krn-7000 and Bacterial-Infections

NKT cells are a subpopulation of T lymphocytes with phenotypic properties of both T and NK cells and a wide range of immune effector properties. In particular, one subset of these cells, known as invariant NKT cells (iNKT cells), has attracted substantial attention because of their ability to be specifically activated by glycolipid antigens presented by a cell surface protein called CD1d. The development of synthetic α-galactosylceramides as a family of powerful glycolipid agonists for iNKT cells has led to approaches for augmenting a wide variety of immune responses, including those involved in vaccination against infections and cancers. Here, we review basic, preclinical and clinical observations supporting approaches to improving immune responses through the use of iNKT cell-activating glycolipids. Results from preclinical animal studies and preliminary clinical studies in humans identify many promising applications for this approach in the development of vaccines and novel immunotherapies.

Topics: Adjuvants, Immunologic; Animals; Antigens; Antigens, Bacterial; Antigens, CD1d; Antigens, Neoplasm; Bacterial Infections; Bacterial Vaccines; Cancer Vaccines; Cytokines; Dendritic Cells; Galactosylceramides; Glycolipids; Humans; Immunologic Memory; Immunotherapy, Active; Ligands; Lymphocyte Activation; Mice; Natural Killer T-Cells; Neoplasms; Primates; Receptors, Antigen, T-Cell, alpha-beta; Vaccination

Glycolipids are complex molecules involved in important cellular processes. Among them, the glycosphingolipid α-galactosylceramide has proven to be of interest in biomedicine for its immunostimulatory capabilities. Given its structural requirements, the use of ceramide glycosyltransferase enzymes capable of synthesizing this molecule under in vivo or in vitro conditions is a potential production strategy. Several GT4 enzymes from

Topics: Bacterial Infections; Bacteroides fragilis; Ceramides; Glycolipids; Glycosyltransferases; Humans; Nitric Oxide Synthase; Uridine Diphosphate

Systemic immunosuppression has been associated with stroke for many years, but the underlying mechanisms are poorly understood. In this study, we demonstrated that stroke induced profound behavioral changes in hepatic invariant NKT (iNKT) cells in mice. Unexpectedly, these effects were mediated by a noradrenergic neurotransmitter rather than a CD1d ligand or other well-characterized danger signals. Blockade of this innervation was protective in wild-type mice after stroke but had no effect in mice deficient in iNKT cells. Selective immunomodulation of iNKT cells with a specific activator (α-galactosylceramide) promoted proinflammatory cytokine production and prevented infections after stroke. Our results therefore identify a molecular mechanism that leads to immunosuppression after stroke and suggest an attractive potential therapeutic alternative to antibiotics, namely, immunomodulation of iNKT cells to prevent stroke-associated infections.

Topics: Adrenergic Agents; Animals; Anti-Bacterial Agents; Bacterial Infections; Brain Ischemia; Cell Movement; Cytokines; Galactosylceramides; Immune Tolerance; Immunomodulation; Infarction, Middle Cerebral Artery; Liver; Lymphocyte Activation; Mice; Mice, Inbred BALB C; Microvessels; Natural Killer T-Cells; Norepinephrine; Propranolol