krn-7000 and Infections

To optimize vaccination strategies, it is important to use protocols that can 'jump-start' immune responses by harnessing cells of the innate immune system to assist the expansion of antigen-specific B and T cells. In this Review, we discuss the evidence indicating that invariant natural killer T (iNKT) cells can positively modulate dendritic cells and B cells, and that their pharmacological activation in the presence of antigenic proteins can enhance antigen-specific B- and T-cell responses. In addition, we describe structural and kinetic analyses that assist in the design of optimal iNKT-cell agonists that could be used in the clinical setting as vaccine adjuvants.

Topics: Adjuvants, Immunologic; Animals; Antigens, CD1d; B-Lymphocytes; Cell Differentiation; Clinical Trials as Topic; Cytokines; Dendritic Cells; Forecasting; Galactosylceramides; Glycolipids; Humans; Immunity, Innate; Immunologic Surveillance; Infections; Lymphocyte Activation; Mice; Models, Molecular; Natural Killer T-Cells; Neoplasms; Receptors, Antigen, T-Cell, alpha-beta; Structure-Activity Relationship; Vaccination

Invariant natural killer T (iNKT) cells are an unusual group of T lymphocytes that recognize glycolipid antigens presented by the major histocompatibility complex class I-related protein CD1d. Because iNKT cells play a regulatory role in the immune system, they are attractive targets for immunotherapy. The marine-sponge-derived glycolipid alpha-galactosylceramide (alpha-GalCer) potently activates iNKT cells. In vivo administration of alpha-GalCer to mice or humans results in rapid and robust cytokine secretion by iNKT cells, followed by the activation of a variety of cell types of the innate and adaptive immune systems. These potent immunomodulatory activities of alpha-GalCer are being exploited for therapeutic purposes. Preclinical studies in mice have demonstrated that alpha-GalCer and related glycolipids can protect mice against a variety of diseases, including cancer, infections, and several autoimmune and inflammatory conditions. Although alpha-GalCer treatment of mice is associated with unwanted side-effects, it has been proven safe in clinical trials with cancer patients. These studies have raised significant enthusiasm for the development of effective and safe iNKT-cell-based immunotherapies for a variety of human diseases.

Topics: Animals; Antigens, CD1; Autoimmune Diseases; Carbohydrate Sequence; Galactosylceramides; Glycolipids; Humans; Infections; Inflammation; Killer Cells, Natural; Mice; Molecular Sequence Data; Molecular Structure; Neoplasms; T-Lymphocyte Subsets

The glycolipid alpha-galactosylceramide (alphaGalCer) has immunomodulatory properties, which have been exploited to combat cancer, chronic inflammatory diseases, and infections. However, its poor solubility makes alphaGalCer a suboptimal compound for in vivo applications. In this study, a pegylated derivative of alphaGalCer is characterized, which exhibits improved physical and biological properties. The new compound, alphaGalCerMPEG, is water-soluble and retains the specificity for the CD1d receptor of alphaGalCer. The in vitro stimulatory properties on immune cells (e.g., dendritic cells and splenocytes) are maintained intact, even when tested at a 33-fold lower concentration of the active moiety than alphaGalCer. NK cells isolated from mice treated with alphaGalCerMPEG also had stronger cytotoxic activity on YAC-1 cells than those obtained from animals receiving either alphaGalCer or CpG. Intranasal immunization studies performed in mice showed that alphaGalCerMPEG exerts stronger adjuvant activities than the parental compound alphaGalCer when tested at 0.35 vs 11.7 nM/dose. Coadministration of beta-galactosidase with alphaGalCerMPEG resulted not only in high titers of Ag-specific Abs in serum (i.e., 1:512,000), but also in the stimulation of stronger Th2 and secretory IgA responses, both at local and remote mucosal effector sites (i.e., nose, lung, and vagina). The new synthetic derivative alphaGalCerMPEG represents a promising tool for the development of immune interventions against infectious and noninfectious diseases.

Topics: Adjuvants, Immunologic; Administration, Intranasal; Animals; Antibody Specificity; Antigens; beta-Galactosidase; Cell Line; Chronic Disease; Dendritic Cells; Galactosylceramides; Humans; Immunity, Mucosal; Immunization; Immunoglobulin A; Immunologic Factors; Infections; Inflammation; Mice; Mucous Membrane; Neoplasms; Oligonucleotides; Polyethylene Glycols; Solubility; Spleen