記述言語：英語   掲載種別：研究論文（学術雑誌）  

Oligomannose-coated liposomes (OMLs) comprised of dipalmitoylphosphatidylcholine, cholesterol and Man3-DPPE at a molar ratio of 1:1:0.1 and particle diameters of about 1000 nm can induce liposome-encased antigen-specific strong Th1 immunity. In this study, we evaluated the effect of particle sizes of OMLs on induction of Th1 immune responses in mice. Spleen cells obtained from mice immunized with antigen-encapsulating OMLs with 1000- and 800-nm diameters secreted remarkably high levels of IFN-γ upon in vitro stimulation. In addition, sera of mice that received these OMLs had significantly higher titers of antigen-specific IgG2a than those of IgG1, which are commonly associated with Th1 responses. In contrast, treatment with antigen-encapsulating OMLs with 400- and 200-nm diameters failed to induce IFN-γ secretion from spleen cells, although these OMLs did elicit elevation of antigen-specific IgGs. In addition, the titers of serum antigen-specific IgG2a were the same as those of IgG1 in mice that received 400-nm OMLs. Resident peritoneal mononuclear phagocytes (MNPs) treated with OMLs of diameter ≥ 600 nm secreted IL-12, which is essential for induction of Th1 immune responses, while those treated with OMLs of ≤ 400 nm failed to produce this cytokine. However, 400-nm OMLs did induce enhanced expression of MHC class II and costimulatory molecules on MNPs, similarly to OMLs of ≥ 600 nm. Taken together, these results strongly indicate that OMLs of diameter ≥ 600 nm are required to induce Th1 immune responses against OML-encased antigens, although OMLs of diameter ≤ 400 nm can activate MNPs.

DOI： 10.1016/j.intimp.2021.108068

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記述言語：英語   掲載種別：研究論文（学術雑誌）  

In this study, we assessed the potential of liposomes coated with a neoglycolipid containing α1-3,α1-6-mannotriose residues (Man3-DPPE; Manα1-6(Manα1-3)Manitol-DPPE) for in vitro activation and maturation of human mononuclear phagocytes. In response to treatment with Man3-DPPE-coated liposomes (Man3-OMLs), PMA-stimulated human THP-1 cells showed enhanced expression of CD40, CD80 and HLA-DR and secreted significant levels of IL-12p40. Among various linkages of Man2-DPPE-coated liposomes, only liposomes coated with Manα1-6Manitol-DPPE (α1-6Man2-DPPE) induced these cellular responses similarly to Man3-OML treatment. Liposomes coated with Manα1-6(Manα1-3)Manα1-6(Manα1-3)Manitol-DPPE (Man5-DPPE) failed to activate the cells. These results suggest that an unsubstituted α1-6Man branch bound to a mannitol unit at the reducing end in Man3-DPPE is required for in vitro activation of human mononuclear phagocytes. Man3-OML-induced IL-12p40 production was not inhibited by BAY11-7082, an inhibitor of the MyD88-dependent signaling network, suggesting that TLRs are not involved in activation of human mononuclear phagocytes by Man3-OMLs. Stimulation of inflammatory monocytes or monocyte-derived dendritic cells (moDCs) with Man3-OMLs also induced enhanced expression of co-stimulatory molecules, HLA-DR, and CCR7, and IL-12p40 production from both types of cells. In response to Man3-OML treatment, moDCs but not inflammatory monocytes produced bioactive IL-12p70, which was enhanced by CD40 ligation. Thus, Man3-OMLs can activate naïve human mononuclear phagocytes and lead human moDCs to a fully matured status in vitro to elicit CTLs and a Th1 response without addition of inflammatory cytokines or TLR agonists.

DOI： 10.1007/s10719-019-09870-6

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記述言語：英語   掲載種別：研究論文（学術雑誌）  

Oligomannose-coated liposomes (OMLs), containing entrapped antigens, serve as effective antigen delivery vehicles and as a novel adjuvant to induce antigen-specific cellular immune responses. However, in vitro activation of antigen-presenting cells (APCs) by OMLs has not yet been demonstrated. In this paper, we found that OMLs can deliver the antigens and the stimulatory signals into inflammatory monocytes in vitro, leading to differentiation of the cells to mature APCs. When OMLs were co-cultured with peripheral blood mononuclear cells from C57BL/6 mice in the presence of mouse serum, OMLs were preferentially incorporated into both Ly6Chigh monocytes and Ly6Clow monocytes, which are referred to as murine inflammatory and resident monocytes, respectively. The expression of CD11c, CD80, CD86, CCR7, and MHC class II on the Ly6Chigh monocytes was significantly enhanced during the 24 h after OML uptake, whereas upregulation of these molecules on the Ly6Clow monocytes was limited. In addition, the antigenic peptide of OVA encased in OMLs was presented on MHC class I of only Ly6Chigh monocytes. Furthermore, OVA-encasing OML-ingesting monocytes can activate CD8+ T cells from OT-1 mice, suggesting that antigens encapsulated in OMLs were cross-presented in inflammatory monocytes. Adoptive transfer of the monocytes that engulf OVA-encasing OMLs led to induction of an antigen-specific Th1 immune response in mice. Taken together, mature APCs can be generated from inflammatory monocytes in peripheral blood by ex vivo treatment of the cells with OMLs without any additional stimuli.

DOI： 10.1016/j.intimp.2018.02.013

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記述言語：英語   掲載種別：研究論文（学術雑誌）  

We have previously demonstrated that administration of oligomannose-coated liposomes (OMLs), in which an antigen is encased, induce antigen-specific Th1 immune responses and CTLs. In the present study, we showed that TLR4 signaling is required for the induction of specific immune responses following OML administration. In C3H/HeJ mice, which express a dysfunctional TLR4, the antigen-specific Th1 immune response could not be elicited following intraperitoneal administration of OVA-encased OMLs (OML/OVA). However, OML uptake by peritoneal cells, the subsequent production of IL-12 and the upregulation of co-stimulatory molecules and MHC class II on the cells in response to OML uptake occurred in C3H/HeJ mice to the same extent as in wild type C3H/HeN mice. In addition, peritoneal phagocytic cells from TLR4(-/-) mice that ingest OML/OVA can activate CD4(+) T cells from OT-II mice. On the other hand, the number of OML-ingesting peritoneal cells that migrated into mesenteric lymph nodes in C3H/HeJ mice was significantly less than that in C3H/HeN mice. Therefore, the chemotactic capability of OML-ingesting peritoneal phagocytes to the draining lymph nodes rather than the activation and maturation of the cells in response to OML uptake is impaired by lack of TLR4 signaling, and disorder of the Th1 immune response elicited by OMLs in mice, which lack TLR4 signaling, is due to the impairment of cell migration following OML uptake.

DOI： 10.1016/j.imlet.2016.07.016

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記述言語：英語   掲載種別：研究発表ペーパー・要旨（国際会議）   出版者・発行元：ACADEMIC PRESS LTD- ELSEVIER SCIENCE LTD  

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