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(1) T Helper Cell Subsets in Experimental Lung Allograft Rejection.[TOP]

Pubmed ID :30502290
Publication Date : //
Human lung transplantation has evolved to an established treatment for pulmonary diseases in their end stages; however, the long-term outcome is worse when compared to all other solid transplantable organs. The major reason for this unfavorable outcome is rejection, either in its acute or chronic form, the latter termed as chronic lung allograft dysfunction.

Authors : Yamada Yoshito, Brüstle Karina, Jungraithmayr Wolfgang,

(2) Immunosuppression overcomes insulin- and vector-specific immune responses that limit efficacy of AAV2/8-mediated insulin gene therapy in NOD mice.[TOP]

Pubmed ID :30514969
Publication Date : //
We report the restoration of euglycaemia in chemically induced diabetic C57BL/6 mice and spontaneously diabetic Non Obese Diabetic (NOD) mice by intravenous systemic administration of a single-stranded adeno-associated virus (ssAAV2/8) codon optimised (co) vector encoding furin cleavable human proinsulin under a liver-specific promoter. There were no immunological barriers to efficacy of insulin gene therapy in chemically induced C57BL/6 mice, which enjoyed long-lasting correction of hyperglycaemia after therapy, up to 250 days. Euglycaemia was also restored in spontaneously diabetic NOD mice, although these mice required a 7-10-fold higher dose of vector to achieve similar efficacy as the C57BL/6 mice and the immunodeficient NOD mice. We detected CD8 T cell reactivity to insulin and mild inflammatory infiltration in the livers of gene therapy recipient NOD mice, neither of which were observed in the treated C57BL/6 mice. Efficacy of the gene therapy in NOD mice was partially improved by targeting the immune system with anti-CD4 antibody treatment, while transfer of NOD mouse AAV2/8-reactive serum to recipients prevented successful restoration of euglycaemia in AAV2/8-HLP-hINSco-treated NOD mice. Our data indicate that both immune cells and antibodies form a barrier to successful restoration of euglycaemia in autoimmune diabetic recipient mice with insulin gene therapy, but that this barrier can be overcome by increasing the dose of vector and by suppressing immune responses.

Authors : Recino Asha, Gan Shu Uin, Sia Kian Chuan, Sawyer Yvonne, Trendell Jenny, Kay Richard, Gribble Fiona M, Reimann Frank, Foale Rob, Notaridou Maria, Holmes Nick, Lever Andrew, Lee Kok Onn, Nathwani Amit, Cooke Anne, Calne Roy, Wallberg Maja,

(3) Limited Foxp3 Regulatory T Cells Response During Acute Infection Is Required to Allow the Emergence of Robust Parasite-Specific CD8 T Cell Immunity.[TOP]

Pubmed ID :30455700
Publication Date : //
While it is now acknowledged that CD4 T cells expressing CD25 and Foxp3 (Treg cells) regulate immune responses and, consequently, influence the pathogenesis of infectious diseases, the regulatory response mediated by Treg cells upon infection by was still poorly characterized. In order to understand the role of Treg cells during infection by this protozoan parasite, we determined in time and space the magnitude of the regulatory response and the phenotypic, functional and transcriptional features of the Treg cell population in infected mice. Contrary to the accumulation of Treg cells reported in most chronic infections in mice and humans, experimental infection was characterized by sustained numbers but decreased relative frequency of Treg cells. The reduction in Treg cell frequency resulted from a massive accumulation of effector immune cells, and inversely correlated with the magnitude of the effector immune response as well as with emergence of acute immunopathology. In order to understand the causes underlying the marked reduction in Treg cell frequency, we evaluated the dynamics of the Treg cell population and found a low proliferation rate and limited accrual of peripheral Treg cells during infection. We also observed that Treg cells became activated and acquired a phenotypic and transcriptional profile consistent with suppression of type 1 inflammatory responses. To assess the biological relevance of the relative reduction in Treg cells frequency observed during infection, we transferred differentiated Treg cells at early moments, when the deregulation of the ratio between regulatory and conventional T cells becomes significant. Intravenous injection of Treg cells dampened parasite-specific CD8 T cell immunity and affected parasite control in blood and tissues. Altogether, our results show that limited Treg cell response during the acute phase of infection enables the emergence of protective anti-parasite CD8 T cell immunity and critically influences host resistance.

Authors : Araujo Furlan Cintia L, Tosello Boari Jimena, Rodriguez Constanza, Canale Fernando P, Fiocca Vernengo Facundo, Boccardo Santiago, Beccaria Cristian G, Adoue Véronique, Joffre Olivier, Gruppi Adriana, Montes Carolina L, Acosta Rodriguez Eva V,

(4) PD-1 blockade augments humoral immunity through ICOS-mediated CD4 T cell instruction.[TOP]

Pubmed ID :30448635
Publication Date : //
Successful applications of PD-1/PD-L1 blockade in multiple cancers highlight the efficacy of immunotherapy mediated by enhancing CD8 T cell immunity both in mouse and human. How PD-1 blockade affects humoral immunity remains unclear. Herein we demonstrated that treatment of anti-PD-1 antibody led to the increase in both total IgG and OVA-specific IgG in OVA-immunized mice. However, no effect was observed on Ab affinity maturation. Accumulation of germinal center (GC) and memory B cells was observed in the spleens together with elevated percentages of plasma cells in the spleens and bone marrow. More interestingly, dramatic infiltration of CD4 T cells was apparent in GCs after PD-1 blockade with a significant increase in the expression of ICOS. When CD4 T cells and B cells from OVA-immunized mice were co-cultured with neutralizing anti-PD-1 Ab in vitro, PD-1 blockade recapitulated the up-regulation of ICOS expression on CD4 T cells with the activation of ERK signaling. Suppression of ERK activation not only reduced ICOS expression on CD4 T cells but also attenuated IgG production upon PD-1 blockade. Taken together, PD-1 blockade enhances humoral immunity. This process partially relies on more accumulation of CD4 T cells in GCs with the up-regulation of ICOS expression and the promotion of B cell terminal differentiation. The regulatory pattern of PD-1 blockade illustrated here provides a new mechanism of how immune checkpoint molecules regulating humoral immune responses.

Authors : Zhang Meiyu, Xia Liliang, Yang Yi, Liu Shuai, Ji Ping, Wang Shujun, Chen Yingying, Liu Zhiduo, Zhang Yanyun, Lu Shun, Wang Ying,

(5) A nanoparticle-incorporated STING activator enhances antitumor immunity in PD-L1-insensitive models of triple-negative breast cancer.[TOP]

Pubmed ID :30429378
Publication Date : //
Triple-negative breast cancer (TNBC) has few therapeutic options, and alternative approaches are urgently needed. Stimulator of IFN genes (STING) is becoming an exciting target for therapeutic adjuvants. However, STING resides inside the cell, and the intracellular delivery of CDNs, such as cGAMP, is required for the optimal activation of STING. We show that liposomal nanoparticle-delivered cGAMP (cGAMP-NP) activates STING more effectively than soluble cGAMP. These particles induce innate and adaptive host immune responses to preexisting tumors in both orthotopic and genetically engineered models of basal-like TNBC. cGAMP-NPs also reduce melanoma tumor load, with limited responsivity to anti-PD-L1. Within the tumor microenvironment, cGAMP-NPs direct both mouse and human macrophages (M), reprograming from protumorigenic M2-like phenotype toward M1-like phenotype; enhance MHC and costimulatory molecule expression; reduce M2 biomarkers; increase IFN-γ-producing T cells; augment tumor apoptosis; and increase CD4+ and CD8+ T cell infiltration. Activated T cells are required for tumor suppression, as their depletion reduces antitumor activity. Importantly, cGAMP-NPs prevent the formation of secondary tumors, and a single dose is sufficient to inhibit TNBC. These data suggest that a minimal system comprised of cGAMP-NP alone is sufficient to modulate the tumor microenvironment to effectively control PD-L1-insensitive TNBC.

Authors : Cheng Ning, Watkins-Schulz Rebekah, Junkins Robert D, David Clément N, Johnson Brandon M, Montgomery Stephanie A, Peine Kevin J, Darr David B, Yuan Hong, McKinnon Karen P, Liu Qi, Miao Lei, Huang Leaf, Bachelder Eric M, Ainslie Kristy M, Ting Jenny P-Y,

(6) Enterovirus-A71 Infection Activates Human Immune Responses and Induces Pathological Changes in Humanized Mice.[TOP]

Pubmed ID :30429352
Publication Date : //
Since the discovery of enterovirus-A71 (EV-A71) half a century ago, it has caused large-scale outbreaks of hand-foot-and-mouth disease worldwide, in particular in the Asia-Pacific region, causing a great concern of public health and economic burden. Detailed mechanisms on the modulation of immune responses after EV-A71 infection have not been fully known, and the lack of appropriate models hinders the development of promising vaccines and drugs. In the present study, NOD- (NSG) mice with human immune system (humanized mice) at the age of four-week-old were found to be susceptible to a human isolate of EV-A71 infection. After infection, humanized mice displayed limb weakness, which is similar to the clinical features found in some of the EV-A71-infected patients. Histopathological examination indicated the presence of vacuolation, gliosis or meningomyelitis in brain stem and spinal cord, which were accompanied by high viral loads detected in these organs. The numbers of activated human CD4 and CD8 T cells were upregulated after EV-A71 infection and EV-A71-specific human T cell responses were found. Furthermore, the secretion of several proinflammatory cytokines, such as human IFN-γ, IL-8 and IL-17A was elevated in the EV-A71-infected humanized mice. Taken together, our results suggested that the humanized mouse model permits insights into the human immune responses and the pathogenesis of EV-A71 infection, which may provide a platform for the evaluation of anti-EV-A71 drug candidates in the future. Despite causing self-limited hand-food-and-mouth disease in younger children, EV-A71 is consistently associated with severe forms of neurological complications and pulmonary edema. Nevertheless, only limited vaccines and drugs have been developed over the years, which is possibly due to a lack of models that can more accurately recapitulate human specificity, since human is the only natural host for wild type EV-A71 infection. Our humanized mouse model did not only mimic histological symptoms in patients, but also allows us to investigate the function of human immune system during the infection. It was found that human T cell responses were activated, accompanied by an increase in the production of proinflammatory cytokines in EV-A71-infected humanized mice, which might contribute to the exacerbation of disease pathogenesis. Collectively, this model allows us to delineate the modulation of human immune responses during EV-A71 infection and may provide a platform to evaluate anti-EV-A71 drug candidates in the future.

Authors : Ke Yanyan, Liu Wai Nam, Her Zhisheng, Liu Min, Tan Sue Yee, Tan Yong Wah, Chan Xue Ying, Fan Yong, Huang Edwin Kunxiang, Chen Huiyi, Chang Kenneth Tou En, Chan Jerry Kok Yen, Hann Chu Justin Jang, Chen Qingfeng,

(7) Vaccination With a FAT1-Derived B Cell Epitope Combined With Tumor-Specific B and T Cell Epitopes Elicits Additive Protection in Cancer Mouse Models.[TOP]

Pubmed ID :30416985
Publication Date : //
Human FAT1 is overexpressed on the surface of most colorectal cancers (CRCs) and in particular a 25 amino acid sequence (D8) present in one of the 34 cadherin extracellular repeats carries the epitope recognized by mAb198.3, a monoclonal antibody which partially protects mice from the challenge with human CRC cell lines in xenograft mouse models. Here we present data in immune competent mice demonstrating the potential of the D8-FAT1 epitope as CRC cancer vaccine. We first demonstrated that the mouse homolog of D8-FAT1 (mD8-FAT1) is also expressed on the surface of CT26 and B16F10 murine cell lines. We then engineered bacterial outer membranes vesicles (OMVs) with mD8-FAT1 and we showed that immunization of BALB/c and C57bl6 mice with engineered OMVs elicited anti-mD8-FAT1 antibodies and partially protected mice from the challenge against CT26 and EGFRvIII-B16F10 cell lines, respectively. We also show that when combined with OMVs decorated with the EGFRvIII B cell epitope or with OMVs carrying five tumor-specific CD4+ T cells neoepitopes, mD8-FAT1 OMVs conferred robust protection against tumor challenge in C57bl6 and BALB/c mice, respectively. Considering that FAT1 is overexpressed in both KRAS and KRAS CRCs, these data support the development of anti-CRC cancer vaccines in which the D8-FAT1 epitope is used in combination with other CRC-specific antigens, including mutation-derived neoepitopes.

Authors : Grandi Alberto, Fantappiè Laura, Irene Carmela, Valensin Silvia, Tomasi Michele, Stupia Simone, Corbellari Riccardo, Caproni Elena, Zanella Ilaria, Isaac Samine J, Ganfini Luisa, Frattini Luca, König Enrico, Gagliardi Assunta, Tavarini Simona, Sammicheli Chiara, Parri Matteo, Grandi Guido,

(8) Novel EXO-T vaccine using polyclonal CD4 T cells armed with HER2-specific exosomes for HER2-positive breast cancer.[TOP]

Pubmed ID :30410365
Publication Date : //
Breast cancer is the leading cause of death in women globally. The human epidermal growth factor receptor 2 (HER2)-positive breast cancer is often associated with poor prognosis and high mortality. Even though anti-HER2 monoclonal antibodies have improved the clinical outcome, resistance to the antibody therapy becomes a major obstacle in the treatment of HER2-positive breast cancer patients. Alternative approaches are therefore needed. HER2-specific vaccines have been developed to trigger patient's immune system against HER2-positive breast cancer. This article describes the development of novel HER2-specific exosome (EXO)-T vaccine using polyclonal CD4 T cells armed with HER2-specific dendritic cell-released EXO and demonstrates its therapeutic effect against HER2-positive tumor in double-transgenic HER2/HLA-A2 mice with HER2-specific self-immune tolerance. Therefore, our novel HER2-specific EXO-T vaccines are likely to assist in the treatment of HER2-positive breast cancer patients.

Authors : Li Rong, Chibbar Rajni, Xiang Jim,

(9) The Combination Therapy of Dietary Galacto-Oligosaccharides With Budesonide Reduces Pulmonary Th2 Driving Mediators and Mast Cell Degranulation in a Murine Model of House Dust Mite Induced Asthma.[TOP]

Pubmed ID :30405619
Publication Date : //
Dietary non-digestible galacto-oligosaccharides (GOS) suppress allergic responses in mice sensitized and challenged with house dust mite (HDM). Budesonide is the standard therapy for allergic asthma in humans but is not always completely effective. To compare the efficacy of budesonide or different doses of GOS alone or with a combination therapy of budesonide and GOS on HDM-allergic responses in mice. BALB/c mice were sensitized and challenged with HDM, while fed a control diet or a diet supplemented with 1 or 2.5 w/w% GOS, and either or not oropharyngeally instilled with budesonide. Systemic and local inflammatory markers, such as mucosal mast cell protease-1 (mMCP-1) in serum, pulmonary CCL17, CCL22, and IL-33 concentrations and inflammatory cell influx in the bronchoalveolar lavage fluid (BALF) were determined. Budesonide or GOS alone suppressed the number of eosinophils in the BALF of HDM allergic mice whereas budesonide either or not combined with GOS lowered both eosinophil and lymphocyte numbers in the BALF of HDM-allergic mice. Both 1 w/w% and 2.5 w/w% GOS and/or budesonide suppressed serum mMCP-1 concentrations. However, budesonide nor GOS alone was capable of reducing Th2 driving chemokines CCL17, CCL22 and IL-33 protein levels in supernatants of lung homogenates of HDM allergic mice, whereas the combination therapy did. Moreover, IL-13 concentrations were only significantly suppressed in mice treated with budesonide while fed GOS. A similar tendency was observed for the frequency of GATA3CD4 Th2 and CD4RORγt Th17 cells in the lungs of the allergic mice. Dietary intervention using GOS may be a novel way to further improve the efficacy of anti-inflammatory drug therapy in allergic asthma by lowering Th2 driving mediators and mast cell degranulation.

Authors : Verheijden Kim A T, Braber Saskia, Leusink-Muis Thea, Jeurink Prescilla V, Thijssen Suzan, Kraneveld Aletta D, Garssen Johan, Folkerts Gert, Willemsen Linette E M,

(10) Incubation of Immune Cell Grafts With MAX.16H5 IgG1 Anti-Human CD4 Antibody Prolonged Survival After Hematopoietic Stem Cell Transplantation in a Mouse Model for Fms Like Tyrosine Kinase 3 Positive Acute Myeloid Leukemia.[TOP]

Pubmed ID :30405611
Publication Date : //
Despite the constant development of innovative therapeutic options for hematological malignancies, the gold-standard therapy regimen for curative treatment often includes allogeneic hematopoietic stem cell transplantation (HSCT). The graft-vs.-leukemia effect (GVL) is one of the main therapeutic goals that arises from HSCT. On the other hand, graft-vs.-host disease (GVHD) is still one of the main and most serious complications following allogeneic HSCT. In acute myeloid leukemia (AML), HSCT together with high-dose chemotherapy is used as a treatment option. An aggressive progression of the disease, a decreased response to treatment, and a poor prognosis are connected to internal tandem duplication (ITD) mutations in the Fms like tyrosine kinase 3 (FLT3) gene, which affects around 30% of AML patients. In this study, C3H/HeN mice received an allogeneic graft together with 32D-FLT3 AML cells to induce acute GVHD and GVL. It was examined if pre-incubation of the graft with the anti-human cluster of differentiation (CD) 4 antibody MAX.16H5 IgG prevented the development of GVHD and whether the graft function was impaired. Animals receiving grafts pre-incubated with the antibody together with FLT3 AML cells survived significantly longer than mice receiving untreated grafts. The observed prolonged survival due to MAX.16H5 incubation of immune cell grafts prior to transplantation may allow an extended application of additional targeted strategies in the treatment of AML.

Authors : Hilger Nadja, Mueller Claudia, Stahl Lilly, Mueller Anne M, Zoennchen Bianca, Dluczek Sarah, Halbich Christoph, Wickenhauser Claudia, Gerloff Dennis, Wurm Alexander A, Behre Gerhard, Kretschmer Anna, Fricke Stephan,