T cell growth factor [keywords]
- A phase I clinical study of immunotherapy for advanced colorectal cancers using carcinoembryonic antigen-pulsed dendritic cells mixed with tetanus toxoid and subsequent IL-2 treatment. [Journal Article]
- J Biomed Sci 2016; 23(1):64.
To better evaluate and improve the efficacy of dendritic cell (DC)-based cancer immunotherapy, we conducted a clinical study of patients with advanced colorectal cancer using carcinoembryonic antigen (CEA)-pulsed DCs mixed with tetanus toxoid and subsequent interleukin-2 treatment. The tetanus toxoid in the vaccine preparation serves as an adjuvant and provides a non-tumor specific immune response to enhance vaccine efficacy. The aims of this study were to (1) evaluate the toxicity of this treatment, (2) observe the clinical responses of vaccinated patients, and (3) investigate the immune responses of patients against CEA before and after treatment.Twelve patients were recruited and treated in this phase I clinical study. These patients all had metastatic colorectal cancer and failed standard chemotherapy. We first subcutaneously immunized patients with metastatic colorectal cancer with 1 × 10(6) CEA-pulsed DCs mixed with tetanus toxoid as an adjuvant. Patients received 3 successive injections with 1 × 10(6) CEA-pulsed DCs alone. Low-dose interleukin-2 was administered subcutaneously following the final DC vaccination to boost the growth of T cells. Patients were evaluated for adverse event and clinical status. Blood samples collected before, during, and after treatment were analyzed for T cell proliferation responses against CEA.No severe treatment-related side effects or toxicity was observed in patients who received the regular 4 DC vaccine injections. Two patients had stable disease and 10 patients showed disease progression. A statistically significant increase in proliferation against CEA by T cells collected after vaccination was observed in 2 of 9 patients.The results of this study indicate that it is feasible and safe to treat colorectal cancer patients using this protocol. An increase in the anti-CEA immune response and a clinical benefit was observed in a small fraction of patients. This treatment protocol should be further evaluated in additional colorectal cancer patients with modifications to enhance T cell responses.ClinicalTrials.gov (identifier NCT00154713 ), September 8, 2005.
- Evaluation of the immunomodulatory effects of a South African commercial traditional immune booster in human peripheral blood mononuclear cells. [Journal Article]
- BMC Complement Altern Med 2016; 16(1):300.
With the burden of HIV and AIDS still very high, South Africa has seen an increase in commercial traditional medicines claiming to have immune-enhancing effects. Because of lack of regulation of the traditional medicine sector, these products have proliferated. This study aimed to evaluate the immunomodulatory effects of uMakhonya®, a commercial traditional immune booster, using various models of normal human peripheral blood mononuclear cells (PBMCs).Immunosuppressed, mitogen-, and peptidoglycan (PG)-stimulated PBMCs were treated with various doses of uMakhonya® and incubated for 24 h. The treated and control samples were analyzed for cytotoxicity, secretion of 12 different inflammatory cytokines, soluble interleukin-2 receptor (sIL-2R) levels, and nitric oxide (NO) secretion.In cytotoxicity assays, uMakhonya® induced dose-dependent cytotoxic effects in all three models, with IC50 values of 512.08, 500, and 487.91 μg/mL for immunosuppressed, phytohaemagglutinin (PHA)-, and PG from Staphylococcus. aureus (PG-S. aureus)-stimulated PBMCs, respectively. UMakhonya® at 100 and 10 μg/mL induced a significant (p < 0.05) increase in the secretion of IL-1α, IL-1β, IL-6, IL-10, tumor necrosis factor alpha (TNF)-α, and granulocyte-macrophage colony-stimulating factor (GM-CSF) in cyclosporine-, immunosuppressed, and PHA-stimulated PBMCs. In the same samples, there was a significant increase (p < 0.05) in sIL-2R concentration, which correlated with an increase in the secretion of inflammatory cytokines. In PBMCs stimulated with PG-S. aureus, uMakhonya® at doses of 100 and 10 μg/mL significantly (p < 0.05) suppressed the secretion of inflammatory cytokines, especially IL-1β and TNF-α. PG-S. aureus-stimulated PBMCs also showed a significant decrease (p < 0.05) in sIL-2R concentration when compared to control samples. UMakhonya® insignificantly (p > 0.05) decreased NO levels in PBMCs after PG-S. aureus stimulation.These results showed that uMakhonya® can induce both pro-inflammatory and anti-inflammatory effects depending on the initial stimuli applied to immune cells.
- Design, synthesis, and evaluation of 4,6-diaminonicotinamide derivatives as novel and potent immunomodulators targeting JAK3. [JOURNAL ARTICLE]
- Bioorg Med Chem 2016 Aug 6.
In organ transplantation, T cell-mediated immune responses play a key role in the rejection of allografts. Janus kinase 3 (JAK3) is specifically expressed in hematopoietic cells and associated with regulation of T cell development via interleukin-2 signaling pathway. Here, we designed novel 4,6-diaminonicotinamide derivatives as immunomodulators targeting JAK3 for prevention of transplant rejection. Our optimization of C4- and C6-substituents and docking calculations to JAK3 protein confirmed that the 4,6-diaminonicotinamide scaffold resulted in potent inhibition of JAK3. We also investigated avoidance of human ether-a-go-go related gene (hERG) inhibitory activity. Selected compound 28 in combination with tacrolimus prevented allograft rejection in a rat heterotopic cardiac transplantation model.
- What is the impact of n-3 PUFAs on inflammation markers in Type 2 diabetic mellitus populations?: a systematic review and meta-analysis of randomized controlled trials. [Journal Article, Review]
- Lipids Health Dis 2016.:133.
To explore the possible role of n-3 polyunsaturated fatty acids (PUFAs) in lowering inflammation markers in individuals with type 2 diabetes mellitus.PubMed, CNKI and Cochrane databases were searched until December 30, 2015; references from papers or reviews were also retrieved and screened. Screening was performed by two independent researchers, and randomized controlled trials reporting the specific n-3 PUFA type, dose, frequency, and duration of treatment, as well as the baseline and follow-up concentrations of inflammation markers, including interleukin 2 (IL-2), interleukin 6 (IL-6), tumor necrosis factor alpha (TNF-α) and C-reactive protein (CRP), were selected for final analysis. Data analysis was performed using RevMan 5.2 software.Eight studies involving 955 participants were included; all reported CRP. Only one included study reported IL-2 or IL-6 while two studies reported TNF-α. N-3 PUFAs significantly reduced CRP concentration compared with control [SMD 95 % CI, 1.90 (0.64, 3.16), Z = 2.96, P = 0.003, random effect model].N-3 PUFAs decrease CRP concentration in type-2 diabetes mellitus. However, larger and rigorously designed RCTs are required to confirm this finding and extend it into other inflammatory biomarkers.
- An additional CD28 costimulatory signal enhances proliferation and cytotoxicity of murine T cell-derived CIK cells. [JOURNAL ARTICLE]
- Asian Pac J Allergy Immunol 2016 Aug 16.
Cytokine induced killer (CIK) cells are ex-vivo expanded T cells endowed with both T and Natural Killer cell properties. The standard protocol for generation of CIK cells is to culture peripheral blood mononuclear cells (PBMC) in the presence of interferon-gamma (IFN-γ), monoclonal antibody (mAb) against CD3 and interleukin-2 (IL-2). However, this protocol lacks costimulatory signal (CD28), crucial for T cell activation. Herein, the proliferation and functional properties of murine thymocytes derived CIK cells generated with or without costimulatory activation provided by anti-CD28 mAb were examined.The proportion of CIK (Thy1.2+NK1.1+ and CD8+NK1.1+) cells in culture and the expression of cytotoxic granules (granzyme B and perforin) and proinflammatory cytokines (IFN-γ and tumor necrosis factor-alpha (TNF-α)) were determined by flow cytometry. Additionally, CIK cell cytotoxicity against YAC-1 murine lymphoma cells was measured by a propidium iodide-based assay.The addition of anti-CD28 to standard CIK culture conditions increased the number of Thy1.2+ NK1.1+ and CD8+ NK1.1+ (the major effector population) cells by almost 40% and 32%, respectively. Furthermore, the cytotoxic potential of CIK cells cultured with the addition of anti-CD28 mAb was also enhanced, with a corresponding increase in CIK cells expressing granzyme B, perforin, IFN-γ and TNF-α.The addition of anti-CD28 mAb generated more effective murine T cell-derived CIK cells.
- Myrrh and artesunate modulate some Th1 and Th2 cytokines secretion in Schistosoma mansoni infected mice. [Journal Article]
- Cent Eur J Immunol 2016; 41(2):138-42.
The effects of artesunate and myrrh on S. mansoni infection and the levels of some Th1 and Th2 cytokines were evaluated in the present study. Six weeks after infection, a group of mice was treated with 4 mg/kg of artesunate and other group was treated with 10 mg/kg of myrrh for 3 successive days. Worm burden was reduced with a percentage of 53.7% and 58.78% after treatment with myrrh and artesunate respectively as well as the levels of IgG antibodies were significantly reduced compared with infected group. No obvious changes were observed in the level of interferon γ after treatment. After treatment with artesunate, interleukin 2 (IL-2) level was significantly decreased, while no significant difference was observed in myrrh-treated group compared with the infected group. On the other hand, the level of IL-10 was not significantly decreased after treatment with artesunate, but it was significantly increased after treatment with myrrh. However, IL-12 levels were significantly decreased after treatment with artesunate. The results demonstrated that, artesunate or myrrh treatment could give a level of protection against S. mansoni infection and modulate the levels of some Th1 and Th2 cytokines in mice infected with S. mansoni.
- Immunosuppressive effect of extracts from leaves of Fraxinus Mandshurica Rupr. [JOURNAL ARTICLE]
- Bioengineered 2016 Aug 17.:0.
Plants provide a rich resource of medicinal material for research and development of new medicine. To discover new compounds as Immunosuppressant from plants, we evaluated the immunosuppressive effect of different fractions and particularly one compound (Calceolarioside A) that were extracted from the leaves of Fraxinus Mandshurica Rupr. The fractions and the compound were tested on the ability to reduce Immunoglobulin E (IgE) secretion by human U266 multiple myeloma cells (U266 cells) and to reduce interleukin-2 (IL-2) secretion by mouse spleen cells. Our results showed that both the butanol extract fraction and the compound of Calceolarioside A inhibited the IgE and IL-2 production in U266 cells and mouse spleen cells respectively, and no cytotoxicity was observed within the effective dose range. These results suggest that Calceolarioside A could potentially serve as an immunosuppressant.
- Total synthesis, structural, and biological evaluation of stylissatin A and related analogs. [Journal Article]
- J Pept Sci 2016 Sep; 22(9):607-17.
The natural product cyclic peptide stylissatin A (1a) was reported to inhibit nitric oxide production in LPS-stimulated murine macrophage RAW 264.7 cells. In the current study, solid-phase total synthesis of stylissatin A was performed by using a safety-catch linker and yielded the peptide with a trans-Phe(7) -Pro(6) linkage, whereas the natural product is the cis rotamer at this position as evidenced by a marked difference in NMR chemical shifts. In order to preclude the possibility of 1b being an epimer of the natural product, we repeated the synthesis using d-allo-Ile in place of l-Ile and a different site for macrocyclization. The resulting product (d-allo-Ile(2) )-stylissatin A (1c) was also found to have the trans-Phe(7) -Pro(6) peptide conformations like rotamer 1b. Applying the second route to the synthesis of stylissatin A itself, we obtained stylissatin A natural rotamer 1a accompanied by rotamer 1b as the major product. Rotamers 1a, 1b, and the epimer 1c were separable by HPLC, and 1a was found to match the natural product in structure and biological activity. Six related analogs 2-7 of stylissatin A were synthesized on Wang resin and characterized by spectral analysis. The natural product (1a), the rotamer (1b), and (d-allo-Ile(2) )-stylissatin A (1c) exhibited significant inhibition of NO(.) . Further investigations were focused on 1b, which also inhibited proliferation of T-cells and inflammatory cytokine IL-2 production. The analogs 2-7 weakly inhibited NO(.) production, but strongly inhibited IL-2 cytokine production compared with synthetic peptide 1b. All analogs inhibited the proliferation of T-cells, with analog 7 having the strongest effect. In the analogs, the Pro(6) residue was replaced by Glu/Ala, and the SAR indicates that the nature of this residue plays a role in the biological function of these peptides. Copyright © 2016 European Peptide Society and John Wiley & Sons, Ltd.
- Co-encapsulation of pancreatic islets and pentoxifylline in alginate-based microcapsules with enhanced immunosuppressive effects. [JOURNAL ARTICLE]
- Prog Biomater 2016.:101-109.
Alginate-based scaffolds have received considerable attention for biomedical application because of their biocompatibility and ease of preparation. The application of alginate hydrogels for encapsulation of pancreatic islets is known as a potential treatment for type I diabetes. In this study, dextran-spermine coated microcapsules of alginate containing pancreatic islets were prepared, and then co-cultured with lymphocytes for 7 days. In addition, to prevent fibrosis and evaluating the effect of anti-inflammatory drugs, pentoxifylline was loaded in the inner layer of microcapsules. Intact and encapsulated islets in an external solution of pentoxifylline were taken as two separate controls in this study. Infrared and scanning electron microscope analyses showed polyelectrolyte complex formation between alginate and dextran-spermine. In vitro tests showed that interleukin-2 secretion from lymphocytes co-cultured with encapsulated islets containing pentoxifylline in the inner layer of microcapsules was 63.6 % lower than the corresponding value for encapsulated islets without the anti-inflammatory drug.
- Inflammatory Biomarkers Predict Domain-Specific Cognitive Decline in Older Adults. [JOURNAL ARTICLE]
- J Gerontol A Biol Sci Med Sci 2016 Aug 13.
Vascular risk factors, including inflammation, may contribute to dementia development. We investigated the associations between peripheral inflammatory biomarkers and cognitive decline in five domains (memory, construction, language, psychomotor speed, and executive function).Community-dwelling older adults from the Ginkgo Evaluation of Memory Study (n = 1,159, aged 75 or older) free of dementia at baseline were included and followed for up to 7 years. Ten biomarkers were measured at baseline representing different sources of inflammation: vascular inflammation (pentraxin 3 and serum amyloid P), endothelial function (endothelin-1), metabolic function (adiponectin, resistin, and plasminogen activating inhibitor-1), oxidative stress (receptor for advanced glycation end products), and general inflammation (interleukin-6, interleukin-2, and interleukin-10). A combined z-score was created from these biomarkers to represent total inflammation across these sources. We utilized generalized estimating equations that included an interaction term between z-scores and time to assess effect of inflammation on cognitive decline, adjusting for demographics (such as age, race/ethnicity, and sex), cardiovascular risk factors, and apolipoprotein E ε4 carrier status. A Bonferroni-adjusted significance level of .01 was used. We explored associations between individual biomarkers and cognitive decline without adjustment for multiplicity.The combined inflammation z-score was significantly associated with memory and psychomotor speed (p < .01). Pentraxin 3, serum amyloid P, endothelin-1, and interleukin-2 were associated with change in at least one cognitive domain (p < .05).Our results suggest that total inflammation is associated with memory and psychomotor speed. In particular, systemic inflammation, vascular inflammation, and altered endothelial function may play roles in domain-specific cognitive decline of nondemented individuals.