231 research outputs found
A Potent CD1d-binding Glycolipid for iNKT-Cell-based Therapy Against Human Breast Cancer
Background/Aim: Invariant natural killer T-cells (iNKT) stimulated by CD1d-binding glycolipids have been shown to exert antitumor effects by a number of studies in a mouse model. Breast cancer is a devastating disease, with different types of breast cancer recurring locally or distant as metastatic/advanced disease following initial treatment. The aim of this study was to examine the tumoricidal effect of a CD1d-binding glycolipid, called 7DW8-5, against a highly invasive human breast cancer cell line both in vitro and in vivo. Materials and Methods: Parental MDA-MB-231 cells and MDA-MB-231 cells transduced with human CD1d were labeled with carboxyfluorescein diacetate succinimidyl ester (CFSE), followed by loading with glycolipids. After co-culturing with human iNKT cells, the cells were permeabilized and stained with Alexa Flour 647-conjugated antibody to active caspase-3, and analyzed using a BD LSR II. For the in vivo tumoricidal effect, MDA-MB-231 cells transduced with human CD1d and luciferase genes were injected into the mammary fat pad of female NOD/SCID/IL2rĪ³null (NSG) mice, followed by the injection of human iNKT cells with or without 7DW8-5, and the levels of luminescence were analyzed with whole-body imaging. Results: Human iNKT cells could kill CD1d-expressing human breast cancer cells in vitro in the presence of 7DW8-5, but not Ī±-GalCer. As for in vivo, the adoptive transfer of human iNKT cells into tumor-challenged NSG mice significantly inhibited the growth of CD1d+ MDA-MB-231 human breast cancer cells in the presence of 7DW8-5. Conclusion: CD1d-binding, glycolipid-based iNKT-cell therapy is suggested as a potent and effective treatment against breast cancer in humans
Superior Protection against Malaria and Melanoma Metastases by a C-glycoside Analogue of the Natural Killer T Cell Ligand Ī±-Galactosylceramide
Ī±-Galactosylceramide (Ī±-GalCer) is a glycolipid that stimulates natural killer T cells to produce both T helper (Th) 1 and Th2 cytokines. This property enables Ī±-GalCer to ameliorate a wide variety of infectious, neoplastic, and autoimmune diseases; however, its effectiveness against any one disease is limited by the opposing activities of the induced Th1 and Th2 cytokines. Here, we report that a synthetic C-glycoside analogue of Ī±-GalCer, Ī±-C-galactosylceramide (Ī±-C-GalCer), acts as natural killer T cell ligand in vivo, and stimulates an enhanced Th1-type response in mice. In two disease models requiring Th1-type responses for control, namely malaria and melanoma metastases, Ī±-C-GalCer exhibited a 1,000-fold more potent antimalaria activity and a 100-fold more potent antimetastatic activity than Ī±-GalCer. Moreover, Ī±-C-GalCer consistently stimulated prolonged production of the Th1 cytokines interferon-Ī³ and interleukin (IL)-12, and decreased production of the Th2 cytokine IL-4 compared with Ī±-GalCer. Finally, Ī±-C-GalCer's enhanced therapeutic activity required the presence of IL-12, which was needed to stimulate natural killer cells for optimal interferon-Ī³ production, but did not affect IL-4. Overall, our results suggest that Ī±-C-GalCer may one day be an excellent therapeutic option for diseases resolved by Th1-type responses
A Multifactorial Mechanism in the Superior Antimalarial Activity of Ī±-C-GalCer
We have previously shown that the C-glycoside analog of Ī±-galactosylceramide (Ī±-GalCer), Ī±-C-GalCer, displays a superior inhibitory activity against the liver stages of the rodent malaria parasite Plasmodium yoelii than its parental glycolipid, Ī±-GalCer. In this study, we demonstrate that NK cells, as well as IL-12, are a key contributor for the superior activity displayed by Ī±-C-GalCer. Surprisingly, the diminished production of Th2 cytokines, including IL-4, by Ī±-C-GalCer has no affect on its superior therapeutic activity relative to Ī±-GalCer. Finally, we show that the in vivo administration of Ī±-C-GalCer induces prolonged maturation of dendritic cells (DCs), as well as an enhanced proliferative response of mouse invariant VĪ±14 (VĪ±14i) NKT cells, both of which may also contribute to some degree to the superior activity of Ī±-C-GalCer in vivo
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A novel mechanism for glycoconjugate vaccine activation of the adaptive immune system
Although glycoconjugate vaccines have provided enormous health benefits globally, they have been less successful in significant high-risk populations. Exploring novel approaches to the enhancement of glycoconjugate effectiveness, we investigated molecular and cellular mechanisms governing the immune response to a prototypical glycoconjugate vaccine. In antigen-presenting cells, a carbohydrate epitope is generated upon endolysosomal processing of group B streptococcal type III polysaccharide coupled to a carrier protein. In conjunction with a carrier protein-derived peptide, this carbohydrate epitope binds to major histocompatibility class II (MHCII) and stimulates carbohydrate-specific CD4+ T-cell clones to produce interleukins 2 and 4ācytokines essential for providing T-cell help to antibody-producing B cells. An archetypical glycoconjugate vaccine constructed to maximize the presentation of carbohydrate epitopes recognized by T cells is 50ā100 times more potent and significantly more protective in an animal model of infection than is a currently used vaccine construct
Synthesis of C6ā²ā²-modified Ī±-C-GalCer analogues as mouse and human iNKT cell agonists
alpha-GalCer analogues that combine known Th1 polarizing C6''-modifications with a C-glycosidic linkage were synthesized. We employed a protecting group strategy that allowed the preparation of both saturated and unsaturated derivatives with variable C6''-substituents. Selected analogues demonstrate promising activity in mice. Interestingly, the introduction of a 6''-O-pyridinylcarbamoyl substituent to alpha-C-GalCer restores its antigenicity in human iNKT cells
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