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T cell growth factor [keywords]
- In vivo and in vitro evidence that (99m)Tc-HYNIC-interleukin-2 is able to detect T lymphocytes in vulnerable atherosclerotic plaques of the carotid artery. [JOURNAL ARTICLE]
- Eur J Nucl Med Mol Imaging 2014 Apr 16.
Recent advances in basic science have established that inflammation plays a pivotal role in the pathogenesis of atherosclerosis. Inflammatory cells are thought to be responsible for the transformation of a stable plaque into a vulnerable one. Lymphocytes constitute at least 20 % of infiltrating cells in these vulnerable plaques. Therefore, the interleukin-2 (IL-2) receptor, being overexpressed on activated T lymphocytes, may represent an attractive biomarker for plaque vulnerability. The aim of this study was to evaluate the specificity of radiolabelled IL-2 [(99m)Tc-hydrazinonicotinamide (HYNIC)-IL-2] for imaging the lymphocytic infiltration in carotid plaques in vivo by planar and single photon emission computed tomography (SPECT)/CT imaging and ex vivo by microSPECT and autoradiography.For the in vivo study, ten symptomatic patients with advanced plaques at ultrasound who were scheduled for carotid endarterectomy underwent (99m)Tc-HYNIC-IL-2 scintigraphy. The images were analysed visually on planar and SPECT images and semi-quantitatively on SPECT images by calculating target to background (T/B) ratios. After endarterectomy, immunomorphological evaluation and immunophenotyping were performed on plaque slices. For the ex vivo studies, four additional patients were included and, after in vitro incubation of removed plaques with (99m)Tc-HYNIC-IL-2, autoradiography was performed and microSPECT images were acquired.Visual analysis defined clear (99m)Tc-HYNIC-IL-2 uptake in seven of the ten symptomatic plaques. SPECT/CT allowed visualization in eight of ten. A significant correlation was found between the number of CD25+ lymphocytes and the total number of CD25+ cells in the plaque and the T/B ratio with adjacent carotid artery as background (Pearson's r = 0.89, p = 0.003 and r = 0.87, p = 0.005, respectively). MicroSPECT imaging showed clear (99m)Tc-HYNIC-IL-2 uptake within the plaque wall and not in the lipidic core. With autoradiography, only CD3+ lymphocytes were found to be labelled.These in vivo and ex vivo studies confirm the specificity of (99m)Tc-HYNIC-IL-2 for imaging activated T lymphocytes in carotid plaques. (99m)Tc-HYNIC-IL-2 is a true marker for the inflamed plaque and therefore of plaque instability.
- Pulmonary Toxicity in Mice Following Exposure to Cerium Chloride. [JOURNAL ARTICLE]
- Biol Trace Elem Res 2014 Apr 16.
The widespread application of lanthanoids (Lns) in manufacturing industries has raised occupational and environmental health concerns about the possible increased health risks to humans exposed to Lns in their working and living environments. Numerous studies have shown that exposures to Ln cause pulmonary injury in animals, but very little is known about the molecular mechanisms of the pulmonary inflammation caused by cerium chloride (CeCl3) exposure. In this study, we evaluated the oxidative stress and molecular mechanism underlying with the pulmonary inflammation associated with chronic lung toxicity in mice treated with nasally instilled CeCl3 for 90 consecutive days. Our findings suggest that significant cerium accumulated in the lung, leading the obvious increase of the lung indices, significant increases in inflammatory cells and levels of lactate dehydrogenase, alkaline phosphate, and total protein, overproduction of reactive oxygen species and peroxidation of lipids, reduced antioxidant capacity, and pulmonary inflammation. CeCl3 exposure also activated nuclear factor κB, increased the expression of tumor necrosis factor α, cyclooxygenase-2, heme oxygenase 1, interleukin 2, interleukin 4, interleukin 6, interleukin 8, interleukin 10, interleukin 18, interleukin 1β, and CYP1A1. However, CeCl3 reduced the expression of nuclear factor κB (NF-κB)-inhibiting factor and heat shock protein 70. These findings suggest that the pulmonary inflammation caused by CeCl3 in mice is closely associated with oxidative stress and inflammatory cytokine expression.
- Successes and limitations of targeted therapies in renal cell carcinoma. [Journal Article]
- Prog Tumor Res 2014.:98-112.
Until recently, the standard treatment for metastatic renal cell carcinoma (RCC) was nonspecific immunotherapy based on interleukin-2 or interferon-α. This was associated with a modest survival benefit and with significant clinical toxicities. The understanding of numerous molecular pathways in RCC, including HIF, VEGF, mTOR, and the consecutive use of targeted therapies since the beginning of 2005 have significantly improved outcomes for patients with metastatic RCC with an overall survival greater than 2 years. At present, at least 7 targeted agents are approved for first and consecutive lines of treatment of clear cell metastatic RCC. Long-term benefit and extended survival may be achieved through the optimal use of targeted therapies: optimal dosing, adverse event management and treatment duration and compliance. Advances in the finding of prognostic factors highlight the potential for personalizing treatment for patients with metastatic RCC. Data regarding the best sequencing of targeted therapies, predictive biomarkers, best timing of surgery, patient risk profiles, understanding of resistance mechanisms and safety of targeted therapies are growing and will provide a further step ahead in the management of advanced RCC. In parallel, a new class of therapeutics is emerging in RCC: immunotherapy; in particular check-point blockade antibodies are showing very promising results. © 2014 S. Karger AG, Basel.
- Plasma Angiopoietin-2 Concentrations are Related to Impaired Lung Function, and Organ Failure in a Clinical Cohort Receiving High Dose Interleukin-2 Therapy. [JOURNAL ARTICLE]
- Shock 2014 Apr 10.
The pathophysiology and therapeutic options in sepsis-induced lung injury remain elusive. High Dose Interleukin-2 therapy (HDIL-2) is an important protocol for advanced malignancies but is limited by systemic inflammation and pulmonary edema that is indistinguishable from sepsis. In pre-clinical models, IL-2 stimulates angiopoietin-2 secretion, which increases endothelial permeability and causes pulmonary edema. However, these relationships have not been fully elucidated in humans. Further, the relevance of plasma angiopoietin-2 to organ function is not clear.We hypothesized that plasma angiopoietin-2 concentrations increase during HDIL-2, and are relevant to clinical pathophysiology.We enrolled 13 subjects with metastatic melanoma or renal cell carcinoma admitted to receive HDIL-2, and collected blood and spirometry data daily. The plasma concentrations of angiopoietin-2 and interleukin-6 were measured with ELISA.At baseline, the mean angiopoietin-2 concentration was 2.5 ng/mL (SD 1.0 ng/mL). Angiopoietin-2 concentrations increased during treatment: the mean concentration on the penultimate day was 16.0 ng/mL (SD 4.5 ng/mL) and increased further to 18.6 ng/mL (SD 4.9 ng/mL; p < 0.05 vs penultimate) during the last day of therapy. The Forced Expiratory Volume in one second (FEV-1) decreased during treatment. Interestingly, plasma angiopoietin-2 concentrations correlated negatively with FEV-1 (Spearman r=-0.78, p < 0.0001). Plasma angiopoietin-2 concentrations also correlated with plasma interleukin-6 concentrations (r = 0.61, p < 0.0001) and Sequential Organ Failure Assessment (SOFA) scores (r = 0.68, p < 0.0001).Plasma angiopoietin-2 concentrations increase during HDIL-2 administration, and correlate with pulmonary dysfunction. HDIL-2 may serve as a clinical model of sepsis and acute lung injury. Further investigation is warranted.
- Effect of additional vitamin E and zinc supplementation on immunological changes in peripartum Sahiwal cows. [JOURNAL ARTICLE]
- J Anim Physiol Anim Nutr (Berl) 2014 Apr 10.
This study was conducted to exploit ameliorative effect of additional vitamin E and/or zinc supplementation on immune response of peripartum Sahiwal cows. Thirty-two pregnant dry Sahiwal cows were blocked into four treatment groups (n = 8), namely control, zinc (Zn), vitamin E (Vit E) and zinc + vitamin E (Zn + Vit E). Feeding regimen was same in all the groups except that the Sahiwal cows in the zinc-, vitamin E- and zinc + vitamin E-fed groups were additionally supplemented with 60 mg Zn/kg DM, 1000 IU vitamin E and 60 mg/kg + 1000 IU Zn + vitamin E, respectively, from day 60 pre-partum to day 90 post-partum. Blood samples were collected on days -60, -45, -30, -15, -7, -3, 0, 3, 7, 15, 30, 45, 60, 90 and 120 with respect to day of parturition and analysed for total immunoglobulin (TIG), immunoglobulin G (IgG), interleukin-2 (IL-2), vitamin E (Vit E) and zinc (Zn) status. Before calving, cows showed a decrease in plasma TIG, IgG, IL-2, Vit E and Zn levels. However, increased levels of plasma TIG, IgG, IL-2, Vit E and Zn were observed after calving. After calving, Sahiwal cows supplemented with Zn + Vit E had higher plasma TIG, IgG and IL-2 in comparison with cows of control and Zn + Vit E-fed groups. In the present study, plasma vitamin E level was higher in Vit E-fed and Zn + Vit E-fed cows; however, zinc level was higher in Zn- and Zn + Vit E-supplemented cows. In conclusion, a reduced immune response during peripartum period in Sahiwal cows was ameliorated by dietary vitamin E and zinc supplementation.
- CD4(+) and CD8(+) regulatory T cells in chronic rhinosinusitis mucosa. [Journal Article]
- Am J Rhinol Allergy 2014 Mar; 28(2):83-9.
Chronic rhinosinusitis (CRS) mucosal inflammation is characterized by an accumulation of effector-memory T cells, but their immune regulatory potential has not been adequately examined. Coexpression of transcription factor, forkhead box P3 (Foxp3), and interleukin-2 receptor, CD25, in CD4(+) and CD8(+) T cells is linked with regulatory function in humans. The aim of this study was to investigate the regulatory T cell (Treg) phenotype of CD4(+) (CD4Treg) and CD8(+) (CD8Treg) T cells in peripheral blood (PB) and sinus mucosa of CRS patients.Prospective study was performed involving 32 CRS with nasal polyp (CRSwNP), 14 CRS without nasal polyp (CRSsNP), and 8 control patients. Sinus and PB T lymphocytes were stained with CD3, CD4, CD8, CD25, and Foxp3 and analyzed using flow cytometry. Relevant clinical characteristics, sinus bacterial culture results, and eosinophilic mucus were examined.Sinus mucosa had a higher percentage of CD4Treg (CD3(+)CD4(+)CD25(+)Foxp3(+)) population compared with PB in all patients. The percentage of PB CD4Treg and CD8Treg (CD3(+)CD8(+)CD25(+)Foxp3(+)) was not significantly different between the study groups. CRS mucosal tissue had a higher percentage of CD4Treg and activated T-helper cells than controls. There was no significant difference in PB and mucosal CD4Treg populations in CRS patients based on the presence of allergy, sinus culture results, or eosinophilic mucus. In controls, increased mucosal CD4Treg correlated with coexisting allergy. Although overall CD4Treg numbers were higher, the regulatory potential of activated CD4(+) T cells (CD4Treg/activated T-helper cell ratio) was significantly lower in CRS mucosa compared with controls. The CD8Treg subset was also significantly reduced in CRSwNP mucosa compared with controls.A higher percentage of CD4Treg and activated T-helper cells in CRS mucosa suggests increased inflammation in CRS, independent of the presence of allergy, microbial culture results, or eosinophilic mucus. However, the decreased ratio of CD4Treg versus activated T-helper cells in CRS and reduced CD8Treg population in CRSwNPs indicates an inflammatory bias and the inability to control mucosal disease.
- A Phase I/Ib Study of Folate Immune (EC90 Vaccine Administered With GPI-0100 Adjuvant Followed by EC17) With Interferon-α and Interleukin-2 in Patients With Renal Cell Carcinoma. [Journal Article]
- J Immunother 2014 May; 37(4):237-44.
Folate immune (EC90 vaccine with GPI-0100 adjuvant followed by EC17) is a novel folate-targeted hapten immunotherapy designed to exploit the overexpression of folate receptors on renal cell carcinoma (RCC) cells. In this open-label, phase I/II clinical study, we report the safety, pharmacokinetics, and antitumor activity of folate immune with concurrent interleukin-2 (IL-2) and interferon-α (IFN-α) in patients with recurrent or metastatic RCC. Twenty-four patients were enrolled. Following 2 phase I cohorts of 6 patients each, we extended the study to 12 additional patients: 18 received weekly vaccination of 1.2 mg of EC90 with 3.0 mg of GPI-0100 adjuvant for 4 weeks. Beginning on cycle 1, day 8, 0.3 mg/kg of EC17 was administered once daily, 5 days per week (Monday-Friday) for 4 consecutive weeks. Beginning on cycle 1, day 15, IL-2 and IFN-α were administered at doses of 12 and 3.0 MIU, respectively, after the EC17 dose, 3 times per week (Monday, Wednesday, and Friday) for 3 weeks. In cycle 2, IL-2 and IFN-α, doses of 7.0 and 3.0 MIU, respectively, were administered 3 days per week (Monday, Wednesday, and Friday) for 4 consecutive weeks. No dose-limiting toxicities were observed. Most adverse events reported were grade 1 or 2, with only twelve grade ≥3 toxicities reported. Sixteen patients had progressive disease, 7 patients were observed to have stable disease, and 1 patient achieved a partial response lasting 71 days. Overall, folate immune plus low-dose IFN-α and IL-2 was safe and well tolerated with some observed clinical activity.
- Chronic schizophrenia is associated with over-expression of the interleukin-2 receptor gamma gene. [JOURNAL ARTICLE]
- Psychiatry Res 2014 Mar 25.
Altered immune response, including low-grade inflammatory processes, is involved in the pathogenesis of schizophrenia, a chronic psychiatric disorder with complex etiology. Distinct gene variants of a number of pro-inflammatory and chemotactic cytokines together with their receptors associate with this disorder. Interleukin-2 receptor gamma (IL-2RG) represents an important signaling component of many interleukin receptors and so far, no data on the functional state of this receptor in schizophrenia have been reported. The aim of this study was to investigate mRNA expression of the IL2RG gene (IL2RG) in schizophrenia patients in comparison with healthy subjects (controls). Total RNA was isolated from peripheral blood of 66 schizophrenia patients and 99 healthy subjects of Armenian population. The mRNA expression was determined by quantitative real-time polymerase chain reaction (RT-PCR) using PSMB2 as housekeeping gene. IL2RG mRNA expression was upregulated in peripheral blood of patients in comparison with controls (patients vs. controls, median [interquartile range]: 2.080 [3.428-1.046] vs. 0.324 [0.856-0.000], p<0.0001). In conclusion, our findings suggest that over-expression of the IL2RG gene may be implicated in altered immune response in schizophrenia and contribute to the pathomechanisms of this disorder.
- Homeostasis and function of regulatory T cells (Tregs) in vivo: lessons from TCR-transgenic Tregs. [Journal Article]
- Immunol Rev 2014 May; 259(1):23-39.
The identification of CD25 and subsequently Forkhead box protein 3 (Foxp3) as markers for regulatory T cells (Tregs) has revolutionized our ability to explore this population experimentally. In a similar vein, our understanding of antigen-specific Treg responses in vivo owes much to the fortuitous generation of T-cell receptor (TCR)-transgenic Tregs. This has permitted tracking of Tregs with a defined specificity in vivo, facilitating analysis of how encounter with cognate antigen shapes Treg homeostasis and function. Here, we review the key lessons learned from a decade of analysis of TCR-transgenic Tregs and set this in the broader context of general progress in the field. Use of TCR-transgenic Tregs has led to an appreciation that Tregs are a highly dynamic proliferative population in vivo, rather than an anergic population as they were initially portrayed. It is now clear that Treg homeostasis is positively regulated by encounter with self-antigen expressed on peripheral tissues, which is likely to be relevant to the phenomenon of peripheral repertoire reshaping that has been described for Tregs and the observation that the Treg TCR specificities vary by anatomical location. Substantial evidence has also accumulated to support the role of CD28 costimulation and interleukin-2 in Treg homeostasis. The availability of TCR-transgenic Tregs has enabled analysis of Treg populations that are sufficient or deficient in particular genes, without the comparison being confounded by repertoire alterations. This approach has yielded insights into genes required for Treg function in vivo, with particular progress being made on the role of ctla-4 in this context. As the prospect of manipulating Treg populations in the clinic becomes reality, a full appreciation of the rules governing their homeostasis will prove increasingly important.
- Effector cells derived from naive T cells used in tumor immunotherapy of mice bearing B16 melanoma. [Journal Article]
- Chin Med J (Engl) 2014 Apr; 127(7):1328-33.
Adoptive cell transfer (ACT) immunotherapy has been used clinically for years to treat malignancies. Improving the killing efficiency of effector cells, such as tumor-specific cytotoxic T lymphocytes (CTLs), is an important component for enhancing the clinical response of cancer immunotherapy. Hence, we explored a novel method for preparing cancer-specific CTLs using naive T lymphocytes.C57BL/6 mice bearing B16 melanoma tumors were pretreated with cyclophosphamide (CTX) by peritoneal injection. The immunosuppressive influence of CTX on tumor regression and the tumor microenvironment was assessed. Naive T cells and T cell pools were isolated via negative selection using immunomagnetic beads. The proliferative potential and cytokine production of different T cell subpopulations were evaluated in vitro. Tumor-specific CTLs derived from naive T cells (naive CD4+ T cells: naive CD8+ T cells = 2:1) and pooled T cells were generated in vitro, respectively. B16 melanoma-bearing C57BL/6 mice were pretreated with CTX, followed by ACT immunotherapy using dendritic cell-induced CTLs. The homing abilities of the effector cells and interleukin-2 (IL-2), interferon-γ, granzyme B, and perforin mRNA levels in tumor tissues were evaluated, and the change in tumor volume was measured.Mice receiving CTX peritoneal pretreatment injections did not display tumor regression compared with control mice. However, a significant downregulation of splenic Tregs and tumor growth factor-β1 (TGF-β1) and interleukin-10 (IL-10) serum levels was observed (P < 0.05). Naive T cells showed a stronger proliferative capacity and elevated cytokine production than did pooled T cells (P < 0.05). In addition, effector cells generated from naive T cells displayed more potent antitumor activity in vivo than those derived from pooled T cells (P < 0.05).Effector cells derived from the naive T cells possess a stronger proliferative potential, homing capacity, and enhanced cytokine production, which leads to a superior antitumor response.