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Bahari A.,Immunology Section | Bahari A.,Ferdowsi University of Mashhad | Mehrzad J.,Immunology Section | Mehrzad J.,Ferdowsi University of Mashhad | And 3 more authors.
Journal of Immunotoxicology | Year: 2015

Glutathione-S-transferases (GST) and aldo-keto reductases (AKR) are key aflatoxin (AF)-detoxifying enzymes. In this study, the expression of GST-M1, GST-T1, AKR-7A2, and AKR-7A3 genes in human monocytes and lymphocytes was analyzed after in vitro exposure to 10 or 100 ng AFB1/ml for 2 h. Unlike in pilot studies that showed that all four examined genes were present in HepG2 cells, in lymphocytes and monocytes, only GST-M1 and AKR-7A2 were detected. In fact, the induced expression of both GST-M1 and AKR-7A2 genes in human monocytes was moreso than that seen in AFB1-exposed lymphocytes. In addition, analyses of the effects of the exposures on cell cycle status were performed as, in cells lacking adequate detoxification capacities, it would be expected the cells would arrest at checkpoints in the cell cycle or progress to apoptotic/necrotic states. The results here indicated that only the high dose of AFB1 led to a change in cell cycle profiles and only in the monocytes (i.e. cells in S phase were significantly reduced). In general, the results here strongly suggest that human immune cell lineages appear to be able to increase their expression of AFB1-detoxifying enzymes (albeit to differing degrees) and, as a result, are able to counter potential toxicities from AFB1 and (likely) its metabolites. © 2014 Informa Healthcare USA, Inc.


Dhama K.,Indian Veterinary Research Institute | Latheef S.K.,Immunology Section | Samad H.A.,Indian Veterinary Research Institute | Chakraborty S.,Pt. Nehru Complex | Rahal A.,DUVASU
Journal of Medical Sciences (Faisalabad) | Year: 2013

Signaling molecules of immune system are cytokines that may either stimulate or suppress the responses of various cells involved in host immune mechanisms and Tumor Necrosis Factor (TNF) is one of the leading members of the group of cytokines. TNF-α from activated macrophages and LT-α/TNF-B from T cells have now become representatives of a distinctive superfamily of cytokine ligands (TNF ligand superfamily) along with their corresponding receptors (TNF receptor superfamily); altogether constituting the TNF Superfamily. These are highly conserved proteins, found in all mammals having important ligand members which interact with the either of the two receptors, TNFR1 andTNFR2, that initiate varied signaling cascades leading to diverse cellular responses. It has been established that the appropriate regulation of TNF ligand and receptor interactions and functions are crucial for the proper immune system activity. Excessive production of various TNF cytokines has been attributed with the development of an array of autoimmune as well as inflammatory conditions. TNF cytokines help to reduce mortality due to cardiovascular diseases. Therapeutic TNF blockers include:monoclonal antibodies to TNF (Infliximab and Adalumimab) and TNF receptor fusion proteins (Etanercept and Lenercept) and are effective against rheumatoid arthritis; ankylosing spondylitis; psoriasis and asthma. Preclinical studies conducted in murine models and the pivotal role played by the TNF superfamily in cytokine mediator system will make it easier for researchers as well as scientists to develop novel drugs in near future. This review has covered all these aspects concerning TNF as mediator of inflammatory diseases and its therapeutic targeting.


Muramatu L.H.,Irmandade da Santa Casa de Misericordia de Sao Paulo | Forte W.C.N.,Immunology Section
Jornal Brasileiro de Pneumologia | Year: 2013

Objective: To analyze pulmonary function parameters and pharmacodynamic response to a bronchodilator, as well as the prescription of bronchodilators, in cystic fibrosis (CF) patients. Methods: This was a retrospective cohort study involving patients 6-18 years of age, diagnosed with CF, and followed at a referral center between 2008 and 2010. We evaluated only those patients who were able to perform pulmonary function tests (PFTs). We analyzed FVC, FEV1, and FEF25-75%, expressed as percentages of the predicted values, prior to and after bronchodilator tests (pre-BD and post-BD, respectively), in 312 PFTs. Repeated measures ANOVA and multiple comparisons were used. Results: The study included 56 patients, divided into two groups: those whose PFT results spanned the 2008-2010 period (n = 37); and those whose PFT results spanned only the 2009-2010 period (n = 19). In the 2008-2010 group, there were significant reductions in post-BD FEV1 between 2008 and 2010 (p = 0.028) and between 2009 and 2010 (p = 0.036), as was also the case for pre-BD and post-BD FEF25-75% in all multiple comparisons (2008 vs. 2009; 2008 vs. 2010; and 2009 vs. 2010). In the 2009-2010 group, there were no significant differences between any of the years for any of the variables studied. Among the 312 PFTs, significant responses to the bronchodilator occurred in only 24 (7.7%), all of which were from patients for whom no bronchodilator had been prescribed during the study period. Conclusions: In the CF patients studied, there was loss of pulmonary function, indicating progressive lung disease, over time. The changes were greater for FEF25-75% than for the other variables, which suggests the initial involvement of small airways.


News Article | February 20, 2017
Site: www.eurekalert.org

An experimental malaria vaccine protected healthy subjects from infection with a malaria strain different from that contained in the vaccine, according to a study published today in the Proceedings of the National Academy of Sciences (PNAS). The research was conducted by scientists at the University of Maryland School of Medicine (UM SOM) and the National Institute of Allergy and Infectious Diseases (NIAID), part of the National Institutes of Health (NIH). The Phase 1 clinical trial is important because in places where malaria is common, there is usually more than one strain of malaria. To be effective in the real world, a vaccine must protect against more than one. The study's lead researcher, Kirsten E. Lyke, MD, associate professor of medicine at the UM SOM Center for Vaccine Development, said the vaccine's versatility was promising. "Our study shows that that this vaccine can protect against at least two strains of malaria," said Dr. Lyke, who has studied malaria for more than a decade. "We need to continue our research, but this is a fantastic finding." Malaria is transmitted to humans through the bite of infected mosquitoes, which inject immature malaria parasites called sporozoites into a person's bloodstream. The parasites travel to the liver, where they mature, multiply and spread via the bloodstream throughout the body causing malaria symptoms including chills, fever, headache, nausea, sweating and fatigue. According to the World Health Organization, 212 million people were infected with malaria globally in 2015 and 429,000 people died, mostly young children in Africa. The species Plasmodium falciparum is the most common cause of malaria morbidity and mortality in Africa. In the United States, travel-related malaria is a concern for international tourists, aid workers and military personnel worldwide. The PfSPZ Vaccine used in this study was developed by Sanaria Inc., of Rockville, Maryland. The vaccine contains weakened P. falciparum sporozoites that do not cause infection but are able to generate a protective immune response that protects against live malaria infection. Earlier research with the vaccine found it to be safe, well-tolerated and protective for more than a year when tested in healthy U.S. adults against a single Africa-derived malaria strain matched to the PfSPZ Vaccine. The study enrolled 31 healthy adults ages 18 to 45 years, and was led by Dr. Lyke and Robert A. Seder, MD, chief of the Cellular Immunology Section of NIAID's Vaccine Research Center (VRC). Participants were assigned to receive three doses of the vaccine over several months by rapid intravenous injection. Nineteen weeks after receiving the final dose of the test vaccine, participants who received the vaccine and a group of non-vaccinated volunteers were exposed in a controlled setting to bites from mosquitoes infected with the same strain of P. falciparum parasites (NF54, from Africa) that were used to manufacture the PfSPZ Vaccine. Nine of the 14 participants (64 percent) who received the PfSPZ Vaccine demonstrated no evidence of malaria parasites; all six of the non-vaccinated participants who were challenged at the same time had malaria parasites in their blood. Of the nine participants who showed no evidence of malaria, six participants were again exposed in a controlled setting to mosquito bites, this time from mosquitoes infected with a different strain of P. falciparum parasite, 33 weeks after the final immunization. In this group, 5 of the 6 participants (83 percent) were protected against malaria infection; none of the six participants who did not receive the vaccine and were challenged were protected. All participants who became infected with malaria immediately received medical treatment. The research team found that the PfSPZ Vaccine activated T cells, a key component of the body's defenses against malaria, and induced antibody responses in all vaccine recipients. Vaccine-specific T-cell responses were comparable when measured against both of the malaria challenge strains, providing some insights into how the vaccine was mediating protection. Ongoing research will determine whether protective efficacy can be improved by changes to the PfSPZ Vaccine dose and number of immunizations. Accordingly, a Phase II efficacy trial testing three different dosages in a three-dose vaccine regimen is now underway in 5- to 12-month-old infants in Western Kenya to assess safety and efficacy against natural infection.


News Article | February 21, 2017
Site: www.eurekalert.org

An investigational malaria vaccine has protected a small number of healthy U.S. adults from infection with a malaria strain different from that contained in the vaccine, according to a study published today in the Proceedings of the National Academy of Sciences (PNAS). The National Institute of Allergy and Infectious Diseases (NIAID), part of the National Institutes of Health, sponsored and co-conducted the Phase 1 clinical trial. Malaria is transmitted to humans through the bite of infected mosquitoes, which inject immature malaria parasites called sporozoites into a person's bloodstream. The parasites travel to the liver, where they mature, multiply and spread via the bloodstream throughout the body causing malaria symptoms including chills, fever, headache, nausea, sweating and fatigue. According to the World Health Organization, 214 million people were infected with malaria globally in 2015 and 438,000 people died, mostly young African children. The species Plasmodium falciparum is the most common cause of malaria morbidity and mortality in Africa. In the United States, travel-related malaria is a concern for international tourists, aid workers and military personnel worldwide. The PfSPZ Vaccine used in this study was developed by Sanaria Inc., of Rockville, Maryland. The vaccine contains weakened P. falciparum sporozoites that do not cause infection but are able to generate a protective immune response against live malaria infection. Earlier research at the NIH Clinical Center with the PfSPZ Vaccine found it to be safe, well-tolerated and protective for more than a year when tested in healthy U.S. adults against a single Africa-derived malaria strain matched to the PfSPZ Vaccine. "An effective malaria vaccine will need to protect people living in endemic areas against multiple strains of the mosquito-borne disease," said NIAID Director Anthony S. Fauci, M.D. "These new findings showing cross-protection with the PfSPZ Vaccine suggest that it may be able to accomplish this goal." The study enrolled 31 healthy adults ages 18 to 45 years, and was led by Julie E. Ledgerwood, D.O. of NIAID's Vaccine Research Center (VRC), and Kirsten E. Lyke, M.D. of the University of Maryland Center for Vaccine Development in Baltimore. Participants were assigned to receive three doses of the PfSPZ Vaccine at eight-week intervals by rapid intravenous injection. Nineteen weeks after receiving the final dose of the test vaccine, participants who received the vaccine and a group of non-vaccinated volunteers were exposed in a controlled setting to bites from mosquitoes infected with the same strain of P. falciparum parasites (NF54, from Africa) that were used to manufacture PfSPZ Vaccine. Nine of the 14 participants (64 percent) who received PfSPZ Vaccine demonstrated no evidence of malaria parasites; all six of the non-vaccinated participants who were challenged at the same time had malaria parasites in their blood. Of the nine participants who showed no evidence of malaria, six participants were again exposed in a controlled setting to mosquito bites, this time from mosquitoes infected with a different strain of P. falciparum parasite, 33 weeks after the final immunization. In this group, 5 of the 6 participants (83 percent) were protected against malaria infection; none of the six participants who did not receive the vaccine and were challenged were protected. All participants who became infected with malaria immediately received medical treatment. "Achieving durable protection against a malaria strain different from the vaccine strain, over eight months after vaccination, is an indication of this vaccine's potential," said Robert A. Seder, M.D., chief of the Cellular Immunology Section of NIAID's Vaccine Research Center and senior author of the PNAS paper. "If we can build on these findings with the PfSPZ Vaccine and induce higher efficacy, we may be on our way to a vaccine that could effectively protect people against a variety of malaria parasites where the disease is prevalent." The research team found that the PfSPZ Vaccine activated T cells, a key component of the body's defenses against malaria, and induced antibody responses in all vaccine recipients. Vaccine-specific T-cell responses were comparable when measured against both of the malaria challenge strains, providing some insights into how the vaccine was mediating protection. Ongoing research will determine whether protective efficacy can be improved by changes to the PfSPZ Vaccine dose and number of immunizations. Accordingly, a Phase 2 efficacy trial testing three different dosages in a three-dose vaccine regimen is now underway in 5-to 12-month-old infants in Western Kenya to assess safety and efficacy against natural infection. Sanaria Inc., designed, manufactured, and provided PfSPZ Vaccine and the heterologous challenge mosquitoes. NIAID supported the development of the experimental vaccine through several Small Business Innovation Research grants: 5R44AI055229-11, 5R44AI058499-08, and 5R44AI058375-08. For more information about the Phase 1 study, see ClinicalTrials.gov using the identifier: NCT02015091. Reference: K. Lyke et al. PrSPZ vaccine induces strain-transcending T cells and durable protection against heterologous controlled human malaria infection. PNAS DOI 10.1073/pnas.1615324114 (2017). NIAID conducts and supports research--at NIH, throughout the United States, and worldwide--to study the causes of infectious and immune-mediated diseases, and to develop better means of preventing, diagnosing and treating these illnesses. News releases, fact sheets and other NIAID-related materials are available on the NIAID website. About the National Institutes of Health (NIH): NIH, the nation's medical research agency, includes 27 Institutes and Centers and is a component of the U.S. Department of Health and Human Services. NIH is the primary federal agency conducting and supporting basic, clinical, and translational medical research, and is investigating the causes, treatments, and cures for both common and rare diseases. For more information about NIH and its programs, visit http://www. .


News Article | February 15, 2017
Site: www.eurekalert.org

An experimental malaria vaccine strategy known as PfSPZ-CVac, together with antimalarial medication, protected all nine clinical trial volunteers given three high-dose vaccinations, according to study results published today in Nature. The study was supported in part by grants and technical assistance from scientists at the National Institute of Allergy and Infectious Diseases (NIAID), part of the National Institutes of Health. The data add to a growing body of scientific evidence showing that vaccines created using live malaria parasites can be safe, well-tolerated, and potentially effective if used in mass vaccination programs to eradicate malaria from geographically defined areas, according to the authors. PfSPZ-CVac, developed by Sanaria Inc., of Rockville, Maryland, is administered intravenously to generate an immune response to protect against malaria infection. The vaccine introduces live Plasmodium falciparum malaria parasites into the bloodstream; these parasites are ordinarily transmitted to humans through the bite of an infected mosquito. Oral antimalarial medication (chloroquine) is given simultaneously to prevent an actual malarial infection. The new study was conducted at the University of Tubingen, Germany. Forty-two healthy adult participants were randomly assigned to receive either three doses of PfSPZ-CVac at one of three dosage levels at 28-day intervals, or a placebo injection. All recipients were simultaneously given oral doses of chloroquine. Participants then underwent controlled exposure to infectious malaria parasites 10 weeks after the final vaccination. All nine participants who received three injections of the highest dose of PfSPZ-CVac (5.12x104) were protected against P. falciparum malaria 10 weeks after their last vaccine dose. Participants who received lower dosages exhibited less (but still statistically significant) immunity to malaria infection. The researchers also found that the highest dosages of vaccine administered three times at 5-day intervals protected 63 percent of participants (5 of 8). The authors suggest that in the field, high doses of the PfSPZ-CVac vaccine will likely be needed to protect against malaria infection. The researchers showed that PfSPZ-CVac induced a response from vaccine recipients' T cells--white blood cells that activate the rest of the immune system--which was proportional to the dosage of the vaccine. In addition, they determined that patients whose CD4+ T cells produced multiple kinds of signaling molecules to activate the immune system were more likely to be protected. Antigen Discovery Inc., based in Irvine, California, studied the antibody responses of the nine participants who had complete protection and identified 22 malaria parasite proteins that could be the targets of protective immune responses. A Phase 2 trial is planned to test PfSPZ-CVac in the African countries of Mali, Ghana, and Gabon to evaluate the optimal dose and schedule for protection in malaria-endemic areas. Through Small Business Innovation Research grants, NIAID supported the preclinical development and, in part, the manufacture of the PfSPZ-CVac Vaccine, as well as the antibody response analysis and the identification of the potential protective malaria protein. NIAID also provided cellular immune analysis. B. Mordmüller et al. Sterile protection against human malaria by chemoattenuated PfSPZ vaccine. Nature DOI 10.1038/nature21060 (2017). NIAID Director Anthony S. Fauci, M.D., and Robert A. Seder, M.D., chief of the Cellular Immunology Section of NIAID's Vaccine Research Center and study co-author, are available for comment. NIAID conducts and supports research--at NIH, throughout the United States, and worldwide--to study the causes of infectious and immune-mediated diseases, and to develop better means of preventing, diagnosing and treating these illnesses. News releases, fact sheets and other NIAID-related materials are available on the NIAID website. About the National Institutes of Health (NIH): NIH, the nation's medical research agency, includes 27 Institutes and Centers and is a component of the U.S. Department of Health and Human Services. NIH is the primary federal agency conducting and supporting basic, clinical, and translational medical research, and is investigating the causes, treatments, and cures for both common and rare diseases. For more information about NIH and its programs, visit http://www. .


Ramakrishnan S.,Immunology Section | Annamalai A.,Immunology Section | Sachan S.,Immunology Section | Kumar A.,Immunology Section | And 5 more authors.
Molecular Immunology | Year: 2015

Toll-like receptors (TLRs) recognize conserved molecular structures of invading pathogens and initiate an immune response to curtail the infection prior to the development of more powerful and specific adaptive immunity. Understanding the interactions between different TLRs in terms of immune response genes is a pre-requisite for using various TLR agonists alone or in combination as adjuvants or as stand-alone agents against various diseases. Lipopolysaccharide (LPS) and resiquimod (R-848) are TLR agonists that are recognized by TLR4 and TLR7, respectively. In this study, the effect of LPS and/or R-848 on chicken peripheral blood mononuclear cells (PBMCs) was investigated. LPS and R-848 synergistically up-regulated the transcripts of interferon-β (IFN-β), IFN-γ, IL-4 and IL-1β as compared to the individual response (P<. 0.05). The results indicate that these agonists synergistically interact and enhance type-I IFN, pro-inflammatory cytokine as well as Th1 and Th2 responses in chicken PBMCs, suggesting their potential as an adjuvant candidate to be used in combination with various poultry vaccines. © 2014 Elsevier Ltd.


Singh M.,Immunology Section | Goswami T.K.,Immunology Section | Dhama K.,Avian Disease Section
Journal of Pure and Applied Microbiology | Year: 2014

Salmonellosis is a disease complex of man and animals caused by various serovars of Salmonella enterica subspecies enterica. Salmonella spp. are facultative intracellular pathogens capable of causing localized and systemic disease of significant morbidity and mortality. The present study was aimed to investigate the immune response elicited in mice following subcutaneous immunization with purified flagellin derived from Salmonella enterica serovar Typhimurium. Humoral immune response in mice was analyzed by indirect enzyme linked immunosorbent immunoassay (ELISA) wherein a significantly greater antibody response was noticed in immunized group of mice compared to the control group. Further confirmation by western blotting showed immunoreactivity of the isolated flagellin against sera obtained from flagellin immunized group on 21st day post immunization. Bacterial colony count in spleen from the mice immunized with flagellin and challenged with Salmonella intra-peritoneally showed complete clearance of the bacteria. In conclusion, bacterial flagellin demonstrated the seroconversion and protective efficacy against homologous bacterial challenge post immunization. Further explorative studies are suggested to unravel its potential application to be used as vaccine antigen or adjuvant.


Toll-like receptors (TLRs) recognize conserved molecular structures of invading pathogens and initiate an immune response to curtail the infection prior to the development of more powerful and specific adaptive immunity. Understanding the interactions between different TLRs in terms of immune response genes is a pre-requisite for using various TLR agonists alone or in combination as adjuvants or as stand-alone agents against various diseases. Lipopolysaccharide (LPS) and resiquimod (R-848) are TLR agonists that are recognized by TLR4 and TLR7, respectively. In this study, the effect of LPS and/or R-848 on chicken peripheral blood mononuclear cells (PBMCs) was investigated. LPS and R-848 synergistically up-regulated the transcripts of interferon- (IFN-), IFN-, IL-4 and IL-1 as compared to the individual response (P<0.05). The results indicate that these agonists synergistically interact and enhance type-I IFN, pro-inflammatory cytokine as well as Th1 and Th2 responses in chicken PBMCs, suggesting their potential as an adjuvant candidate to be used in combination with various poultry vaccines.


PubMed | Immunology Section
Type: Journal Article | Journal: Journal of immunotoxicology | Year: 2015

Glutathione-S-transferases (GST) and aldo-keto reductases (AKR) are key aflatoxin (AF)-detoxifying enzymes. In this study, the expression of GST-M1, GST-T1, AKR-7A2, and AKR-7A3 genes in human monocytes and lymphocytes was analyzed after in vitro exposure to 10 or 100ng AFB1/ml for 2h. Unlike in pilot studies that showed that all four examined genes were present in HepG2 cells, in lymphocytes and monocytes, only GST-M1 and AKR-7A2 were detected. In fact, the induced expression of both GST-M1 and AKR-7A2 genes in human monocytes was moreso than that seen in AFB1-exposed lymphocytes. In addition, analyses of the effects of the exposures on cell cycle status were performed as, in cells lacking adequate detoxification capacities, it would be expected the cells would arrest at checkpoints in the cell cycle or progress to apoptotic/necrotic states. The results here indicated that only the high dose of AFB1 led to a change in cell cycle profiles and only in the monocytes (i.e. cells in S phase were significantly reduced). In general, the results here strongly suggest that human immune cell lineages appear to be able to increase their expression of AFB1-detoxifying enzymes (albeit to differing degrees) and, as a result, are able to counter potential toxicities from AFB1 and (likely) its metabolites.

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