumor growth in HNSCC. [ABSTRACT FROM AUTHOR]

OBJECTIVE Low-dose interleukin-2 (IL-2) is a historical treatment for metastatic renal cell carcinoma (mRCC). Increased vascular endothelial growth factor (VEGF) levels inhibit dendritic cell (DC) differentiation and augment production of immunosuppressive regulatory T (Treg) cells. Bevacizumab is an antibody that binds to VEGF, has activity in mRCC and may augment the anti-tumour immune effects of IL-2. To determine the clinical and immunomodulatory effects of this combination, a prospective, phase II trial of bevacizumab plus low-dose IL-2 was conducted. PATIENTS AND METHODS Patients with untreated mRCC received bevacizumab (10 mg/kg i.v. every 2 weeks) and IL-2 (125 000 units/kg/day subcutaneously from Monday to Friday for 6 consecutive weeks followed by a 2-week rest period). Endpoints included progression-free survival, Response Evaluation Criteria in Solid Tumors-defined objective response rate, immunomodulatory effects and safety. RESULTS Between January 2005 and September 2007, twenty-six patients with untreated mRCC were enrolled. The median progression-free survival was 9.6 months (95% CI, 4.1-16.9 months) The objective response rate was 15% and an additional 38% of patients had tumour burden reduction of < 30%. Grade 3 constitutional adverse events (fatigue, fever/ chills) and neutropenia were observed in 42% and 12% of patients, respectively. Peripheral blood CD1c + myeloid and CD303 + plasmacytoid DC increased during treatment as did IL-8 levels and CD4 + CD25 + FoxP3 + Treg cells. No changes in T helper type 1/2- associated cytokines were observed. CONCLUSION Bevacizumab plus low-dose IL-2 has modest clinical activity in mRCC. Toxicity was largely IL-2 related without enhancement of bevacizumab-related toxicity. Biological data indicate inhibition of VEGF levels and increase of immunosuppressive Treg cells without an effect on DC activation. [ABSTRACT FROM AUTHOR]

Cytokine immunotherapy is being evaluated as adjunct treatment in infectious diseases. The effects on innate and adaptive immunity in vivo are insufficiently known. Here, we investigate whether combination treatment with antiretroviral therapy (ART) and Interleukin-2 (IL-2) of patients with primary HIV-1 infection induces sustained increases in circulating NKT cell and NK cell numbers and effector functions and investigate how changes are coordinated in the two compartments. Patients with primary HIV-1 infection starting ART were analyzed for numbers, phenotype and function of NKT cells, NK cells and dendritic cells (DC) in peripheral blood before, during and after IL-2 treatment. NKT cells expanded during IL-2 treatment as expected from previous studies. However, their response to α-galactosyl ceramide antigen were retained but not boosted. Myeloid DC did not change their numbers or CD1d-expression during treatment. In contrast, the NK cell compartment responded with rapid expansion of the CD56 effector subset and enhanced IFNγ production. Expansions of NKT cells and NK cells retracted back towards baseline values at 12 months after IL-2 treatment ended. In summary, NKT cells and NK cells respond to IL-2 treatment with different kinetics. Effects on cellular function are distinct between the cell types and the effects appear not to be sustained after IL-2 treatment ends. These results improve our understanding of the effects of cytokine immunotherapy on innate cellular immunity in early HIV-1 infection. [ABSTRACT FROM AUTHOR]

Study Type - Therapy (case series) Level of Evidence 4 OBJECTIVE To determine if the fractional percentage of tumour volume (FPTV) removed with debulking nephrectomy was associated with progression-free survival (PFS) after subsequent targeted therapy, as a debulking nephrectomy is the standard of care in metastatic renal cell carcinoma (mRCC), but there are few data. PATIENTS AND METHODS The Cleveland Clinic Taussig Cancer Institute Urologic Oncology database was retrospectively reviewed from 2005 to 2008 to identify patients with mRCC who had undergone debulking nephrectomy followed by vascular endothelial growth factor (VEGF)-targeted therapy, defined as sunitinib-, sorafenib- or bevacizumab-based therapy. FPTV was calculated as the largest diameter of the primary tumour divided by the total tumour burden (as per the Response Evaluation Criteria in Solid Tumors, RECIST) through investigator re-review of imaging. PFS was defined from the start date of systemic therapy to disease progression per RECIST criteria. RESULTS Forty-six patients were identified (80% men, median age 61 years, all clear cell histology and 67% with an Eastern Cooperative Oncology Group performance status of 0). Patients received treatment with bevacizumab ± interleukin-2 (18), sunitinib (14), sorafenib (11) or sunitinib + bevacizumab (three). The median diameter of the primary tumour was 10.0 cm. The median (range) FPTV removed was 95 (80-99)%. In univariable analysis, the FPTV removed ( P= 0.002) and normal haemoglobin level ( P= 0.04) were associated with improved PFS. In multivariable analysis, the FPTV removed ( P < 0.001), male gender ( P= 0.001) and corrected calcium ( P= 0.05) were independent predictors of PFS. CONCLUSION A greater percentage of tumour burden removed at debulking nephrectomy is significantly associated with improved PFS on subsequent VEGF-targeted systemic therapy. [ABSTRACT FROM AUTHOR]

The article presents a study on the efficacy of rapamycin in diffuse systemic sclerosis (SSc) treatment. It is stated in the study that rapamycin blocks T cell response to cytokines, especially interleukin-2. It notes that the study evaluated the potential efficacy of rapamycin or methotrexate (MTX) using the modified Rodnan skin thickness score (MRSS) and the Health Assessment Questionnaire. It also mentions that the study found that the MRSS improved significantly after drug administration.

Background: Atopic dermatitis (AD) is a T cell dependent chronic relapsing inflammatory skin disorder successfully treated with cyclosporine A (CsA). Clinical observations indicate that even low-dose CsA therapy is successful in severely affected AD patients. We studied the impact of low-dose CsA therapy on the ability of T helper cells to be activated, and examined whether regulatory T (Treg) cells are increased in these patients. Methods: Peripheral T cells were activated in a whole blood sample and interleukin-2 producing cells were measured by intracellular cytokine staining. Regulatory T cells were analyzed by intracellular FoxP3 staining. Regulatory T cells (CD4+CD25+CD127low) and effector T cells (CD4+CD25−CD127+) were sorted by flow cytometry and used for suppression assays. Results: A group of AD patients treated with low-dose CsA had a significantly larger Treg cell population than a healthy control subject group. In individual patients, onset of low-dose CsA therapy reduced the ability of T cells to be activated to 42 ± 18% ( P < 0.005) and significantly increased Treg cells, both in absolute numbers (1.6-fold change) and frequencies (1.7-fold change). Treg cells from AD patients showed similar suppressive capacities as Treg cells from healthy donors. Furthermore, Treg cells from AD patients had skin homing properties. Conclusion: Our results indicate that the therapeutic effect of low-dose CsA therapy in AD patients might be not only mediated by the inhibition of T cell hyperactivity but also by an increased population of Treg cells. [ABSTRACT FROM AUTHOR]

Background: Previous biochemotherapy regimens for metastatic melanoma have required attenuated dosages of interleukin 2 (IL-2) that may have compromised efficacy.Methods: In a phase 2 study, the authors tested sequential temozolomide (75 mg/m2 per day orally for 3 weeks) followed by high-dose, IL-2 (600,000 U/kg per dose intravenously; maximum, 14 doses over 5 days).Results: Thirty-eight patients with treatment-naive American Joint Committee on Cancer stage IV melanoma (8 patients with M1a disease, 6 patients with M1b disease, and 24 patients with M1c disease) were enrolled. Ten patients had a history of treated brain metastases. Thirty-one patients who received at least 2 cycles of IL-2 were evaluable for response. Grade 3 toxicities included hyperbilirubinemia (9 patients), hematologic toxicities (leukopenia in 5 patients, thrombocytopenia in 3 patients), diarrhea (2 patients), and oliguria (1 patient). One patient had grade 4 nausea. The overall response rate (ORR) was 16% and included 3 complete responses that lasted 10.8 months, > or =32 months, and > or =36 months and 2 partial responses that lasted 13 months and 14 months. Responses were observed in patients with M1a disease and in patients with M1c disease. Sixteen patients had stable disease (15 patients progressed). The median progression-free survival (PFS) was 5.3 months (95% confidence interval [CI], 3.7-7.5 months). The probability of PFS at 6 months was 0.52 (95% CI, 0.33-0.67). Among 38 enrolled patients, 16 patients remained alive at a median follow-up of 6.7 months (range, 1.9-36.1 months). The median overall survival (OS) was 12.1 months (95% CI, 9.1-16.4 months), and the probability of 12-month OS was 0.54 (95% CI, 0.34-0.70 months).Conclusions: The current results indicated that it is safe to administer HD IL-2 sequentially with temozolomide and that this combination has lower toxicity than previously used concurrent biochemotherapy regimens. However, The ORR and the durability of responses with this combination did not exceed those of single-agent HD IL-2. [ABSTRACT FROM AUTHOR]

In the last 3 years there has been a dramatic increase in the treatment options for patients with metastatic renal cancer. In addition to the cytokines interferon and interleukin 2, recently approved agents include sorafenib, sunitinib, temsirolimus and bevacizumab. A plethora of agents that are likely to have clinical activity are currently in the development ‘pipeline’. This brief review is intended to overview recent developments, and to identify advances that are likely to influence treatment decisions. [ABSTRACT FROM AUTHOR]

Background: The treatment of metastatic renal cell carcinoma (RCC) with high-dose interleukin-2 (HD IL-2) has resulted in durable tumor regression in a minority of patients. The current study presents the authors' 20-year experience administering this immunotherapeutic agent.Methods: Patients with metastatic RCC (n = 259) were treated with HD IL-2 alone from January 13, 1986 through December 31, 2006 at the Surgery Branch of the National Cancer Institute. Potential predictive factors for response and survival, both pretreatment and treatment-related, were first subjected to univariate analysis and then to multivariate logistic regression or a Cox proportional hazards model. Finally, the authors investigated Memorial Sloan-Kettering Cancer Center (MSKCC) prognostic factors for survival to assess their predictive value in the patient population in the current study.Results: A total of 23 patients experienced a complete response and 30 patients achieved a partial response, for an overall objective response rate of 20%. All partial responders had developed disease recurrence at the time of last follow-up, but only 4 complete responders had experienced disease recurrence by that time. Despite toxicities, only 2 patients developed treatment-related mortalities over this same time period. A higher baseline weight (P = .05) and MSKCC prognostic factors (P = .02) were found to be the variables most associated with response. For survival >4 years and overall survival, several pretreatment and treatment-related factors maintained significance, but none more so than response (P < .0001).Conclusions: HD IL-2 can induce complete tumor regression in a small number of patients, and many patients have experienced extended disease-free intervals. Given its relative safety, HD IL-2 should still be considered a first-line therapy in patients with metastatic RCC who have an overall good performance status. [ABSTRACT FROM AUTHOR]

Interleukin-2 receptor (IL2R) antibody has emerged as an attractive induction therapy for organ transplant. However, the long-term outcome of basiliximab induction in simultaneous pancreas and kidney (SPK) transplant remains speculative. We retrospectively analyzed the long-term survivals of 91 consecutive SPK recipients with basiliximab as induction, combination of steroid, tacrolimus (TAC) and mycophenolate acid (MFA) – either mycophenolate mofetil (MMF) or sodium mycophenolate (myfortic) as maintenance. At one, three, five, and seven-yr, the actual patient survival rate were 91.2%, 90.3%, 88.1%, and 88.2%, respectively; kidney graft survivals were 90.1%, 84.7%, 78.6%, and 70.6%, respectively; and pancreas graft survivals were 86.8%, 80.6%, 71.4%, and 58.8% respectively. There was a low incidence of rejection and CMV infection. Basiliximab induction with TAC, MFA, and steroid maintenance therapy can provide excellent long-term outcome for SPK recipients. [ABSTRACT FROM AUTHOR]

The article presents medical research into immunotherapy for metastatic renal cell carcinoma. Treatments with cytokines interleukin-2 and interferon-alpha show consistent clinical results in antineoplastic activity. Interferon-alpha is a glycoprotein produced by the body in response to foreign antigens and viral infections.

Background Specific immunotherapy with intact allergen vaccine is a well-documented treatment for allergic diseases. Different vaccine formulations are currently commercially available, the active ingredient either being intact allergens or chemically modified allergoids. The rationale behind allergoids is to decrease allergenicity while maintaining immunogenicity. However, data from the German health authorities based on reporting of adverse events over a 10-year period did not indicate increased safety of allergoids over intact allergens. Objective The objective of this study was to investigate the effect of chemical modification on allergenicity and immunogenicity comparing four commercial allergoid products for birch pollen immunotherapy with an intact allergen vaccine. Methods Solid-phase IgE inhibition and histamine release assays were selected as model systems for allergenicity, and a combination of human T cell proliferation and IgG titres following mouse immunizations were used to address the immunogenicity of the intact allergen vaccine and the four allergoids. In all assays, the products were normalized with respect to the manufacturer's recommended maintenance dose. Results IgE inhibition experiments showed a change in epitope composition comparing intact allergen vaccine with allergoid. One allergoid product induced enhanced histamine release compared to the intact allergens, while the other three allergoids showed reduced release. Standard T cell stimulation assays using lines from allergic patients showed a reduced response for all allergoids compared with the intact allergen vaccine regardless of the cell type used for antigen presentation. All allergoids showed reduced capacity to induce allergen-specific IgG responses in mice. Conclusion While some allergoids were associated with reduced allergenicity, a clear reduction in immunogenicity was observed for all allergoid products compared with the intact allergen vaccine, and the commercial allergoids tested therefore do not fulfil the allergoid concept. [ABSTRACT FROM AUTHOR]

The aim of this randomized prospective study was to assess the efficacy and safety of a triple therapy with interferon- α (IFN- α)-ribavirin-interleukin-2 (IL-2) for the treatment of patients with genotype 1 infection and high viral load nonresponsive to primary IFN-ribavirin therapy. Twenty hepatitis C virus (HCV) genotype 1 patients with high viral load and Metavir fibrosis score ≥2 without HIV co-infection who were previously nonviral responders to standard treatment with IFN plus ribavirin were intensively re-treated with IFN- α2a (3 millions (M) IU every 2 days) combined with ribavirin (1000–1200 mg/day) for a 24-week period. Patients were randomized to receive four cycles of subcutaneous injection of IL-2 (3 MIU/day, 5 days a week every 3 weeks) during either the first 12 weeks (group 1, n = 10) or the last 12 weeks (group 2, n = 10) of combination therapy. At the end of triple therapy, six patients (30%) achieved a biochemical response and 4 (20%) a viral response followed by a relapse after triple therapy withdrawal. After 12 weeks of therapy, no difference in viral oad was observed between the groups. The decrease in viral load in group 2 was not raised after the addition of IL-2 to IFN plus ribavirin combination therapy. No serious adverse effects were observed. In conclusion, in patients with poor predictive factors of response, the addition of IL-2 to IFN ribavirin combination therapy does not exert a favourable impact on HCV treatment. [ABSTRACT FROM AUTHOR]

Di Filippo S. Anti-IL-2 receptor antibody vs. polyclonal anti-lymphocyte antibody as induction therapy in pediatric transplantation.Pediatr Transplantation 2005.© 2005 Blackwell MunksgaardCurrent concerns in pediatric transplantation focus on chronic rejection which commonly leads to graft loss, and on long-term maintenance immunosuppression toxicity. Acute rejection has been associated with the subsequent development of chronic rejection. Therefore, induction therapy may provide potential benefits by preventing early acute rejection episodes and allowing delayed administration of calcineurin inhibitors or steroid avoidance. This review of the literature showed that induction therapy can reduce early and recurrent acute rejection episodes after pediatric solid organ transplantation. Whether this might result in better long-term graft survival has still to be confirmed. However, induction therapy has beneficial effects in high-risk recipients and allows steroid avoidance or calcineurin inhibitor minimization. Because they are very well tolerated, anti-IL-2 receptor antibodies are increasingly preferred to rabbit-antithymocyte globulin, but the former have not yet been proven to be more effective or to have less late toxicity than polyclonal agents. Benefits in early outcome and no increase in adverse events lead to recommend the use of IL-2 receptor antagonists as induction therapy after pediatric organ transplantation. [ABSTRACT FROM AUTHOR]

To characterize the clinical features of bone metastases in patients with renal cell carcinoma (RCC) treated with interleukin-2 therapy. Bone lesions contribute to significant morbidity and mortality, and although present in up to half of patients with RCC, their behaviour and response to therapy have not been well characterized. We evaluated skeletal metastases in 19 patients with bone lesions who received either moderate- or high-dose interleukin-2 therapy. Data on bone disease, including location and number of bone lesions, need for bone-specific therapies and use of pain medications, were noted. The response of bone lesions to interleukin-2 was compared with the response of other systemic metastatic sites. Skeletal metastases resulted in significant morbidity by causing pain (75%) and other complications requiring surgical and/or radiotherapeutic intervention (94%) before beginning interleukin-2 therapy. In most patients the response of bone lesions to interleukin-2 was similar to that in their other systemic sites. Treatment with interleukin-2 had no significant effect on the requirement for pain medication for bone pain. However, it may have prevented skeletal complications requiring surgery or radiotherapy. None of the patients had hypercalcaemia; there was no significant association between bone metastases and elevated alkaline phosphatase levels. Skeletal metastases are a significant contributor to morbidity among patients with RCC. Bone lesions respond similarly to interleukin-2 therapy as other systemic sites. Bisphosphonates appear promising for these predominantly osteolytic lesions. [ABSTRACT FROM AUTHOR]

Several recent developments have hallmarked progress in tumour immunology and immunotherapy. The use of interleukin-2 (IL-2) in cancer patients demonstrated that an immunological manipulation was capable of mediating the regression of established growing cancers in humans. The identification of the genes encoding cancer antigens and the development of means for effectively immunizing patients against these antigens has opened important new avenues of exploration for the development of effective active and cell-transfer immunotherapies for patients with cancer. [ABSTRACT FROM AUTHOR]

Abstract: Several studies have shown a significant reduction of acute cellular graft rejection in adult liver and kidney graft recipients treated with monoclonal anti-interleukin-2 (IL-2)-receptor antibodies. The mechanism was inhibition of activated T-helper cells by blocking the α-chain (CD25) of the IL-2 receptor. The pilot study described here evaluated the use of basiliximab in pediatric liver transplantation (LTx), which is the first report on its use in children. Fifty-two liver-transplanted children were analyzed in this study. A matched-pair historical control group (n = 26) received cyclosporin A (CsA) and prednisolone, and patients in the basiliximab group (n = 26) were treated with low-dose CsA and basiliximab (after reperfusion and on day 4 post-transplant). The incidences were compared of acute graft rejections, infectious complications, and the adverse effects of immunosuppressive medication within the first 6 months post-transplant. The incidence of acute rejection was significantly higher in the control group (61.5% vs. 11.5%, p = 0.0004). The frequency of infectious complications was similar (46.1% vs. 53.8%). Patients in the basiliximab group showed less arterial hypertension; however, the differences were not statistically significant (30.7% vs. 7.7%, p = 0.07). Nephrotoxicity, hepatotoxicity or neurotoxicity were only seen in the control group (7.7%; 3.8%; 3.8%, respectively). Hence, the use of basiliximab in combination with CsA and steroids in pediatric liver transplant recipients is safe and reduces the incidence of acute graft rejection. Further studies are needed to confirm our preliminary results and to analyze long-term effects on post-transplant lymphoproliferative disease, chronic rejection, and patient survival. [ABSTRACT FROM AUTHOR]

AbstractAim and backgroundRecent data in the literature indicate that antigen-presenting cells (APC) are inactive in tumour tissue because of local immunosuppression. Tumour-infiltrating lymphocyte (TIL) signal activation transducing mechanisms are also seriously impaired. Administration of granulocyte macrophage-colony stimulating factor (GM-CSF) may lead to APC recovery and interleukin (IL)-2 may restore local TIL activation. Moreover, IL-2 increases the systemic lymphocyte population, an event that seems to correlate with a better prognosis. Study designThe present phase I–II study was carried out to examine whether intralesional injection of GM-CSF followed by subcutaneous IL-2 would induce a clinical response in advanced, pretreated elderly melanoma patients. MethodsSixteen patients over 60 years of age received intralesional GM-CSF (150 ng per lesion on day 1), generally divided between the two largest cutaneous lesions, followed by perilesional subcutaneous IL-2 (3 000 000 IU) for 5 days (days 3–7 inclusive) every 3 weeks. ResultsFour clinical responses [two partial (PR) and two minimal (MR)] (25%), which also involved lesions that had not been directly treated, and nine cases of stable disease were observed. The response duration for PR and MR was 9, 4, 4 and 2.5+ months, respectively. Stable disease (56%) recorded in the nine patients was short-term (3–6 months). Three patients rapidly progressed after two, two and one therapy cycles, respectively. The patient who reached the best PR had a fairly high absolute lymphocyte count (1600–2400/mm3). The second one, who reached complete remission after subsequent locoregional chemotherapy and hyperthermia, however, had a low absolute lymphocyte count that had doubled by the end of treatment. Blood lymphocyte values in the other patients were too varied to allow any correlation with clinical response. Therapy was well tolerated and only mild fever was observed, with the exception of one patient who had grade 3 fever, with muscle pain and arthralgia. ConclusionsConsidering the very low toxicity observed, this treatment might be indicated in elderly patients for whom systemic therapy is no longer a viable option. Improved scheduling and timing could result from further studies. [ABSTRACT FROM AUTHOR]

Competitive inhibition of interleukin 2-dependent lymphocytes by daclizumab demonstrates some beneficial effects in the treatment of graft-versus-host disease (GVHD). Sixteen patients with steroid refractory GVHD received daclizumab (1 mg/kg BW) on d 1, 2 (-5), 7, 14 and 21. Twelve patients suffered from grade III–IV acute GVHD and four patients from extensive chronic GVHD. Responses were observed in nine patients (six acute, three chronic GVHD). Fourteen out of 16 patients acquired infections during daclizumab treatment and three deaths were infection related. Daclizumab demonstrates limited activity and is associated with an increased incidence of infectious complications. [ABSTRACT FROM AUTHOR]

AbstractAn 88-year-old woman presented to us with angiosarcoma of the scalp that had developed over a 6-month period following previous trauma. Despite explicit information concerning the extremely malignant potential of the tumour the patient refused any surgical intervention. However, she agreed to receive local, intralesional interferon α-2b and interleukin-2 therapy. After partial remission of the tumour, the intralesional cytokine injections were combined with surface radiotherapy. This combination therapy led to a 2-year remission of both the tumour and sonographically suspicious cervical lymph nodes. Apart from the typical, moderate side-effects of interferon α-2b and interleukin-2 the therapy was well tolerated. In conclusion, in our limited experience intralesional cytokine therapy – alone as well as in combination with surface irradiation – seems to be an alternative therapeutic option for patients who is not a candidate for surgery. [ABSTRACT FROM AUTHOR]

Abstract Background: Varicella in an immunocompromised host is often serious or life threatening. A live attenuated varicella vaccine was developed in Japan. It has been reported that the varicella vaccine is safe and highly protective against severe varicella in children with leukemia and other malignancies. It is important to investigate the persistence of varicella-zoster virus (VZV)-specific cell-mediated immunity in patients with malignancies who have been immunized with varicella vaccine. Methods: Sixteen patients with malignancies and 11 controls had been immunized with attenuated live varicella vaccine. The duration from vaccination to the study ranged from 2 to 16 years (mean 10 years). Nineteen patients and 20 controls had experienced natural varicella infection. Peripheral blood mononuclear cells (PBMC) from patients and controls were cultured with VZV antigen for 6 days and the percentage of cluster of differentiation antigen (CD)25 among CD4 lymphocytes was calculated by flow cytometry. Controls: The percentage of CD25-positive cells among CD4 lymphocytes significantly increased in response to the VZV antigen in vaccinated patients and patients with past natural varicella infection as observed in the controls. Conclusions: These data show that VZV-specific cell-mediated immunity is induced and persists in patients with malignancies after immunization with live varicella vaccine. [ABSTRACT FROM AUTHOR]

Treatment with intravenous recombinant human interleukin-2 (rh IL-2) is frequently accompanied by the capillary leak syndrome and disturbances of the coagulation system. Although the exact mechanisms are still not fully understood, the involvement of the endothelium is proven. This investigation aimed to elucidate more precisely the role of the endothelium in the generation of IL-2-based side-effects. In nine tumour patients receiving intravenous rh IL-2, parameters characterizing endothelial cell activation as well as activation of the coagulation system were evaluated. A significant increase of the circulating endothelial leucocyte adhesion molecule-1 (cELAM-1) and the vasoconstrictor peptide endothelin-1 (ET-1) was observed (P < 0.05), indicating activation of endothelial cells. The simultaneous increase of tissue-plasminogen activator and plasminogen activator inhibitor type-1 during therapy (P < 0.05) corroborated this observation. A decrease in platelet count parallelled by an increase of fibrin degradation products, the prolongation of partial thromboplastin time, and the decrease of fibrinogen (P < 0.05) suggested the development of disseminated intravascular coagulation (DIC), induced by activated endothelium and intensified by transient hepatic failure. We concluded that activation of the endothelium mediated by IL-2 was accompanied by a loss of endothelial integrity and capillary leak. The activated endothelium can trigger DIC via activation of the coagulation cascade. The increased ET-1 might act as an endogenous counter-regulator of the disadvantageous haemodynamic side-effects induced by IL-2. [ABSTRACT FROM AUTHOR]

Witzke O, Winterhagen T, Reinhardt W, Heemann U, Grosse-Wilde H, Kreuzfelder E, Roggendorf M, Philipp T (Departments of Medicine, Immunology and Virology, University of Essen, Germany). Comparison between subcutaneous and intravenous interleukin-2 treatment in HIV disease. J Intern Med 1998; 244: 235–40. ObjectivesTherapy of HIV-infection using intravenous interleukin-2 (IL-2) is known to be effective in terms of increasing CD4-counts but is associated with significant side-effects and hospitalization. However, the combination with protease-inhibitor therapy has not been tested yet. The aim of the present study was to investigate the safety and efficacy of intravenous vs. subcutaneous IL-2 regimes using 9 Mio I.U. of IL-2, in combination with protease-inhibitor therapy. DesignAll patients were treated with a combination of two reverse transcriptase inhibitors and a protease-inhibitor prior to IL-2 administration for at least 6 weeks. Ten patients were assigned to the intravenous IL-2 group (group A), 10 to the subcutaneous group (group B). ResultsIn both treatment groups, CD4 count significantly increased shortly after the end of therapy (group A: 223% over baseline [day 7]; group B: 264% over baseline [day 7]). During the follow-up CD4 counts slowly decreased thereafter but remained above baseline 3 months following IL-2 treatment. The CD8 lymphocytes showed a similar but less pronounced pattern with a maximum at day 7 (group A: 116% over baseline, group B: 158% over baseline) and reached baseline earlier in the follow-up-period. Altogether the CD4/CD8-ratio was elevated through long periods on follow-up. Throughout follow-up, there were no apparent changes in viral load during IL-2 therapy in either groups. IL-2 therapy was administered for a mean time of 4.2 ± 0.1 days in the intra-venous group and of 4.8 ± 0.1 days in the subcutaneous group until therapy was terminated at day 5 or due to side-effects. Only 1/10 patients completed the 5-day course of intravenous therapy in contrast to 6/10 in the subcutaneous group. ConclusionsSubcutaneous interleukin-2 using 9 Mio IU day-1 in combination with protease-inhibitors showed equal efficacy as intravenous therapy and was associated with less side-effects. [ABSTRACT FROM AUTHOR]

The article presents a study regarding interferon-γ and interleukin-2 production in the mucosa of children with Crohn's disease or ulcerative colitis. Lymphocyte-secreting T cells and the expression of lymphokine messenger RNA were quantified and investigated to perform this experiment, which indicates an ongoing cell-mediated immune response in the mucosa of Crohn's disease.

African sleeping sickness is accompanied by a severe immunosuppression. As part of our efforts to examine the mechanisms by which this suppressive state is induced, we studied alterations in human T-lymphocyte function caused by Trypanosoma brucei rhodesiense. To this end, we used an in vitro system in which phytohaemagglutinin (PHA)-stimulated human peripheral blood mononuclear cells (PBMC) were cultured in a medium containing soluble, non-dialysable parasite products. We were able to demonstrate significant suppression of both lympho-proliferation and interleukin-2 receptor (IL-2R) expression. These effects were found to be dose-dependent and reversible after 48 hr of culture. The suppressive effects of living trypanosomes and the soluble parasite products on lympho- proliferation and interleukin-2 receptor expression were similar in that both precluded the entry of PHA-activated PBMC into the cell cycle. Eighty to ninety-eight per cent of the activated cells remained arrested in the G0/Gla (early G1) phase even 48 hr after stimulation, i.e. when last tested. Parasite-induced expression could not be overcome by the addition of recombinant human 11-2. These results suggest that immunosuppression associated with African trypanosomiasis may result from parasite-induced alteration of very early events during lymphocyte activation, leading to a virtually complete block in cell cycle progression and inhibition of IL-2R expression. [ABSTRACT FROM AUTHOR]

Breaking the balance between effector T cells, including Th17 (T helper cell 17) cells, and regulatory T cells (Tregs) is a key link in the pathogenesis of rheumatic immune diseases, which lead to a new concept of regulating immune balance in the treatment of rheumatic immune diseases. Interleukin (IL)‐2 can effectively regulate the differentiation, development and functional activity of regulatory T cells, thus restoring the immune balance between regulatory T cells and effector T cells. Therefore, low‐dose IL‐2 has been used in the treatment of rheumatic immune diseases, and it has become a promising new choice to achieve therapeutic purpose by regulating the immune balance of T cell. Here, we discuss the role of T cells immune imbalance in the pathogenesis of rheumatic immune diseases and the mechanism of IL‐2 in the treatment of rheumatic immune diseases by regulating T cells immune balance and summarize the relevant clinical trials. [ABSTRACT FROM AUTHOR]

The article discusses Sezary syndrome as a leukemic form of cutaneous T-cell lymphoma. It talks about erythroderma and polyarthritis. It talks about the results of the computed tomography undertaken revealing inguinal lymphadenopathy. It discusses the skin biopsy undertaken. It also discusses the decrease in the level of interleukin-2 receptor.

For over 2 decades, a series of clinical trials has tested the efficacy of interleukin‐2 as postremission therapy for patients with acute myeloid leukemia. In this issue, Kolitz et al describe a large clinical trial testing this hypothesis that ultimately failed to answer the question because of patients failing to complete the prescribed therapy. [ABSTRACT FROM AUTHOR]

The article discusses various research studies published in a number of journals on various medical topics. Topics discussed include response of high-dose interleukin-2 (HD IL-2) therapy in patients with metastatic melanoma, challenges associated with transplantation of a tissue-engineered airway to replace trachea, and a squalenoylated and nonpegylated doxorubicin nanomedicine.

The authors reflect on a study by de Lastours and colleagues regarding the impact of low-dose interleukin-2 (IL-2) treatment on peripheral blood Epstein-Barr virus DNA (EBV) levels among the participants in the ANRS 119 trial. The authors state that the study has extended existing knowledge on EBV replication, the risk of lymphoma with IL-2 treatment, and B cell proliferation. The authors add that the cases of HL in the IL-2 arm most represent a chance event.

The article informs that a statement has been released as of January 2014 by the Society for Immunotherapy of Cancer (SITC) on treating patients with melanoma by using tumor immunotherapy including interferon-a2, pegylated interferon and interleukin-2.