Browsing by Subject "interleukin 12"
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Item Open Access Inflammasome induction and immunostimulatory effects of CpG-ODN loaded liposomes containing DC-cholesterol(Turkish Society of Immunology, 2013) Bayyurt, B.; Gürsel I.Objectives: This study aims to investigate the effects of cholesterol content and cationic property of liposomes on immune response. Materials and methods: Liposomes containing high amounts of 3β-[N-(N',N'-dimethylaminoethane)-carbamoyl] cholesterol hydrochloride (DC-cholesterol) were prepared and loaded with K- and D-type CpG oligonucleotide (CpG-ODN) via dehydration-rehydration (DRV) method. After splenocytes and peritoneal exudate cells (PECs) primed with lipopolysaccharide (LPS) was incubated either with free or liposomal CpG-ODN counterparts, supernatants were collected and used in cytokine (IFN-g, IL-1γ and IL-1β) ELISA. Additionally, supernatants of PECs primed with LPS and stimulated with liposomes containing different doses of DC-cholesterol were collected and used in IL-1β ELISA assay. Results: Low-dose CpG-ODN loaded liposomal formulations induced higher immune activation than free CpG-ODN at the same dose. While high-dose liposomal CpG-ODN formulations decreased pro-inflammatory cytokine production in splenocytes, they increased the secretion of IL-1β. Inflammasome activation was increased in a dose dependent manner when PECs primed with LPS were incubated with only liposomes. Varying lipid molar ratios of DC-Cholesterol containing liposomes increased IL-1β production based on increasing lipid molar ratio. Conclusion: This study revealed that type and lipid ratio of liposomes may alter the cellular efficacy of the loaded immune-stimulatory agent and may initiate inflammasome activation. © 2014 Turkish Journal of Immunology.Item Open Access Myeloid expression of adenosine a2A receptor suppresses T and NK cell responses in the solid tumor microenvironment(American Association for Cancer Research Inc., 2014) Cekic, C.; Day, Y.-J.; Sag, D.; Linden J.High concentrations of adenosine in tumor microenvironments inhibit antitumor cytotoxic lymphocyte responses. Although T cells express inhibitory adenosine A2A receptors (A2AR) that suppress their activation and inhibit immune killing of tumors, a role for myeloid cell A2ARs in suppressing the immune response to tumors has yet to be investigated. In this study, we show that the growth of transplanted syngeneic B16F10 melanoma or Lewis lung carcinoma cells is slowed in Adora2af/f-LysMCre+/- mice, which selectively lack myeloid A2ARs. Reduced melanoma growth is associated with significant increases in MHCII and IL12 expression in tumor-associated macrophages and with >90% reductions in IL10 expression in tumor-associated macrophages, dendritic cells (DC), and Ly6C+ or Ly6G+ myeloid-derived suppressor cells (MDSC). Myeloid deletion of A2ARs significantly increases CD44 expression on tumor-associated T cells and natural killer (NK) cells. Depletion of CD8+ T cells or NK cells in tumor-bearing mice indicates that both cell types initially contribute to slowing melanoma growth in mice lacking myeloid A2A receptors, but tumor suppression mediated by CD8+ T cells is more persistent. Myeloid-selective A2AR deletion significantly reduces lung metastasis of melanomas that express luciferase (for in vivo tracking) and ovalbumin (as a model antigen). Reduced metastasis is associated with increased numbers and activation of NK cells and antigen-specific CD8+ T cells in lung in filtrates. Overall, the findings indicate that myeloid cell A2ARs have direct myelosuppressive effects that indirectly contribute to the suppression of T cells and NK cells in primary and metastatic tumor microenvironments. The results indicate that tumor-associated myeloid cells, including macrophages, DCs, and MDSCs all express immunosuppressive A2ARs that are potential targets of adenosine receptor blockers to enhance immune killing of tumors. ©2014 AACR.