title: A synthetic analogue of phosphatidylinositol mannoside is an efficient adjuvant.
abstract: We recently described the synthesis of an ether linked analogue of phosphatidylinositol dimannoside (PIM(2)ME). In the current study, PIM(2)ME was found to significantly enhance the release of the key Th1 cytokine interleukin-12 (IL-12) by dendritic cells (DCs) of naive mice in vitro, but not interleukin-10 (IL-10). Based on this result, it was hypothesized that PIM(2)ME would be an effective adjuvant for cell-mediated immune responses. Injections of PIM(2)ME alone did not lead to weight loss and did not have toxic side effects, based on biomarkers of toxicity in serum,demonstrating that the compound induced no apparent adverse side effects. Mice were vaccinated with the core antigens of the hepatitis C virus by itself or with three different adjuvants, namely PIM(2)ME, a commercial preparation of monophosphoryl lipid A (MPL) or a preparation of aluminium hydroxide gel (alum). A control group of animals received the antigen only with no adjuvants. Immune responses to the Hepatitis C viral antigens were monitored by measuring antigen-specific production of interferon-gamma (IFN-gamma), the p40 subunit of interleukin-12 (IL-12) and interleukin-10 (IL-10) to assess cell-mediated immune responses. Vaccination of mice with Hepatitis C viral antigens with the adjuvant PIM(2)ME led to a significant increase in cell-mediated immune responses (IFN-gamma and IL-12). Injection of Hepatitis C viral antigens in alum led to no enhancement of the cell-mediated immune response. We conclude that PIM(2)ME is an efficacious adjuvant for enhancing cell-mediated immunity, and induces no observable adverse effects.
authors.affiliation: AgResearch, Hopkirk Research Institute, AgResearch Grasslands, Tennent Drive, Private Bag 11008, Palmerston North, New Zealand. michel.denis@agresearch.co.nz
authors.forename: Michel
authors.initials: M
authors.lastname: Denis
authors.forename: Gary D
authors.initials: GD
authors.lastname: Ainge
authors.forename: David S
authors.initials: DS
authors.lastname: Larsen
authors.forename: Wayne B
authors.initials: WB
authors.lastname: Severn
authors.forename: Gavin F
authors.initials: GF
authors.lastname: Painter
mesh_terms: D000276:Adjuvants, Immunologic / Q000008:administration & dosage / Q000138:chemical synthesis* / Q000494:pharmacology*; D000818:Animals; D015415:Biomarkers / Q000097:blood; D002478:Cells, Cultured; D018984:Epitopes, T-Lymphocyte / Q000276:immunology; D005260:Female; D007111:Immunity, Cellular / Q000187:drug effects; D007371:Interferon-gamma / Q000096:biosynthesis; D016753:Interleukin-10 / Q000096:biosynthesis; D053762:Interleukin-12 Subunit p40 / Q000096:biosynthesis; D051379:Mice; D008810:Mice, Inbred C57BL; D010716:Phosphatidylinositols / Q000008:administration & dosage / Q000138:chemical synthesis* / Q000494:pharmacology*; D011897:Random Allocation; D013154:Spleen / Q000166:cytology / Q000276:immunology / Q000378:metabolism; D018417:Th1 Cells / Q000276:immunology / Q000378:metabolism
chemical_list: D000276:Adjuvants, Immunologic; D015415:Biomarkers; D018984:Epitopes, T-Lymphocyte; D053762:Interleukin-12 Subunit p40; D010716:Phosphatidylinositols; C034154:phosphatidylinositol mannoside; D016753:Interleukin-10; D007371:Interferon-gamma