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(1) CD1b-autoreactive T cells contribute to hyperlipidemia-induced skin inflammation in mice.[TOP]

Pubmed ID :28463230
Publication Date : //
A large proportion of human T cells are autoreactive to group 1 CD1 proteins, which include CD1a, CD1b, and CD1c. However, the physiological role of the CD1 proteins remains poorly defined. Here, we have generated a double-transgenic mouse model that expresses human CD1b and CD1c molecules (hCD1Tg) as well as a CD1b-autoreactive TCR (HJ1Tg) in the ApoE-deficient background (hCD1Tg HJ1Tg Apoe-/- mice) to determine the role of CD1-autoreactive T cells in hyperlipidemia-associated inflammatory diseases. We found that hCD1Tg HJ1Tg Apoe-/- mice spontaneously developed psoriasiform skin inflammation characterized by T cell and neutrophil infiltration and a Th17-biased cytokine response. Anti-IL-17A treatment ameliorated skin inflammation in vivo. Additionally, phospholipids and cholesterol preferentially accumulated in diseased skin and these autoantigens directly activated CD1b-autoreactive HJ1 T cells. Furthermore, hyperlipidemic serum enhanced IL-6 secretion by CD1b+ DCs and increased IL-17A production by HJ1 T cells. In psoriatic patients, the frequency of CD1b-autoreactive T cells was increased compared with that in healthy controls. Thus, this study has demonstrated the pathogenic role of CD1b-autoreactive T cells under hyperlipidemic conditions in a mouse model of spontaneous skin inflammation. As a large proportion of psoriatic patients are dyslipidemic, this finding is of clinical significance and indicates that self-lipid-reactive T cells might serve as a possible link between hyperlipidemia and psoriasis.

Authors : Bagchi Sreya, He Ying, Zhang Hong, Cao Liang, Van Rhijn Ildiko, Moody D Branch, Gudjonsson Johann E, Wang Chyung-Ru,

(2) BNN-20, a synthetic microneurotrophin, strongly protects dopaminergic neurons in the "weaver" mouse, a genetic model of dopamine-denervation, acting through the TrkB neurotrophin receptor.[TOP]

Pubmed ID :28461162
Publication Date : //
Neurotrophic factors are among the most promising treatments aiming at slowing or stopping and even reversing Parkinson's disease (PD). However, in most cases, they cannot readily cross the human blood-brain-barrier (BBB). Herein, we propose as a therapeutic for PD the small molecule 17-beta-spiro-[5-androsten-17,2'-oxiran]-3beta-ol (BNN-20), a synthetic analogue of DHEA, which crosses the BBB and is deprived of endocrine side-effects. Using the "weaver" mouse, a genetic model of PD, which exhibits progressive dopaminergic neurodegeneration in the Substantia Nigra (SN), we have shown that long-term administration (P1-P21) of BNN-20 almost fully protected the dopaminergic neurons and their terminals, via i) a strong anti-apoptotic effect, probably mediated through the Tropomyosin receptor kinase B (TrkB) neurotrophin receptor's PI3K-Akt-NF-κB signaling pathway, ii) by exerting an efficient antioxidant effect, iii) by inducing significant anti-inflammatory activity and iv) by restoring Brain-Derived Neurotrophic Factor (BDNF) levels. By intercrossing "weaver" with NGL mice (dual GFP/luciferase-NF-κΒ reporter mice, NF-κΒ.GFP.Luc), we obtained Weaver/NGL mice that express the NF-κB reporter in all somatic cells. Acute BNN-20 administration to Weaver/NGL mice induced a strong NF-κB-dependent transcriptional response in the brain as detected by bioluminescence imaging, which was abolished by co-administration of the TrkB inhibitor ANA-12. This indicates that BNN-20 exerts its beneficial action (at least in part) through the TrkB-PI3K-Akt-NF-κB signaling pathway. These results could be of clinical relevance, as they suggest BNN-20 as an important neuroprotective agent acting through the TrkB neurotrophin receptor pathway, mimicking the action of the endogenous neurotrophin BDNF. Thus BNN-20 could be proposed for treatment of PD.

Authors : Botsakis Konstantinos, Mourtzi Theodora, Panagiotakopoulou Vasiliki, Vreka Malamati, Stathopoulos Georgios T, Pediaditakis Iosif, Charalampopoulos Ioannis, Gravanis Achilleas, Delis Foteini, Antoniou Katerina, Zisimopoulos Dimitrios, Georgiou Christos D, Panagopoulos Nikolaos T, Matsokis Nikolaos, Angelatou Fevronia,

(3) Expression patterns of bovine CD1 in vivo and assessment of the specificities of the anti-bovine CD1 antibodies.[TOP]

Pubmed ID :25815476
Publication Date : //
Research addressing the in vivo effects of T cell activation by lipids, glycolipids, and lipopeptides is hampered by the absence of a suitable animal model. Mice and rats do not express CD1a, CD1b, and CD1c molecules that present pathogen-derived lipid antigens in humans. In cattle, two CD1A and three CD1B genes are transcribed. The proteins encoded by these genes differ in their antigen binding domains and in their cytoplasmic tails, suggesting that they may traffic differently in the cell and thus have access to different antigens. In the current study, we describe the genomic organization of the bovine CD1 locus and transcription of bovine CD1 genes in freshly isolated dendritic cells and B cells from different tissues. After determining the specificity of previously only partly characterized anti-CD1 antibodies by testing recombinant single chain bovine CD1 proteins and CD1-transfected cells, we were able to determine cell surface protein expression on freshly isolated cells. Our study suggests that CD1b1 and CD1b3 are more broadly expressed than CD1b5, and CD1a2 is more broadly expressed than CD1a1. Pseudoafferent lymph dendritic cells express CD1B genes, but no transcription is detected in lymph nodes. Even though B cells transcribe CD1B genes, there is no evidence of protein expression at the cell surface. Thus, patterns of CD1 protein expression are largely conserved among species.

Authors : Nguyen Thi Kim Anh, Reinink Peter, El Messlaki Chema, Im Jin S, Ercan Altan, Porcelli Steven A, Van Rhijn Ildiko,

(4) Serotonin skews human macrophage polarization through HTR2B and HTR7.[TOP]

Pubmed ID :23355731
Publication Date : //
Besides its role as a neurotransmitter, serotonin (5-hydroxytryptamine, 5HT) regulates inflammation and tissue repair via a set of receptors (5HT(1-7)) whose pattern of expression varies among cell lineages. Considering the importance of macrophage polarization plasticity for inflammatory responses and tissue repair, we evaluated whether 5HT modulates human macrophage polarization. 5HT inhibited the LPS-induced release of proinflammatory cytokines without affecting IL-10 production, upregulated the expression of M2 polarization-associated genes (SERPINB2, THBS1, STAB1, COL23A1), and reduced the expression of M1-associated genes (INHBA, CCR2, MMP12, SERPINE1, CD1B, ALDH1A2). Whereas only 5HT(7) mediated the inhibitory action of 5HT on the release of proinflammatory cytokines, both 5HT(2B) and 5HT(7) receptors mediated the pro-M2 skewing effect of 5HT. In fact, blockade of both receptors during in vitro monocyte-to-macrophage differentiation preferentially modulated the acquisition of M2 polarization markers. 5HT(2B) was found to be preferentially expressed by anti-inflammatory M2(M-CSF) macrophages and was detected in vivo in liver Kupffer cells and in tumor-associated macrophages. Therefore, 5HT modulates macrophage polarization and contributes to the maintenance of an anti-inflammatory state via 5HT(2B) and 5HT(7), whose identification as functionally relevant markers for anti-inflammatory/homeostatic human M2 macrophages suggests their potential therapeutic value in inflammatory pathologies.

Authors : de las Casas-Engel Mateo, Domínguez-Soto Angeles, Sierra-Filardi Elena, Bragado Rafael, Nieto Concha, Puig-Kroger Amaya, Samaniego Rafael, Loza Mabel, Corcuera María Teresa, Gómez-Aguado Fernando, Bustos Matilde, Sánchez-Mateos Paloma, Corbí Angel L,

(5) Autoreactive CD1b-restricted T cells: a new innate-like T-cell population that contributes to immunity against infection.[TOP]

Pubmed ID :21860021
Publication Date : //
Group 1 CD1 (CD1a, -b, and -c) presents self and foreign lipid antigens to multiple T-cell subsets in humans. However, in the absence of a suitable animal model, the specific functions and developmental requirements of these T cells remain unknown. To study group 1 CD1-restricted T cells in vivo, we generated double transgenic mice (HJ1Tg/hCD1Tg) that express group 1 CD1 molecules in a similar pattern to that observed in humans (hCD1Tg) as well as a TCR derived from a CD1b-autoreactive T-cell line (HJ1Tg). Using this model, we found that similar to CD1d-restricted NKT cells, HJ1 T cells exhibit an activated phenotype (CD44(hi)CD69(+)CD122(+)) and a subset of HJ1 T cells expresses NK1.1 and is selected by CD1b-expressing hematopoietic cells. HJ1 T cells secrete proinflammatory cytokines in response to stimulation with CD1b-expressing dendritic cells derived from humans as well as hCD1Tg mice, suggesting that they recognize species conserved self-lipid antigen(s). Importantly, this basal autoreactivity is enhanced by TLR-mediated signaling and HJ1 T cells can be activated and confer protection against Listeria infection. Taken together, our data indicate that CD1b-autoreactive T cells, unlike mycobacterial lipid antigen-specific T cells, are innate-like T cells that may contribute to early anti-microbial host defense.

Authors : Li Sha, Choi Hak-Jong, Felio Kyrie, Wang Chyung-Ru,

(6) Cutting edge: Guillain-Barre syndrome-associated IgG responses to gangliosides are generated independently of CD1 function in mice.[TOP]

Pubmed ID :18097001
Publication Date : //
CD1 molecules present a variety of microbial glycolipids and self-glycolipids to T cells, but their potential role in humoral responses to glycolipid Ags remains to be established. To address this issue directly, we used GM1/GD1a-deficient mice, which, upon immunization with heat-killed Campylobacter jejuni, develop Guillain-Barré syndrome-associated IgG Abs against the GM1/GD1a sugar chain epitopes of bacterial lipo-oligosaccharides (LOS). Our results showed that anti-ganglioside Abs of the IgG1, IgG2b, and IgG3 isotypes were produced in the absence of group 2 CD1 (CD1d) expression. Unlike mouse and human group 2 CD1 molecules that specifically bound LOS, none of the group 1 CD1 molecules (CD1a, CD1b, and CD1c in humans) were capable of interacting with LOS. Thus, these results indicate CD1-independent pathways for anti-ganglioside Ab production.

Authors : Matsumoto Yukie, Yuki Nobuhiro, Van Kaer Luc, Furukawa Koichi, Hirata Koichi, Sugita Masahiko,

(7) CD1 expression and CD1-restricted T cell activity in normal and tumour-bearing human liver.[TOP]

Pubmed ID :16924493
Publication Date : //
CD1d-restricted natural killer T (NKT) cells expressing invariant Valpha14Jalpha18 T cell receptor alpha-chains are abundant in murine liver and are implicated in the control of malignancy, infection and autoimmunity. Invariant NKT cells have potent anti-metastatic effects in mice and phase I clinical trials involving their homologues in humans are ongoing. However, invariant NKT cells are less abundant in human liver ( approximately 0.5% of hepatic T cells) than in murine liver (up to 50%) and it is not known if other hepatic T cells are CD1-restricted. We have examined expression of CD1a, CD1b, CD1c and CD1d mRNA and protein in human liver and evaluated the reactivity of mononuclear cells (MNC) from histologically normal and tumour-bearing human liver specimens against these CD1 isoforms. Messenger RNA for all CD1 isotypes was detectable in all liver samples. CD1c and CD1d were expressed at the protein level by hepatic MNC. CD1d, only, was detectable at the cell surface, but CD1c and CD1d were found at an intracellular location in significant numbers of liver MNC. CD1b was not expressed by MNC from healthy livers but was detectable within MNC in all tumour samples tested. Hepatic T cells exhibited reactivity against C1R cells expressing transfected CD1c and CD1d, but neither CD1a nor CD1b. These cells secreted interferon-gamma (IFN-gamma) but not interleukin-4 (IL-4) upon stimulation. In contrast, similar numbers of peripheral T cells released 13- and 16-fold less IFN-gamma in response to CD1c and CD1d, respectively. CD1c and CD1d expression and T cell reactivity were not altered in tumour-bearing liver specimens compared to histologically normal livers. These data suggest that, in addition to invariant CD1d-restricted NKT cells, autoreactive T cells that recognise CD1c and CD1d and release inflammatory cytokines are abundant in human liver.

Authors : Kenna Tony, O'Brien Margaret, Hogan Andrew E, Exley Mark A, Porcelli Steven A, Hegarty John E, O'Farrelly Cliona, Doherty Derek G,

(8) Tissue distribution, regulation and intracellular localization of murine CD1 molecules.[TOP]

Pubmed ID :9809580
Publication Date : //
CD1 molecules are MHC-unlinked class Ib molecules consisting of classical (human CD 1a-c) and non-classical subsets (human CD1d and murine CD1). The characterization of non-classical subsets of CD1 is limited due to the lack of reagents. In this study, we have generated two new anti-mouse CD1 monoclonal antibodies, 3H3 and 5C6, by immunization of hamsters with purified CD1 protein. These antibodies recognize CD1-transfected cells and have no reactivity to cells isolated from CD1-/- mice. Both antibodies precipitate the 52 kDa heavy chain and 12 kDa beta2m from thymocytes and splenocytes by radio-immunoprecipitation. Deglycosylation of CD1 reduces molecular mass of the heavy chain by 7.5 kDa, which can be detected by 3H3 but not 5C6. 3H3 and 5C6 detect surface CD1 expression on cells from the thymus, spleen, lymph node and bone marrow, but not on intestinal epithelial cells. Developmentally, CD1 is expressed on thymocytes prior to TCR rearrangement and remains constant throughout thymic development. CD1 is expressed early in the fetal liver (day 14) and remains expressed in hepatocytes postnatally. These data support evidence of a role for CD1 in the selection and/or expansion of NK1- T cells of both thymic origin and extrathymic origin. Unlike classical class I molecules, murine CD1 levels are not affected by IFN-gamma, but like human CD1b can be up-regulated by IL-4 and GM-CSF although only moderately. Similar to human CD1b, murine CD1 is found by immunofluorescence microscopy on the cell surface, and in various intracellular vesicles, including early and late endosomes. Localization in endocytic compartments indicates that murine CD1 may be capable of binding endocytosed antigens.

Authors : Mandal M, Chen X R, Alegre M L, Chiu N M, Chen Y H, Castaño A R, Wang C R,

(9) Structural analysis of the rat homologue of CD1. Evidence for evolutionary conservation of the CD1D class and widespread transcription by rat cells.[TOP]

Pubmed ID :7517972
Publication Date : //
The cDNA encoding the rat homologue of CD1 was isolated and the complete nucleotide sequence was determined. It contained an open reading frame of 1008 bp that was capable of encoding a polypeptide with 336 amino acids composed of hydrophobic leader and transmembrane sequences, three extracellular domains, and 5' and 3' untranslated sequences. Comparison of the amino acid sequence of rat CD1 with those of other species revealed that it showed the highest similarity to mouse CD1, which belongs to the CD1D class of the CD1 system and is distinct from the classic CD1 class including CD1a, CD1b, and CD1c expressed primarily on human thymocytes and some dendritic cells. Widespread transcription of rat CD1 was readily detected by Northern blot analysis in nonlymphoid organs, including the liver, kidney, and heart, as well as in lymphoid organs, including the thymus, lymph node, and spleen. Intestinal expression was also demonstrated by the more sensitive reverse transcription-PCR method. Immunoprecipitation with a rabbit anti-rat CD1 Ab showed that rat CD1 was expressed on the cell surface as a beta 2-microglobulin-associated heterodimer. Southern blot analysis of inbred rat strains suggested that rat CD1 shows limited polymorphism and that only one CD1 gene is detectable in the F344 rat genome. These results provide evidence for the conservation of CD1D class through mammalian evolution and an apparent lack of the classic CD1 class genes in rodents. Functional similarity of rodent CD1 is implied.

Authors : Ichimiya S, Kikuchi K, Matsuura A,

(10) A novel antigen of the dermal-epidermal junction defined by an anti-CD1b monoclonal antibody (NU-T2).[TOP]

Pubmed ID :8215581
Publication Date : //
NU-T2 is a mouse monoclonal IgG1 antibody to the CD1b molecule, (cross-)reacting with an antigen of the dermal-epidermal junction (NU-T2 DEJ AG). Further immunohistochemical characterization of the NU-T2 DEJ AG showed it to display unique properties that differentiate it from other known antigens of the dermal-epidermal junction. Indeed, the NU-T2 DEJ AG is primate-specific and present only in epithelial basement membranes. In normal human skin it is expressed within the lowermost lamina lucida of the dermal-epidermal junction but not in the deep part of epidermal appendages nor in the deep part of epidermal appendages nor in the basement membrane of dermal vessels, smooth muscles or nerves. In diseases with intraepidermal or intradermal cleavage, NU-T2 reactivity was observed at the floor of the blister. In various skin specimens with a cleavage through the lamina lucida (NaCl--or dispase-split skin, bullous pemphigoid, junctional epidermolysis bullosa), NU-T2 immunoreactivity seemed reduced, being localized at the dermal side of the cleavage. These results suggest that the antigen recognized by NU-T2 is a novel component of the lamina lucida of the dermal-epidermal junction, that seems to be important for dermal-epidermal adhesion.

Authors : Kanitakis J, Zambruno G, Wang Y Z, Roche P, Berti E, Schmitt D,