E-040. Lutzomyia longipalpis Salivary Peptide Maxadilan Alters Murine Dendritic Cell Surface Expression of CD80/86, CCR7 and Cytokine Secretion and Reprograms Dendritic Cell-Mediated Cytokine Production in Cultures Containing Allogenenic CD4+ T Cells

R. G. Titus, K. Pauken, R. Morris, W. Wheat;
Colorado State Univ., Ft Collins, CO.

Leishmania protozoan parasites are transmitted exclusively by phlebotomine sand flies of the genera Phlebotomus and Lutzomyia. In addition to parasites, the infectious bite inoculum contains arthropod salivary components. One well-characterized salivary component from Lutzomyia longipalpis is maxadilan (MAX), a vasodilator acting via the type I receptor for the pituitary cyclic AMP activating peptide (PACAP). MAX has been shown to elicit immunomodulatory effects potentially dictating immune responses to Leishmania parasites. When exposed to MAX, both resting and LPS-stimulated dendritic cells (DCs) show reduced CD80 and CD86 expression on most DCs in vitro. However, CD86 expression is increased significantly on a subpopulation of DCs. Furthermore, MAX treatment promoted secretion of type 2 cytokines (IL-6 and IL-10) while reducing production of type 1 cytokines (IL-12p40, TNFα, and IFN-γ) by LPS-stimulated DCs. A similar trend was observed in cultures of MAX-treated DCs containing naïve allogeneic CD4+ T cells. Type 2 cytokines (IL-6, IL-13) increased while type 1 cytokines (TNFα, IFNγ) decreased. Additionally, the proinflammatory cytokine IL-1β was increased in cultures containing MAX-treated mature DCs. MAX treatment of LPS-stimulated DCs also prevented optimal surface expression of CCR7 in vitro. These MAX-dependent effects were evident in DCs from both Leishmania major (Lm)-susceptible (BALB/c) and -resistant (C3H/HeN) murine strains. These data suggest that MAX may modulate DC phenotype by alteration of cell surface expression patterns of costimulatory molecules, cytokine production, and of surface chemokine receptors as well as modify the capacity of DCs to direct T cell cytokine secretion. Modification of DC phenotype and function by MAX likely affects crucial cellular components that determine the pathological response to infection with Lm.