cord-factors and Influenza--Human

A broad coverage influenza vaccine against multiple viral strains based on the viral nucleoprotein (NP) is a goal pursued by many laboratories. If the goal is to formulate the vaccine with recombinant NP it is essential to count on adjuvants capable of inducing cellular immunity. This work have studied the effect of the monophosphoryl lipid A and trehalose dimycolate, known as the Ribi Adjuvant System (RAS), in the immune response induced in mice immunized with recombinant NP. The NP was formulated with RAS and used to immunize BALB/c mice. Immunizations with NP-RAS increased the humoral and cellular immune responses compared to unadjuvanted NP. The predominant antibody isotype was IgG2a, suggesting the development of a Th1 response. Analysis of the cytokines from mice immunized with NP-RAS showed a significant increase in the production of IFN-g and a decreased production of IL-10 and IL-4 compared to controls without RAS. These results are similar to those usually obtained using Freund’s adjuvant, known to induce Th1 and CTL responses when co-administered with purified proteins, and suggest that a similar approach may be possible to enhance the performance of a T-cell vaccine containing NP.

Topics: Animals; Antibodies, Viral; Cell Wall Skeleton; Cord Factors; Female; Humans; Immunity, Cellular; Immunization; Influenza Vaccines; Influenza, Human; Interferon-gamma; Interleukin-10; Interleukin-4; Lipid A; Mice; Mice, Inbred BALB C; Nucleocapsid Proteins; RNA-Binding Proteins; T-Lymphocytes, Cytotoxic; Th1 Cells; Viral Core Proteins

Trehalose 6,6'-dimycolate (TDM), an immunomodulator, potentiates non-specific resistance in mice to influenza virus infection. When mice were injected intravenously with TDM, the striking proliferation of a minority of T-lymphocytes bearing gamma/delta T-cell receptors (gamma delta T-cells) that accumulated in granulomatous lungs was thought to be associated with the maintenance of acquired resistance to lethal influenza virus infection. To clarify the cellular basis of the defence against influenza virus, mice were depleted of gamma delta T-cells, alpha/beta (alpha beta) T-cells, or natural killer (NK) cells by in vivo administration of corresponding antibodies prior to influenza virus infection. The depletion of gamma delta T-cells significantly abrogated the augmented resistance of TDM-treated mice to infection, as did depletion of either alpha beta T-cells or NK cells. To gain insight into the functional ability of gamma delta T-cells, we evaluated the cytotoxic activity of this T-cell subset against a panel of target cell lines that were stably transfected with the influenza virus haemagglutinin (HA) gene from A/PR/8/34(H1N1) and A/Aichi/2/68(H3N2) strains. The gamma delta T-cells from TDM-treated mice showed profound cytotoxicity against the target cells expressing HA of either the H1 or H3 subtype, in a non-major histocompatibility complex-restricted manner. Taken together, these results indicate that gamma delta T-cells play a non-specific role, in conjunction with alpha beta T-cells and NK cells, in protecting mice against influenza virus infection, and that the recognition and destruction of HA-expressing target cells by the activated gamma delta T-cells is one of the steps involved in this anti-influenza virus immunosurveillance.

Topics: Adjuvants, Immunologic; Animals; Cells, Cultured; Chick Embryo; Cord Factors; Cytotoxicity Tests, Immunologic; Disease Models, Animal; Female; Hemagglutinin Glycoproteins, Influenza Virus; Humans; Immunity, Innate; Influenza A virus; Influenza, Human; Killer Cells, Natural; Lymphocyte Depletion; Mice; Mice, Inbred BALB C; Receptors, Antigen, T-Cell, alpha-beta; Receptors, Antigen, T-Cell, gamma-delta; T-Lymphocytes

We have purified the cell-wall skeletons (CWS) of Mycobacterium bovis BCG, Nocardia rubra, Propionibacterium acnes and Listeria monocytogenes as the adjuvant-active principles of these bacterial cells. These cell-wall skeleton preparations were shown to have antitumor activities in experimental tumor systems. Especially BCG-CWS and N. rubra-CWS were applied for the treatment of human cancer. The synthetic immunoadjuvants such as cord factor, mycoloyl and quinonyl derivatives of N-acetylmuramyldipeptides were prepared and their immunological properties were investigated. The effectiveness of synthetic adjuvants on the stimulation of nonspecific host resistance against bacterial and viral infections was also discussed.

Topics: Adjuvants, Immunologic; Antineoplastic Agents; BCG Vaccine; Cell Wall; Cord Factors; Humans; Influenza, Human; Listeria; Neoplasms; Nocardia; Stomach Neoplasms