HIPS-Talk: “Immune stimulatory molecules as a novel therapeutic option for the treatment of intracellular pathogens“

  • Überblick

    Intracellular pathogens like protozoan parasites from the genus Leishmania or bacteria like Mycobacterium spp. invade immune cells of the host, subvert the killing machinery thereby enabling its multiplication and transmission. Immune modulators that activate-or re-activate infected target cells represent promising therapeutic options that may support clearing of intracellular pathogens by enhancing the immune response of the host. It is known that immune stimulatory molecules can be used for the activation of antigen presenting cells (APC) or natural killer T (NKT) cells. NKT cells are a innate-like, heterogeneous cell population, but the majority of these cells express an invariant T cell receptor that recognizes glycolipids presented via CD1d on APCs. Upon ligation, NKT cells produce fast, large amounts of different cytokines, including pro-inflammatory IFNγ or anti-inflammatory cytokines like IL-4, IL-13 or IL-10 thereby regulating the host immune response. In recent years, it has been shown that NKT cells can be activated directly by recognition of microbial lipids presented via CD1d or indirectly by soluble mediators like IL-12 provided by stimulated APCs. We recently isolated a glycolipid from the membrane of the protozoan parasite Entamoeba (E.) histolytica, the lipopeptidephosphoglycan (EhLPPG). This molecule, especially the glycophosphatidylinositol (GPI) anchor of EhLPPG exhibits immune stimulatory properties through engagement of Toll-like receptors and production of IL-12p70 from macrophages and DCs. Via presentation by CD1d, EhLPPG activates NKT cells to produce a variety of cytokines, especially the protective cytokine IFNγ. However, the use of natural compounds like EhLPPG is restricted by its limited availability since only small amounts can be isolated from the membrane of E. histolytica trophozoites. In cooperation with Prof. Fujimoto (Keio University, Japan) and Prof. Fukase (Osaka University, Japan), we developed synthetic analogs deduced from the GPI anchor of EhLPPG. We analyzed the synthetic molecules for their ability to stimulate cytokine production in NKT cells, peripheral blood cells and macrophages thereby supporting the clearance of intracellular infections with L. major parasites in vitro. Experimental treatment of cutaneous leishmaniasis in a respective mouse model for the disease decreased the L. major-dependent footpad swelling, increased the ulceration free time and decreased the L. major spreading to the draining lymph nodes. We suggest that targeted administration of immune stimulatory molecules represents a new therapeutic strategy that may support existing anti-leishmanial drug therapies for the local treatment of cutaneous leishmaniasis and potentially other intracellular pathogens.


    Datum: 12.07.2016, 17:00

    Veranstaltungsort

    HIPS

    Gebäude und Raum

    Blg E8.1, Seminarraum (Erdgeschoss)

    Referent

    Dr. Hanna Lotter

    Abteilung Molekulare Parasitologie

    Bernhard Nocht Institut für Tropenmedizin

    Gastgeber

    Prof. Dr. Claus-Michael Lehr

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