Showing papers by "Carlos A. Guzmán published in 2005"

The mucosal adjuvant macrophage-activating lipopeptide-2 directly stimulates B lymphocytes via the TLR2 without the need of accessory cells.

Abstract: The macrophage-activating lipopeptide-2 (MALP-2) is an agonist of the TLR heterodimer 2/6, which exhibits potent activity as mucosal adjuvant, promoting strong humoral and cellular responses. Although B cells expressing TLR2/6 are potential targets, very little is known about the effect of MALP-2 on B cells. Studies were performed using total spleen cells or purified B cells from WT mice or animals deficient in TLR2, T cells, B cells, or specific subpopulations of B cells. They demonstrated that MALP-2 promotes a T cell-independent activation and maturation of B cells (mainly follicular but also B-1a and marginal zone B cells) via TLR2. MALP-2 also increased the frequency of IgM- and IgG-secreting cells, but bystander cells were required for IgA secretion. Activated B cells exhibited increased expression of activation markers and ligands that are critical for cross-talk with T cells (CD19, CD25, CD80, CD86, MHC I, MHC II, and CD40). Immunization of mice lacking T cells showed that MALP-2-mediated stimulation of TLR2/6 was unable to circumvent the need of T cell help for efficient Ag-specific B cell activation. Immunization of mice lacking B cells demonstrated that B cells are critical for MALP-2-dependent improvement of T cell responses. The knowledge emerging from this work suggests that MALP-2-mediated activation of B cells through TLR2/6 is critical for adjuvanticity. B cell stimulation by pattern recognition receptors seems to be a basic mechanism that can be exploited to improve the immunogenicity of vaccine formulations.

Characterization of a B220+ lymphoid cell subpopulation with immune modulatory functions in nasal-associated lymphoid tissues.

Abstract: Complex mechanisms operate on mucosal tissues to regulate immune responsiveness and tolerance. When the lymphocyte subpopulations from murine nasal-associated lymphoid tissues (NALT) were characterized, we observed an accumulation of B220(low)CD3(low)CD4(-)CD8(-)CD19(-)c-Kit(+) cells. TCR transgenic mice and athymic mice were used for monitoring T cell lineage and the presence of extrathymic T cell precursors. The majority of cells from NALT exhibited a T cell precursor phenotype (CD4(-)CD8(-)CD19(-)c-Kit(+)). Fas-independent apoptosis was their main mechanism of cell death. We also demonstrated that B220(low)CD4(-)CD8(-)CD19(-) cells from NALT exhibited the potential to down-regulate the activation of mature T cells. However, the innate immunity receptor TLR2 was also highly expressed by this cell subpopulation. Moreover, nasal stimulation with a TLR2/6 agonist resulted in a partial activation of the double-negative cells. These results suggest that the immune responses in NALT may be in part modulated by a cell subpopulation that maintains a tolerogenic milieu by its proapoptotic status and suppressive activity, which can be reverted through stimulation of a TLR signaling cascade.

PQS and c-diGMP and its conjugates as adjuvants and their uses in pharmaceutical compositions

Abstract: The present invention relates to new adjuvants and the uses in pharmaceutical compositions, like in vaccines. In particular, the present invention provides new compounds useful as adjuvants and/or immunomodulators for prophylactic and/or therapeutic vaccination in the treatment of infectious diseases, inflammatory diseases, autoimmune diseases, tumours, allergies as well as for the control of fertility in human or animal populations. The compounds are particularly useful not only as systemic, but preferably as mucosal adjuvants. In addition, the invention relates to its uses as active ingredients in pharmaceutical compositions.

New adjuvants on the basis of bisacyloxypropylcysteine conjugates and their uses in pharmaceutical compositions

Abstract: The present invention relates to new adjuvants and the uses in pharmaceutical compositions, like in vaccines. In particular, the present invention provides new conjugates of the bisacyloxycysteine type useful as adjuvants and/or immunomodulators for prophylactic and/or therapeutic vaccination in the treatment of infectious diseases, inflammatory diseases, autoimmune diseases, tumours, allergies as well as for the control of fertility in human or animal populations. The compounds are particularly useful not only as systemic, but preferably as mucosal adjuvants. In addition, the invention relates to its uses as active ingredients in pharmaceutical compositions.