Oligomannose-coated liposome as a novel adjuvant for the induction of cellular immune responses to control disease status

Abstract

Professional phagocytic cells, such as dendritic cells, are mainly responsible for phagocytosis, antigen presentation, and cytokine secretion, which induce subsequent activation of T cell-mediated immunity. Thus, strategies that deliver antigens and stimulatory signals to the cells have significant implications for vaccine design. In this paper, we summarize the potential for liposomes coated with the neoglycolipids containing oligomannose residues (OMLs) as a novel adjuvant for induction of Th1 immune responses and CTLs specific for the encased antigen. OMLs preferentially take up peripheral phagocytic cells. In response to OML uptake, the cells secrete IL-12 selectively, enhance the expression of costimulatory molecules, and migrate into lymphoid tissues from peripheral tissues. OMLs also have the ability to deliver encapsulated protein antigens to the MHC class I and class II pathways to generate antigen-specific CTLs and Th1 cells, respectively, and lipid antigen to CD1d to activate NKT cells. Since administration of OML-based vaccines can eliminate an established tumor, inhibit elevation of the serum IgE level, and prevent progression of protozoan infections in several murine, human, and bovine models, OML-based vaccines have revealed their potential for clinical use in vaccination for a variety of diseases in which CTLs and/or Th1 cells act as effector cells.

Figure 1

Representation of an OML. Man3-DPPE was prepared by reductive amination of an aldehyde group at the end of the mannotriose (Man3) with an amino group of DPPE. OMLs are prepared from DPPC, cholesterol, and Man3-DPPE at a molar ratio of 10 : 10 : 1 by intense vortex dispersion with antigen-containing PBS and are extruded through a 1 μm pore membrane.

Figure 2

Uptake of OMLs by peritoneal phagocytic cells. Peritoneal phagocytic cells are classified into CD11b⁺CD11c⁻ (R1) and CD11b⁺CD11c⁺ (R2) cells, which belong to macrophage and dendritic cell lineages based on the cell surface markers, respectively. Both macrophage and DC-like cells effectively took up OMLs, when OMLs were administrated into peritoneal cavity.

Figure 3

Preferential secretion of IL-12 from phagocytic cells. (a) The peritoneal phagocytic cells were collected 1 h after the administration of liposomes into peritoneal cavity and cultured for 18 h. IL-12 and IL-6 secreted into culture media were determined. Note that specific IL-12 production and suppression of IL-6 production were observed in the cells that took up OMLs (Man3 or Man5), while carbohydrate uncoated liposomes (Bare lipo) and liposomes coated with lacto-N-tetraose, which has terminal galactose residue (LNT), were not affected in secretion of IL-12 and IL-6. (b) Intracellular staining of IL-12 of peritoneal phagocytic cells that ingested OMLs. IL-12 was produced by CD11b⁺CD11c⁺ (R2 in Figure 2) cells.

Figure 4

Elimination of established tumor by administration of OML-based vaccine. Mice (n = 25) were challenged by s.c. injection of E.G7-OVA tumor cells in the right dorsal area on day 0. On day 9, OML/OVA, Bare/OVA, or PBS was injected into the side where the tumor had grown. (a) Suppression of tumor growth. (b) Surviving mice, expressed as a percentage of the total number of mice in each group.