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T cell growth factor [keywords]
- Highly Efficient Expression of Interleukin-2 under the Control of Rabbit β-Globin Intron II Gene Enhances Protective Immune Responses of Porcine Reproductive and Respiratory Syndrome (PRRS) DNA Vaccine in Pigs. [Journal Article]
- PLoS One 2014; 9(3):e90326.
Highly pathogenic porcine reproductive and respiratory syndrome virus (HP-PRRSV) had caused catastrophic losses in swine industry in China. The current inactivated vaccine provided only limited protection, and the attenuated live vaccine could protect piglets against the HP-PRRSV but there was a possibility that the attenuated virus returned to high virulence. In this study, the eukaryotic expression vector pVAX1© was modified under the control of rabbit β-globin intron II gene and the modified vector pMVAX1© was constructed. Porcine interleukin-2 (IL-2) and GP3-GP5 fusion protein of HP-PRRSV strain SD-JN were highly expressed by pMVAX1©. Mice inoculated with pMVAX1©-GP35 developed significantly higher PRRSV-specific antibody responses and T cell proliferation than those vaccinated with pVAX1©-GP35. pMVAX1©-GP35 was selected as PRRS DNA vaccine candidate and co-administrated with pVAX1©-IL-2 or pMVAX1©-IL-2 in pigs. pMVAX1©-IL-2+pMVAX1©-GP35 could provide enhanced PRRSV-specific antibody responses, T cell proliferation, Th1-type and Th2-type cytokine responses and CTL responses than pMVAX1©-GP35 and pVAX1©-IL-2+pMVAX1©-GP35. Following homologous challenge with HP-PRRSV strain SD-JN, similar with attenuated PRRS vaccine group, pigs inoculated with pMVAX1©-IL-2+pMVAX1©-GP35 showed no clinical signs, almost no lung lesions and no viremia, as compared to those in pMVAX1©-GP35 and pVAX1©-IL-2+pMVAX1©-GP35 groups. It indicated that pMVAX1©-IL-2 effectively increases humoral and cell mediated immune responses of pMVAX1©-GP35. Co-administration of pMVAX1©-IL-2 and pMVAX1©-GP35 might be attractive candidate vaccines for preventing HP-PRRSV infections.
- Iraq Dust Is Respirable, Sharp, and Metal-Laden and Induces Lung Inflammation With Fibrosis in Mice via IL-2 Upregulation and Depletion of Regulatory T Cells. [Journal Article]
- J Occup Environ Med 2014 Mar; 56(3):243-51.
Determine whether surface dust grab samples taken from a large military base in Iraq are toxic and respirable.X-ray diffraction for mineral content, x-ray fluorescence for elemental content, in vivo mouse dust challenges for assessment of histological changes, bronchoalveolar lavage for cytokines, polarizing light microscopy for crystals in lung tissue, and Fluorescence Activated Cell Sorting for cell surface and intracellular markers were utilized.Camp Victory, Iraq dust taken during wartime contains respirable particles 2.5 microns in size, constituting particulate matter air pollution. Dust particles are angular and have sharp edges. Trace metals (including titanium) calcium and silicon are present. Mice with airway instillation of dust have polarizable crystals in lung and septate inflammation. Regulatory T cells (CD4CD25FOXP3) are decreased in thymus and spleen. Interleukin-2 (IL-2) is upregulated in bronchoalveolar lavage.Respirable Iraq dust leads to lung inflammation in mice similar to that seen in patients with polarizable crystals, which seem to be titanium.
- Toxoplasma gondii: Protective immunity induced by rhoptry protein 9 (TgROP9) against acute toxoplasmosis. [JOURNAL ARTICLE]
- Exp Parasitol 2014 Mar 3.
Toxoplasma gondii rhoptry protein 9 (ROP9) is involved in the early stages of host invasion, and contains B cell epitopes. The aim of this study was to evaluate the immune protective efficacy of a DNA vaccine encoding TgROP9 gene against acute T. gondii infection in mice. A DNA vaccine (pVAX-ROP9) encoding TgROP9 inserted into eukaryotic expression vector pVAX I was constructed, and the efficacy of intramuscular vaccination of Kunming mice with pVAX-ROP9 was analyzed. Mice immunized with pVAX-ROP9 induced a high level of specific anti-T. gondii antibodies, as well as a mixed IgG1/IgG2a response with predominance of IgG2a production. Also, injection of pVAX-ROP9 induced a specific lymphocyte proliferative responses and Th1-type cellular immune response with production of IFN-γ and interleukin-2. The percentages of CD4+ and CD8+ T cells were significantly increased in mice immunized with pVAX-ROP9, compared to empty vector, PBS or blank controls. Immunization with pVAX-ROP9 significantly (P<0.05) prolonged survival time (12.9±2.9days) after challenge infection with the virulent T. gondii RH strain (Type I), compared with the control groups which died within 6days. DNA vaccination with pVAX-ROP9 triggered strong humoral and cellular responses, and induced effective protection in mice against acute T. gondii infection, indicating that TgROP9 is a promising vaccine candidate against acute toxoplasmosis.
- Novel acid-labile subunit ( IGFALS ) mutation p.T145K (c.434C>A) in a patient with ALS deficiency, normal stature and immunological dysfunction. [Journal Article]
- Horm Res Paediatr 2013; 80(6):424-30.
We report a novel missense mutation p.T145K in the insulin-like growth factor (IGF) acid-labile subunit (IGFALS) gene identified in a Turkish patient with normal growth, transient pancytopenic episodes and signs of immunological dysfunction. Because of recurrent cutaneous mycoses and absence of pubertal development until the age of 14.75 years we determined several endocrine parameters in order to rule out autoimmune-polyendocrine syndromes. Despite a normal height between the 25th and 50th percentile we found severely decreased IGF-1 and undetectably low IGFBP-3 levels. Laboratory signs of immunological dysfunction included reduced total lymphocyte count with diminished B and T helper cell fractions, decreased serum concentrations of IgM and IgG subclass 4, and elevated antinuclear antibody and anti-dsDNA titers as well as persistently high interleukin-2-receptor levels. Further endocrine work-up revealed elevated fasting insulin and undetectably low ALS serum levels, leading to the diagnosis of ALS deficiency. Sequencing of the coding region of the IGFALS gene showed a novel homozygous missense mutation (c.434C>A; p.T145K). Since immunological abnormalities have not been reported in more than 20 ALS-deficient patients so far and our patient was born to consanguineous parents, a second autosomal recessive defect is likely to underlie the immunological phenotype, although a causative role of IGFALS p.T145K cannot be entirely ruled out.
- Soluble interleukin-2 receptor level on day 7 as a predictor of graft-versus-host disease after HLA-haploidentical stem cell transplantation using reduced-intensity conditioning. [JOURNAL ARTICLE]
- Int J Hematol 2014 Mar 6.
In the present study, we analyzed the kinetics of serum soluble interleukin-2 receptor (sIL-2R) using data from 77 patients undergoing HLA-haploidentical transplantation using reduced-intensity conditioning (RIC), who were at an advanced stage or at high risk for relapse, to clarify the usefulness of sIL-2R as a biomarker of acute graft-versus-host disease (GVHD). Anti-T-lymphocyte globulin and methylprednisolone were used as GVHD prophylaxis. While the median sIL-2R in 38 patients not developing GVHD was suppressed at levels <740 U/ml, sIL-2R in 25 patients developing severe GVHD peaked on day 11 (1,663 U/ml), and thereafter decreased to <1,000 U/ml after day 30. The occurrence of GVHD was not limited to times of high sIL-2R level, but occurred at any time point on the sIL-2R curve. Most patients developing GVHD, however, experienced a higher sIL-2R level early in their transplant course. The combination of RIC and glucocorticoids sufficiently suppressed sIL-2R levels after HLA-haploidentical transplantation. In a multivariate analysis to identify factors associated with GVHD, day 7 sIL-2R >810 U/ml was the only factor significantly associated with the occurrence of severe GVHD (p = 0.0101).
- Rabies virus glycoprotein and immune response pattern using recombinant protein or recombinant RNA viral vectors. [JOURNAL ARTICLE]
- Vaccine 2014 Mar 2.
The present study shows the humoral and cellular aspects of immune response generated by a recombinant rabies virus glycoprotein (rRVGP) as compared to those generated by viral vector carrying the RNA coding for this protein (RVGP-RNA). The rRVGP was synthesized by stably transfected Drosophila melanogaster Schneider 2 (S2) cells and the RVGP-RNA was carried by a recombinant Semiliki Forest Virus (SFV-RVGP). The data show that protein as well as the RNA vaccine was capable of inducing reasonably acceptable levels of antibodies as compared to the optimized commercial whole virus vaccine. As expected, the RNA vaccine was clearly more effective than the protein vaccines in inducing a cellular immune response, as evaluated by the IgG2a/IgG1 ratio and synthesis of interferon gamma (IFNγ) and interleukin 2 (IL2). Our study supports the importance of vaccine designing taking into consideration the concept of DNA/RNA ability to induce an effective cell immune response.
- Regression of Metastatic Clear Cell Kidney Cancer With Interleukin-2 Treatment Following Nivolumab (Anti-PD-1) Treatment. [Journal Article]
- J Immunother 2014 Apr; 37(3):187-91.
Aldesleukin [interleukin-2 (IL-2)] induces durable complete responses in some kidney cancer and melanoma patients. Nivolumab is an investigational antibody drug targeting programmed death-1 (PD-1) as a treatment, demonstrating activity in multiple cancer types. An expanding complement of immunotherapeutics raises important issues regarding the best way to use them. There are issues beyond identifying an agent that provides the superior front-line response: when does one therapy potentiate another immune therapy? When is the capacity of immune response exhausted and an approach without immune mechanism the better therapy? In this case report, we present a patient with metastatic renal cell carcinoma with no tumor regression evident on a PD-1 blockade (given on an investigational trial), who then achieved near-complete response to bolus high-dose IL-2 therapy, maintaining a persistent response off therapy. This case emphasizes on the need to develop improved predictors of response to immune therapies, especially as they can be applied to optimize sequential immunotherapeutic modalities versus predict when to turn to alternative targeted agents in renal cell carcinoma, and is an example of efficacious IL-2 application as a second-line treatment.
- A phase I study of high-dose interleukin-2 with sorafenib in patients with metastatic renal cell carcinoma and melanoma. [Journal Article]
- J Immunother 2014 Apr; 37(3):180-6.
This study was designed to evaluate the safety and feasibility of high-dose interleukin-2 (HD IL-2) followed by sorafenib in patients with metastatic melanoma (MM) and renal cell carcinoma (RCC). Biomarkers relevant to the antitumor effects of IL-2 that may be altered by sorafenib including the percentages of natural T-regulatory cells (Tregs), myeloid-derived suppressor cells (MDSC), and STAT5 phosphorylation (pSTAT5) in T cells were evaluated. We hypothesized that the proposed treatment schedule is feasible and safe and may lead to enhanced tumor response. A phase I dose escalation trial was conducted in patients with either metastatic RCC or MM. HD IL-2 (600,000 IU/kg IV q8h×8-12 doses) was administered on days 1-5 and 15-19, followed by sorafenib on days 29-82. The sorafenib dose was escalated. The percentage of Tregs, MDSC, and pSTAT5 in T cells were evaluated in peripheral blood by flow cytometry. Twelve of the 18 patients were evaluable for dose-limiting toxicity. No dose-limiting toxicity was observed. The treatment-related toxicity was predictable and did not seem to be additive with this schedule of administration. Partial responses were seen in 3 patients. No significant changes in the percentage of circulating Treg and MDSC were observed, whereas sorafenib did not adversely affect the ability of IL-2 to induce pSTAT5 in T cells. HD IL-2 followed by sorafenib was safe and feasible in patients with MM and RCC and did not adversely affect T-cell signaling through STAT5 in response to IL-2.
- Immunologics and Chemotherapeutics for Renal Cell Carcinoma. [REVIEW]
- Semin Intervent Radiol 2014 Mar; 31(1):91-97.
Treatment of metastatic renal cell carcinoma remains a challenge for clinicians. Traditional chemotherapy is ineffective and immunotherapy with interleukin-2 is only occasionally beneficial. The development of numerous agents targeting vascular endothelial growth factor and mammalian target of rapamycin signaling pathways that have been studied in phase III trials have resulted in significant improvement in survival for patients with clear cell renal cell carcinoma. Currently available U.S. Food and Drug Administration-approved first line targeted agents include sunitinib, pazopanib, temsirolimus, and bevacizumab (with interferon), while axitinib, everolimus, and sorafenib are most extensively used following progression as second- or third line therapy. Attempts to augment the activity of these agents by combining them together or with chemotherapy or immunotherapy have not yet proven to improve outcomes. As a result, the sequential use of single agents remains the current standard of care.
- An anti-interleukin-2 receptor drug attenuates T- helper 1 lymphocytes-mediated inflammation in an acute model of endotoxin-induced uveitis. [Journal Article]
- PLoS One 2014; 9(3):e90216.
The aim of the present study was to evaluate the anti-inflammatory efficacy of Daclizumab, an anti-interleukin-2 receptor drug, in an experimental uveitis model upon a subcutaneous injection of lipopolysaccharide into Lewis rats, a valuable model for ocular acute inflammatory processes. The integrity of the blood-aqueous barrier was assessed 24 h after endotoxin-induced uveitis by evaluating two parameters: cell count and protein concentration in aqueous humors. The histopathology of all the ocular structures (cornea, lens, sclera, choroid, retina, uvea, and anterior and posterior chambers) was also considered. Enzyme-linked immunosorbent assays of the aqueous humor samples were performed to quantify the levels of the different chemokine and cytokine proteins. Similarly, a biochemical analysis of oxidative stress-related markers was also assessed. The inflammation observed in the anterior chamber of the eyes when Daclizumab was administered with endotoxin was largely prevented since the aqueous humor protein concentration substantially lowered concomitantly with a significant reduction in the uveal and vitreous histopathological grading. Th1 lymphocytes-related cytokines, such as Interleukin-2 and Interferon-γ, also significantly reduced with related anti-oxidant systems recovery. Daclizumab treatment in endotoxin-induced uveitis reduced Th1 lymphocytes-related cytokines, such as Interleukin-2 and Interferon gamma, by about 60-70% and presented a preventive role in endotoxin-induced oxidative stress. This antioxidant protective effect of Daclizumab may be related to several of the observed Daclizumab effects in our study, including IL-6 cytokine regulatory properties and a substantial concomitant drop in INFγ. Concurrently, Daclizumab treatment triggered a significant reduction in both the uveal histopathological grading and protein concentration in aqueous humors, but not in cellular infiltration.