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https://www.readbyqxmd.com/read/27151882/cracc-targeting-fc-fusion-protein-induces-activation-of-nk-cells-and-dcs-and-improves-t-cell-immune-responses-to-antigenic-targets
#1
Yasser A Aldhamen, David P W Rastall, Weimin Chen, Sergey S Seregin, Cristiane Pereira-Hicks, Sarah Godbehere, Norbert E Kaminski, Andrea Amalfitano
The CD2-like receptor activating cytotoxic cell (CRACC) receptor is a member of the SLAM family of receptors that are found on several types of immune cells. We previously demonstrated that increasing the abundance of the adaptor protein EAT-2 during vaccination enhanced innate and adaptive immune responses to vaccine antigens. Engagement of the CRACC receptor in the presence of the EAT-2 adaptor generally results in immune cell activation, while activating CRACC signaling in cells that lack EAT-2 adaptor inhibits their effector and regulatory functions...
June 8, 2016: Vaccine
https://www.readbyqxmd.com/read/26792800/in-vivo-synthesis-of-cyclic-di-gmp-using-a-recombinant-adenovirus-preferentially-improves-adaptive-immune-responses-against-extracellular-antigens
#2
Fadel S Alyaqoub, Yasser A Aldhamen, Benjamin J Koestler, Eric L Bruger, Sergey S Seregin, Cristiane Pereira-Hicks, Sarah Godbehere, Christopher M Waters, Andrea Amalfitano
There is a compelling need for more effective vaccine adjuvants to augment induction of Ag-specific adaptive immune responses. Recent reports suggested the bacterial second messenger bis-(3'-5')-cyclic-dimeric-guanosine monophosphate (c-di-GMP) acts as an innate immune system modulator. We recently incorporated a Vibrio cholerae diguanylate cyclase into an adenovirus vaccine, fostering production of c-di-GMP as well as proinflammatory responses in mice. In this study, we recombined a more potent diguanylate cyclase gene, VCA0848, into a nonreplicating adenovirus serotype 5 (AdVCA0848) that produces elevated amounts of c-di-GMP when expressed in mammalian cells in vivo...
February 15, 2016: Journal of Immunology: Official Journal of the American Association of Immunologists
https://www.readbyqxmd.com/read/26170711/recent-advances-in-gene-therapy-for-lysosomal-storage-disorders
#3
REVIEW
David Pw Rastall, Andrea Amalfitano
Lysosomal storage disorders (LSDs) are a group of genetic diseases that result in metabolic derangements of the lysosome. Most LSDs are due to the genetic absence of a single catabolic enzyme, causing accumulation of the enzyme's substrate within the lysosome. Over time, tissue-specific substrate accumulations result in a spectrum of symptoms and disabilities that vary by LSD. LSDs are promising targets for gene therapy because delivery of a single gene into a small percentage of the appropriate target cells may be sufficient to impact the clinical course of the disease...
2015: Application of Clinical Genetics
https://www.readbyqxmd.com/read/25655760/strengthened-tumor-antigen-immune-recognition-by-inclusion-of-a-recombinant-eimeria-antigen-in-therapeutic-cancer-vaccination
#4
Dionisia Quiroga, Yasser A Aldhamen, Daniel M Appledorn, Sarah Godbehere, Andrea Amalfitano
The need for novel, effective adjuvants that are capable of eliciting stronger cellular and humoral adaptive immune responses to antigenic targets is well understood in the vaccine development field. Unfortunately, many adjuvants investigated thus far are either too toxic for human application or too weak to induce a substantial response against difficult antigens, such as tumor-associated antigens (TAAs). In spite of this trend, clinical investigations of recombinant Eimeria antigen (rEA) have revealed this protein to be a non-toxic immunogenic agent with the ability to trigger a Th1-predominant response in both murine and human subjects...
April 2015: Cancer Immunology, Immunotherapy: CII
https://www.readbyqxmd.com/read/25591727/autoimmune-disease-associated-variants-of-extracellular-endoplasmic-reticulum-aminopeptidase-1-induce-altered-innate-immune-responses-by-human-immune-cells
#5
Yasser A Aldhamen, Yuliya Pepelyayeva, David P W Rastall, Sergey S Seregin, Efthalia Zervoudi, Despoina Koumantou, Charles F Aylsworth, Dionisia Quiroga, Sarah Godbehere, Dimitris Georgiadis, Efstratios Stratikos, Andrea Amalfitano
Endoplasmic reticulum aminopeptidase 1 (ERAP1) gene polymorphisms have been linked to several autoimmune diseases; however, the molecular mechanisms underlying these associations are not well understood. Recently, we demonstrated that ERAP1 regulates key aspects of the innate immune response. Previous studies show ERAP1 to be endoplasmic reticulum-localized and secreted during inflammation. Herein, we investigate the possible roles that ERAP1 polymorphic variants may have in modulating the innate immune responses of human peripheral blood mononuclear cells (hPBMCs) using two experimental methods: extracellular exposure of hPBMCs to ERAP1 variants and adenovirus (Ad)-based ERAP1 expression...
2015: Journal of Innate Immunity
https://www.readbyqxmd.com/read/25230938/stimulation-of-innate-immunity-by-in-vivo-cyclic-di-gmp-synthesis-using-adenovirus
#6
Benjamin J Koestler, Sergey S Seregin, David P W Rastall, Yasser A Aldhamen, Sarah Godbehere, Andrea Amalfitano, Christopher M Waters
The bacterial second messenger cyclic di-GMP (c-di-GMP) stimulates inflammation by initiating innate immune cell recruitment and triggering the release of proinflammatory cytokines and chemokines. These properties make c-di-GMP a promising candidate for use as a vaccine adjuvant, and numerous studies have demonstrated that administration of purified c-di-GMP with different antigens increases protection against infection in animal models. Here, we have developed a novel approach to produce c-di-GMP inside host cells as an adjuvant to exploit a host-pathogen interaction and initiate an innate immune response...
November 2014: Clinical and Vaccine Immunology: CVI
https://www.readbyqxmd.com/read/25087231/erap1-functions-override-the-intrinsic-selection-of-specific-antigens-as-immunodominant-peptides-thereby-altering-the-potency-of-antigen-specific-cytolytic-and-effector-memory-t-cell-responses
#7
David P W Rastall, Yasser A Aldhamen, Sergey S Seregin, Sarah Godbehere, Andrea Amalfitano
Endoplasmic reticulum aminopeptidase 1 (ERAP1) is a critical component of the adaptive immune system that has been shown to increase or decrease the presentation of specific peptides on MHC class I molecules. Here, we have demonstrated that ERAP1 functions are not only important during the presentation of antigen-derived peptides, but these functions can also completely change which antigen-derived peptides ultimately become selected as immunodominant T-cell epitopes. Our results suggest that ERAP1 may do this by destroying epitopes that would otherwise become immunodominant in the absence of adequate ERAP1 functionality...
December 2014: International Immunology
https://www.readbyqxmd.com/read/24374770/manipulation-of-eat-2-expression-promotes-induction-of-multiple-beneficial-regulatory-and-effector-functions-of-the-human-innate-immune-system-as-a-novel-immunomodulatory-strategy
#8
Yasser A Aldhamen, Sergey S Seregin, Charles F Aylsworth, Sarah Godbehere, Andrea Amalfitano
The signaling lymphocytic activation molecule (SLAM) receptor-associated adaptor Ewing's sarcoma-associated transcript-2 (EAT-2) is primarily expressed in innate immune cells including dendritic cells (DCs), macrophages and NK cells. A recent human HIV vaccine study confirmed that EAT-2 expression was associated with the enhanced immunogenicity induced by the MRKAd5/HIV vaccine. We previously harnessed the capability of EAT-2 to modulate signaling mediated by SLAM receptors and demonstrated that by incorporating EAT-2 expression into vaccines, one could enhance innate and adaptive immune responses in mice, even in the face of pre-existing immunity to the vaccine vectors...
May 2014: International Immunology
https://www.readbyqxmd.com/read/24248368/rationally-designed-inhibitor-targeting-antigen-trimming-aminopeptidases-enhances-antigen-presentation-and-cytotoxic-t-cell-responses
#9
Efthalia Zervoudi, Emmanuel Saridakis, James R Birtley, Sergey S Seregin, Emma Reeves, Paraskevi Kokkala, Yasser A Aldhamen, Andrea Amalfitano, Irene M Mavridis, Edward James, Dimitris Georgiadis, Efstratios Stratikos
Intracellular aminopeptidases endoplasmic reticulum aminopeptidases 1 and 2 (ERAP1 and ERAP2), and as well as insulin-regulated aminopeptidase (IRAP) process antigenic epitope precursors for loading onto MHC class I molecules and regulate the adaptive immune response. Their activity greatly affects the antigenic peptide repertoire presented to cytotoxic T lymphocytes and as a result can regulate cytotoxic cellular responses contributing to autoimmunity or immune evasion by viruses and cancer cells. Therefore, pharmacological regulation of their activity is a promising avenue for modulating the adaptive immune response with possible applications in controlling autoimmunity, in boosting immune responses to pathogens, and in cancer immunotherapy...
December 3, 2013: Proceedings of the National Academy of Sciences of the United States of America
https://www.readbyqxmd.com/read/24244554/regulation-of-epithelial-differentiation-in-rat-intestine-by-intraluminal-delivery-of-an-adenoviral-vector-or-silencing-rna-coding-for-schlafen-3
#10
Pavlo L Kovalenko, Lisi Yuan, Kelian Sun, Lyudmyla Kunovska, Sergey Seregin, Andrea Amalfitano, Marc D Basson
Although we stimulate enterocytic proliferation to ameliorate short gut syndrome or mucosal atrophy, less effort has been directed at enterocytic differentiation. Schlafen 3 (Slfn3) is a poorly understood protein induced during IEC-6 enterocytic differentiation. We hypothesized that exogenous manipulation of Slfn3 would regulate enterocytic differentiation in vivo. Adenoviral vector coding for Slfn3 cDNA (Ad-GFP-Slfn3) or silencing RNA for Slfn3 (siSlfn3) was introduced intraluminally into rat intestine. We assessed Slfn3, villin, sucrase-isomaltase (SI), Dpp4, and Glut2 by qRT-PCR, Western blot, and immunohistochemistry...
2013: PloS One
https://www.readbyqxmd.com/read/24028501/endoplasmic-reticulum-aminopeptidase-1-alleles-associated-with-increased-risk-of-ankylosing-spondylitis-reduce-hla-b27-mediated-presentation-of-multiple-antigens
#11
Sergey S Seregin, David P W Rastall, Irini Evnouchidou, Charles F Aylsworth, Dionisia Quiroga, Ram P Kamal, Sarah Godbehere-Roosa, Christopher F Blum, Ian A York, Efstratios Stratikos, Andrea Amalfitano
Ankylosing spondylitis (AS) is a chronic systemic arthritic disease that leads to significant disability and loss of quality of life in the ∼0.5% of the worldwide human population it affects. There is currently no cure for AS and mechanisms underlying its pathogenesis remain unclear. AS is highly genetic, with over 70% of the genetic risk being associated with the presence of HLA-B27 and endoplasmic reticulum aminopeptidase-1 (ERAP1) alleles. Furthermore, gene-gene interactions between HLA-B27 and ERAP1 AS risk alleles have recently been confirmed...
December 2013: Autoimmunity
https://www.readbyqxmd.com/read/23894499/endoplasmic-reticulum-aminopeptidase-1-functions-regulate-key-aspects-of-the-innate-immune-response
#12
Yasser A Aldhamen, Sergey S Seregin, David P W Rastall, Charles F Aylsworth, Yuliya Pepelyayeva, Christopher J Busuito, Sarah Godbehere-Roosa, Sungjin Kim, Andrea Amalfitano
Endoplasmic reticulum aminopeptidase-1 (ERAP1) is a multifunctional, ubiquitously expressed enzyme whose peptide-trimming role during antigen processing for presentation by MHC I molecules is well established, however, a role for ERAP1 in modulating global innate immune responses has not been described to date. Here we demonstrate that, relative to wild type mice, mice lacking ERAP1 exhibit exaggerated innate immune responses early during pathogen recognition, as characterized by increased activation of splenic and hepatic NK and NKT cells and enhanced production of pro-inflammatory cytokines such as IL12 and MCP1...
2013: PloS One
https://www.readbyqxmd.com/read/23741302/stream-hydrological-fragmentation-drives-bacterioplankton-community-composition
#13
Stefano Fazi, Eusebi Vázquez, Emilio O Casamayor, Stefano Amalfitano, Andrea Butturini
In Mediterranean intermittent streams, the hydrological fragmentation in summer and the successive water flow re-convergence in autumn allow exploring how local processes shape the microbial community within the same habitat. The objectives of this study were to determine how bacterial community composition responded to hydrological fragmentation in summer, and to evaluate whether the seasonal shifts in community composition predominate over the effects of episodic habitat fragmentation. The bacterial community was assessed along the intermittent stream Fuirosos (Spain), at different levels of phylogenetic resolution by in situ hybridization, fingerprinting, and 16S rRNA gene sequencing...
2013: PloS One
https://www.readbyqxmd.com/read/23639554/activation-of-human-natural-killer-cells-by-the-novel-innate-immune-modulator-recombinant-eimeria-antigen
#14
Charles F Aylsworth, Yasser A Aldhamen, Sergey S Seregin, Sarah Godbehere, Andrea Amalfitano
The safe and effective activation of the innate and adaptive immune systems are crucial in the implementation of immunotherapeutic modalities for the prevention and treatment of human diseases. Eimeria antigen (EA) and its recombinantly expressed analog (rEA) are extremely effective activators of innate immunity in mice. The effects of rEA in the mouse are primarily mediated through the TLR11/12 MyD88 signaling system. Human cells lack functional TLR11 and TLR12, suggesting that rEA would not be effective in providing beneficial immune activation in humans...
August 2013: Human Immunology
https://www.readbyqxmd.com/read/23624851/novel-adenoviral-vector-induces-t-cell-responses-despite-anti-adenoviral-neutralizing-antibodies-in-colorectal-cancer-patients
#15
Michael A Morse, Arvind Chaudhry, Elizabeth S Gabitzsch, Amy C Hobeika, Takuya Osada, Timothy M Clay, Andrea Amalfitano, Bruce K Burnett, Gayathri R Devi, David S Hsu, Younong Xu, Stephanie Balcaitis, Rajesh Dua, Susan Nguyen, Joseph P Balint, Frank R Jones, H Kim Lyerly
First-generation, E1-deleted adenovirus subtype 5 (Ad5)-based vectors, although promising platforms for use as cancer vaccines, are impeded in activity by naturally occurring or induced Ad-specific neutralizing antibodies. Ad5-based vectors with deletions of the E1 and the E2b regions (Ad5 [E1-, E2b-]), the latter encoding the DNA polymerase and the pre-terminal protein, by virtue of diminished late phase viral protein expression, were hypothesized to avoid immunological clearance and induce more potent immune responses against the encoded tumor antigen transgene in Ad-immune hosts...
August 2013: Cancer Immunology, Immunotherapy: CII
https://www.readbyqxmd.com/read/22837489/a-common-single-nucleotide-polymorphism-in-endoplasmic-reticulum-aminopeptidase-2-induces-a-specificity-switch-that-leads-to-altered-antigen-processing
#16
Irini Evnouchidou, James Birtley, Sergey Seregin, Athanasios Papakyriakou, Efthalia Zervoudi, Martina Samiotaki, George Panayotou, Petros Giastas, Olivia Petrakis, Dimitris Georgiadis, Andrea Amalfitano, Emmanuel Saridakis, Irene M Mavridis, Efstratios Stratikos
Endoplasmic reticulum aminopeptidases 1 and 2 (ERAP1 and ERAP2) cooperate to trim antigenic peptide precursors for loading onto MHC class I molecules and help regulate the adaptive immune response. Common coding single nucleotide polymorphisms in ERAP1 and ERAP2 have been linked with predisposition to human diseases ranging from viral and bacterial infections to autoimmunity and cancer. It has been hypothesized that altered Ag processing by these enzymes is a causal link to disease etiology, but the molecular mechanisms are obscure...
September 1, 2012: Journal of Immunology: Official Journal of the American Association of Immunologists
https://www.readbyqxmd.com/read/22745373/vaccines-expressing-the-innate-immune-modulator-eat-2-elicit-potent-effector-memory-t-lymphocyte-responses-despite-pre-existing-vaccine-immunity
#17
Yasser Ali Aldhamen, Sergey S Seregin, Nathaniel J Schuldt, David P W Rastall, Chyong-Jy J Liu, Sarah Godbehere, Andrea Amalfitano
The mixed results from recent vaccine clinical trials targeting HIV-1 justify the need to enhance the potency of HIV-1 vaccine platforms in general. Use of first-generation recombinant adenovirus serotype 5 (rAd5) platforms failed to protect vaccinees from HIV-1 infection. One hypothesis is that the rAd5-based vaccine failed due to the presence of pre-existing Ad5 immunity in many vaccines. We recently confirmed that EAT-2-expressing rAd5 vectors uniquely activate the innate immune system and improve cellular immune responses against rAd5-expressed Ags, inclusive of HIV/Gag...
August 1, 2012: Journal of Immunology: Official Journal of the American Association of Immunologists
https://www.readbyqxmd.com/read/22720732/immunogenicity-when-utilizing-adenovirus-serotype-4-and-5-vaccines-expressing-circumsporozoite-protein-in-na%C3%A3-ve-and-adenovirus-ad5-immune-mice
#18
Nathaniel J Schuldt, Yasser A Aldhamen, Sarah Godbehere-Roosa, Sergey S Seregin, Youssef A Kousa, Andrea Amalfitano
BACKGROUND: Induction of potent long lasting effector T cell responses against liver stage malaria antigens strongly correlates with protection from malaria. While Adenovirus serotype 5 (Ad5) based malaria vaccine platforms have the ability to induce potent effector T cell responses against transgenes, high rates of pre-existing Ad5 immunity in malaria endemic regions has prompted study of alternative Ad serotype based malaria vaccines as replacements for Ad5 based malaria vaccines. The research described in this article examines the utility of alternative serotype adenovirus serotype 4 (Ad4) expressing a sporozoite surface protein (circumsporozoite protein (CSP)) (Ad4-CSP) to induce immune responses against CSP...
2012: Malaria Journal
https://www.readbyqxmd.com/read/22683663/malaria-vaccines-focus-on-adenovirus-based-vectors
#19
REVIEW
Nathaniel J Schuldt, Andrea Amalfitano
Protection against malaria through vaccination is known to be achievable, as first demonstrated over 30 years ago. Vaccination via repeated bites with Plasmodium falciparum infected and irradiated mosquitoes provided short lived protection from malaria infection to these vaccinees. Though this method still remains the most protective malaria vaccine to date, it is likely impractical for widespread use. However, recent developments in sub-unit malaria vaccine platforms are bridging the gap between high levels of protection and feasibility...
July 27, 2012: Vaccine
https://www.readbyqxmd.com/read/22566830/immune-recognition-of-gene-transfer-vectors-focus-on-adenovirus-as-a-paradigm
#20
Yasser Ali Aldhamen, Sergey S Seregin, Andrea Amalfitano
Recombinant Adenovirus (Ad) based vectors have been utilized extensively as a gene transfer platform in multiple pre-clinical and clinical applications. These applications are numerous, and inclusive of both gene therapy and vaccine based approaches to human or animal diseases. The widespread utilization of these vectors in both animal models, as well as numerous human clinical trials (Ad-based vectors surpass all other gene transfer vectors relative to numbers of patients treated, as well as number of clinical trials overall), has shed light on how this virus vector interacts with both the innate and adaptive immune systems...
2011: Frontiers in Immunology
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