Pilot--Immunomodulation /Vaccine Optimization /Chlamydia

Morehouse School Of Medicine, Atlanta GA

Investigators

Linked publications & trials

Abstract

Genital infection by Chlamydia trachomatis is the most common bacterial sexually transmitted disease (STD)[unreadable] in the United States with an excess of $2 billion spent on over four million annual clinical cases. Like several[unreadable] other intracellular bacterial pathogens that require a robust T helper type 1 (Th1) immunity for control (e.g.,[unreadable] Listeria and Mycobacteria), there are no vaccines against C. trachomatis. Progress in the immunobiology of[unreadable] Chlamydia has indicated that novel approaches to identify and target immunomodulatory factors that regulate[unreadable] the induction of Th1 cells are crucial for designing effective vaccines against these pathogens. Recently, it was[unreadable] found that chlamydia-pulsed, interleukin (IL)-10 deficient dendritic cells (DCs) were potent antigen-presenting[unreadable] cells that induced a rapid and robust Th1 response and the complementary humoral immune response which[unreadable] conferred sterilizing immunity against genital chlamydial infection in mice. The effectiveness of chlamydiapulsed[unreadable] IL-10 deficient DCs is not due merely to the absence of IL-10 but to acquisition of certain[unreadable] immunobiologic properties that include rapid maturation and expression of a unique set of immunomodulatory[unreadable] molecules. The main objective of this study is to elucidate the molecular and immunobiological basis for the[unreadable] potency of chlamydia-pulsed IL-10 deficient DCs, including defining novel molecular elements that can be[unreadable] applied in designing and delivering efficacious vaccines against Chlamydia. The central hypothesis to be[unreadable] tested is that chlamydia-primed IL-10 deficient DCs are quantitatively and qualitatively distinct in their[unreadable] metabolic characteristics relating to T cell activation compared to wild-type (WT) DCs. To investigate[unreadable] this hypothesis, we will use a combination of proteomics and immunological techniques, including twodimensional[unreadable] gel electrophoresis (2-DE), matrix-assisted laser-desorption/ionization time-of-flight (MALDI-TOF),[unreadable] in vivo gene silencing via short interfering RNA (siRNA), and analysis of genetically-engineered specific gene[unreadable] knockout or transgenic mice, to identify and immunologically characterize certain gene products that contribute[unreadable] to early DC maturation and promote efficient APCs function for an enhanced Th1 activation. Additional in vivo[unreadable] and ex vivo biochemical techniques will be used to deliver chlamydia-specific vaccine constructs in the[unreadable] presence or absence of the relevant molecules identified, to determine the effect on vaccine efficacy in vivo, in[unreadable] a murine model of genital Chlamydia infection. The ultimate goal is to identify and characterize certain[unreadable] immunomodulatory molecules that can be used to design and deliver efficacious vaccines against Chlamydia.[unreadable]