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MOUSE ANTI HUMAN CD4

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[#ABS10421] MOUSE ANTI HUMAN CD4

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(1) , A Human Gut Commensal, Is as Potent as COPAXONE® in an Animal Model of Multiple Sclerosis.[TOP]

Pubmed ID :30984162
Publication Date : //
Multiple sclerosis (MS) is a demyelinating disease of the central nervous system. We and others have shown that there is enrichment or depletion of some gut bacteria in MS patients compared to healthy controls (HC), suggesting an important role of the gut bacteria in disease pathogenesis. Thus, specific gut bacteria that are lower in abundance in MS patients could be used as a potential treatment option for this disease. In particular, we and others have shown that MS patients have a lower abundance of compared to HC, whereas the abundance of is increased in patients that receive disease-modifying therapies such as Copaxone® (Glatiramer acetate-GA). This inverse correlation between the severity of MS disease and the abundance of suggests its potential for use as a therapeutic option to treat MS. Notably we have previously identified a specific strain (), that suppresses disease in the animal model of MS, experimental autoimmune encephalomyelitis (EAE) compared with sham treatment. In the present study we analyzed whether the disease suppressing effects of synergize with those of the disease-modifying drug Copaxone® to more effectively suppress disease compared to either treatment alone. Treatment with was as effective in suppressing disease as treatment with Copaxone®, whereas the combination of plus Copaxone® was not more effective than either individual treatment. -treated mice had an increased frequency and number of CD4FoxP3 regulatory T cells in periphery as well as gut and a decreased frequency of pro-inflammatory IFN-γ and IL17-producing CD4 T cells in the CNS, suggesting suppresses disease by boosting anti-inflammatory immune responses and inhibiting pro-inflammatory immune responses. In conclusion, our study indicates that the human gut commensal can suppress disease as efficiently as Copaxone® and may provide an alternative treatment option for MS patients.

Authors : Shahi Shailesh K, Freedman Samantha N, Murra Alexandra C, Zarei Kasra, Sompallae Ramakrishna, Gibson-Corley Katherine N, Karandikar Nitin J, Murray Joseph A, Mangalam Ashutosh K,



(2) Strategies for the Induction of Immune Tolerance to Enzyme Replacement Therapy in Mucopolysaccharidosis Type I.[TOP]

Pubmed ID :30976609
Publication Date : //
Enzyme replacement therapy with laronidase is an established treatment for Mucopolysaccharidosis type I (MPS I), but its efficacy may be limited by the development of anti-drug antibodies, which inhibit cellular uptake of the enzyme. In a related disorder, infantile Pompe disease, immune tolerance induction with low-dose, short-course methotrexate appears to reduce antibody formation. We investigated a similar regimen using oral methotrexate in three MPS I patients. All patients developed anti-laronidase immunoglobulin G (IgG) and immunoglobulin M (IgM) antibodies, and they had clinically relevant levels of cellular uptake inhibition. We then explored several immune tolerance induction strategies in MPS I mice: (1) methotrexate, (2) combination of non-depleting anti-CD4 and anti-CD8 monoclonal antibodies, (3) methotrexate with anti-CD4 and anti-CD8 monoclonals, (4) anti-CD4 monoclonal, and (5) anti-CD8 monoclonal. Treated mice received 10 weekly laronidase injections, and laronidase was delivered with adjuvant on day 49 to further challenge the immune system. Most regimens were only partially effective at reducing antibody responses, but two courses of non-depleting anti-CD4 monoclonal antibody (mAb) ablated immune responses to laronidase in seven of eight MPS I mice (87.5%), even after adjuvant stimulation. Immune tolerance induction with methotrexate does not appear to be effective in MPS I patients, but use of non-depleting anti-CD4 monoclonal is a promising strategy.

Authors : Ghosh Arunabha, Liao Aiyin, O'Leary Claire, Mercer Jean, Tylee Karen, Goenka Anu, Holley Rebecca, Jones Simon A, Bigger Brian W,



(3) CD28 Signaling Controls Metabolic Fitness of Pathogenic T Cells in Medium and Large Vessel Vasculitis.[TOP]

Pubmed ID :30975299
Publication Date : //
In giant cell arteritis, vessel-wall infiltrating CD4 T cells and macrophages form tissue-destructive granulomatous infiltrates, and the artery responds with a maladaptive response to injury, leading to intramural neoangiogenesis, intimal hyperplasia, and luminal occlusion. Lesion-residing T cells receive local signals, which represent potential therapeutic targets.

Authors : Zhang Hui, Watanabe Ryu, Berry Gerald J, Nadler Steven G, Goronzy Jörg J, Weyand Cornelia M,



(4) Cryptotanshinone has curative dual anti-proliferative and immunotherapeutic effects on mouse Lewis lung carcinoma.[TOP]

Pubmed ID :30972427
Publication Date : //
Lung cancer is currently the leading cause of cancer-related mortality with very limited effective therapy. Screening of a variety of traditional Chinese medicines (TCMs) for their capacity to inhibit the proliferation of human lung cancer A549 cells and to induce the in vitro maturation of human DCs led to the identification of cryptotanshinone (CT), a compound purified from the TCM Salvia miltiorrhiza Bunge. Here, CT was shown to inhibit the proliferation of mouse Lewis lung carcinoma (LLC) cells by upregulating p53, downregulating cyclin B1 and Cdc2, and, consequently, inducing G2/M cell-cycle arrest of LLC cells. In addition, CT promoted maturation of mouse and human DCs with upregulation of costimulatory and MHC molecules and stimulated DCs to produce TNFα, IL-1β, and IL-12p70, but not IL-10 in vitro. CT-induced maturation of DCs depended on MyD88 and also involved the activation of NF-κB, p38, and JNK. CT was effective in the treatment of LLC tumors and, when used in combination with low doses of anti-PD-L1, cured LLC-bearing mice with the induction of subsequent anti-LLC long-term specific immunity. CT treatment promoted T-cell infiltration and elevated the expression of genes typical of Th1 polarization in LLC tumor tissue. The therapeutic effect of CT and low doses of anti-PD-L1 was reduced by depletion of CD4 and CD8 T cells. This paper provides the first report that CT induces immunological antitumor activities and may provide a new promising antitumor immunotherapeutic.

Authors : Liu Shuo, Han Zhen, Trivett Anna L, Lin Hongsheng, Hannifin Sean, Yang De, Oppenheim Joost J,



(5) Effective cancer immunotherapy by natural mouse conventional type-1 dendritic cells bearing dead tumor antigen.[TOP]

Pubmed ID :30961656
Publication Date : //
The manipulation of dendritic cells (DCs) for cancer vaccination has not reached its full potential, despite the revolution in cancer immunotherapy. DCs are fundamental for CD8+ T cell activation, which relies on cross-presentation of exogenous antigen on MHC-I and can be fostered by immunogenic cancer cell death. Translational and clinical research has focused on in vitro-generated monocyte-derived DCs, while the vaccination efficacy of natural conventional type 1 DCs (cDC1s), which are associated with improved anti-tumor immunity and specialize on antigen cross-presentation, remains unknown.

Authors : Wculek Stefanie K, Amores-Iniesta Joaquín, Conde-Garrosa Ruth, Khouili Sofía C, Melero Ignacio, Sancho David,



(6) Unleashing Type-2 Dendritic Cells to Drive Protective Antitumor CD4 T Cell Immunity.[TOP]

Pubmed ID :30955881
Publication Date : //
Differentiation of proinflammatory CD4 conventional T cells (T) is critical for productive antitumor responses yet their elicitation remains poorly understood. We comprehensively characterized myeloid cells in tumor draining lymph nodes (tdLN) of mice and identified two subsets of conventional type-2 dendritic cells (cDC2) that traffic from tumor to tdLN and present tumor-derived antigens to CD4 T, but then fail to support antitumor CD4 T differentiation. Regulatory T cell (T) depletion enhanced their capacity to elicit strong CD4 T responses and ensuing antitumor protection. Analogous cDC2 populations were identified in patients, and as in mice, their abundance relative to T predicts protective ICOS PD-1 CD4 T phenotypes and survival. Further, in melanoma patients with low T abundance, intratumoral cDC2 density alone correlates with abundant CD4 T and with responsiveness to anti-PD-1 therapy. Together, this highlights a pathway that restrains cDC2 and whose reversal enhances CD4 T abundance and controls tumor growth.

Authors : Binnewies Mikhail, Mujal Adriana M, Pollack Joshua L, Combes Alexis J, Hardison Emily A, Barry Kevin C, Tsui Jessica, Ruhland Megan K, Kersten Kelly, Abushawish Marwan A, Spasic Marko, Giurintano Jonathan P, Chan Vincent, Daud Adil I, Ha Patrick, Ye Chun J, Roberts Edward W, Krummel Matthew F,



(7) Human Biofield Therapy and the Growth of Mouse Lung Carcinoma.[TOP]

Pubmed ID :30947564
Publication Date : //
Biofield therapies have gained popularity and are being explored as possible treatments for cancer. In some cases, devices have been developed that mimic the electromagnetic fields that are emitted from people delivering biofield therapies. However, there is limited research examining if humans could potentially inhibit the proliferation of cancer cells and suppress tumor growth through modification of inflammation and the immune system. We found that human NSCLC A549 lung cancer cells exposed to Sean L. Harribance, a purported healer, showed reduced viability and downregulation of pAkt. We further observed that the experimental exposure slowed growth of mouse Lewis lung carcinoma evidenced by significantly smaller tumor volume in the experimental mice (274.3 ± 188.9 mm) than that of control mice (740.5 ± 460.2 mm; P < .05). Exposure to the experimental condition markedly reduced tumoral expression of pS6, a cytosolic marker of cell proliferation, by 45% compared with that of the control group. Results of reversed phase proteomic array suggested that the experimental exposure downregulated the PD-L1 expression in the tumor tissues. Similarly, the serum levels of cytokines, especially MCP-1, were significantly reduced in the experimental group ( P < .05). Furthermore, TILs profiling showed that CD8/CD4 immune cell population was increased by almost 2-fold in the experimental condition whereas the number of intratumoral CD25/CD4 (T-reg cells) and CD68 macrophages were 84% and 33%, respectively, lower than that of the control group. Together, these findings suggest that exposure to purported biofields from a human is capable of suppressing tumor growth, which might be in part mediated through modification of the tumor microenvironment, immune function, and anti-inflammatory activity in our mouse lung tumor model.

Authors : Yang Peiying, Jiang Yan, Rhea Patrea R, Coway Tara, Chen Dongmei, Gagea Mihai, Harribance Sean L, Cohen Lorenzo,



(8) Lactobacillus fermentum species ameliorate dextran sulfate sodium-induced colitis by regulating the immune response and altering gut microbiota.[TOP]

Pubmed ID :30939976
Publication Date : //
We evaluated immunometabolic functions of novel Lactobacillus fermentum strains (KBL374 and KBL375) isolated from feces of healthy Koreans. The levels of inflammatory cytokines, such as interleukin (IL)-2, interferon-γ, IL-4, IL-13, and IL-17A, were decreased, and that of the anti-inflammatory cytokine IL-10 was increased, in human peripheral blood mononuclear cells (PBMCs) treated with the L. fermentum KBL374 or KBL375 strain. When these strains were orally administered to mice with dextran sulfate sodium (DSS)-induced colitis, both L. fermentum KBL374 and KBL375 showed beneficial effects on body weight, disease activity index score, colon length, cecal weight, and histological scores. Furthermore, both L. fermentum KBL374 and KBL375 modulated the innate immune response by improving gut barrier function and reducing leukocyte infiltration. Consistent with the PBMC data, both L. fermentum KBL374- and KBL375-treated DSS mice demonstrated decreased Th1-, Th2-, and Th17-related cytokine levels and increased IL-10 in the colon compared with the DSS control mice. Administration of L. fermentum KBL374 or KBL375 to mice increased the CD4+CD25+Foxp3+Treg cell population in mesenteric lymph nodes. Additionally, L. fermentum KBL374 or KBL375 administration reshaped and increased the diversity of the gut microbiota. In particular, L. fermentum KBL375 increased the abundance of beneficial microorganisms, such as Lactobacillus spp. and Akkermansia spp. Both L. fermentum KBL374 and KBL375 may alleviate inflammatory diseases, such as inflammatory bowel disease, in the gut by regulating immune responses and altering the composition of gut microbiota.

Authors : Jang You Jin, Kim Woon-Ki, Han Dae Hee, Lee Kiuk, Ko Gwangpyo,



(9) Efficacy and safety assessment of a TRAF6-targeted nanoimmunotherapy in atherosclerotic mice and non-human primates.[TOP]

Pubmed ID :30936448
Publication Date : //
Macrophage accumulation in atherosclerosis is directly linked to the destabilization and rupture of plaque, causing acute atherothrombotic events. Circulating monocytes enter the plaque and differentiate into macrophages, where they are activated by CD4 T lymphocytes through CD40-CD40 ligand signalling. Here, we report the development and multiparametric evaluation of a nanoimmunotherapy that moderates CD40-CD40 ligand signalling in monocytes and macrophages by blocking the interaction between CD40 and tumour necrosis factor receptor-associated factor 6 (TRAF6). We evaluated the biodistribution characteristics of the nanoimmunotherapy in apolipoprotein E-deficient (Apoe) mice and in non-human primates by in vivo positron-emission tomography imaging. In Apoe mice, a 1-week nanoimmunotherapy treatment regimen achieved significant anti-inflammatory effects, which was due to the impaired migration capacity of monocytes, as established by a transcriptome analysis. The rapid reduction of plaque inflammation by the TRAF6-targeted nanoimmunotherapy and its favourable toxicity profiles in both mice and non-human primates highlights the translational potential of this strategy for the treatment of atherosclerosis.

Authors : Lameijer Marnix, Binderup Tina, van Leent Mandy M T, Senders Max L, Fay Francois, Malkus Joost, Sanchez-Gaytan Brenda L, Teunissen Abraham J P, Karakatsanis Nicolas, Robson Philip, Zhou Xianxiao, Ye Yuxiang, Wojtkiewicz Gregory, Tang Jun, Seijkens Tom T P, Kroon Jeffrey, Stroes Erik S G, Kjaer Andreas, Ochando Jordi, Reiner Thomas, Pérez-Medina Carlos, Calcagno Claudia, Fisher Edward A, Zhang Bin, Temel Ryan E, Swirski Filip K, Nahrendorf Matthias, Fayad Zahi A, Lutgens Esther, Mulder Willem J M, Duivenvoorden Raphaël,



(10) Efficient Therapeutic Function and Mechanisms of Human Polyclonal CD8CD103Foxp3 Regulatory T Cells on Collagen-Induced Arthritis in Mice.[TOP]

Pubmed ID :30915372
Publication Date : //
To investigate the potential therapeutic effect in a rheumatoid arthritis model of stable human CD8 regulatory T cells (hCD8Tregs) induced by TGF-1 and rapamycin (RAPA) .

Authors : Sun Juan, Yang Yiming, Huo Xiaona, Zhu Beibei, Li Zhenhua, Jiang Xueyu, Xie Rufeng, Gao Li, Sun Ying, Fan Huahua, Zhu Yongming, Yang Jie,