ABSTRACT
The Lariat device is an epicardial nonimplant suture delivery device capable of left atrial appendage closure. The current study offers promising results but is limited by small sample size and multiple foundational issues with study design. aMaze, a large multi-center prospective randomized trial is currently underway and will provide additional insight into the safety of this device and its efficacy in maintenance of sinus rhythm after atrial fibrillation ablation.
Subject(s)
Atrial Appendage , Atrial Fibrillation , Stroke , Humans , Prospective Studies , Treatment OutcomeABSTRACT
CD1d-restricted natural killer T cells (NKT cells) possess a wide range of effector and regulatory activities that are related to their ability to secrete both T helper 1 (Th1) cell- and Th2 cell-type cytokines. We analyzed presentation of NKT cell activating alpha galactosylceramide (alphaGalCer) analogs that give predominantly Th2 cell-type cytokine responses to determine how ligand structure controls the outcome of NKT cell activation. Using a monoclonal antibody specific for alphaGalCer-CD1d complexes to visualize and quantitate glycolipid presentation, we found that Th2 cell-type cytokine-biasing ligands were characterized by rapid and direct loading of cell-surface CD1d proteins. Complexes formed by association of these Th2 cell-type cytokine-biasing alphaGalCer analogs with CD1d showed a distinctive exclusion from ganglioside-enriched, detergent-resistant plasma membrane microdomains of antigen-presenting cells. These findings help to explain how subtle alterations in glycolipid ligand structure can control the balance of proinflammatory and anti-inflammatory activities of NKT cells.
Subject(s)
Antigen-Presenting Cells/immunology , Antigens, CD1d/immunology , Galactosylceramides/immunology , Lymphocyte Activation/immunology , Natural Killer T-Cells/immunology , Th2 Cells/immunology , Animals , Antigen-Presenting Cells/drug effects , Antigen-Presenting Cells/metabolism , Antigens, CD1d/metabolism , Cytokines/biosynthesis , Cytokines/immunology , Female , Galactosylceramides/pharmacology , Humans , Kinetics , Lymphocyte Activation/drug effects , Membrane Microdomains/immunology , Membrane Microdomains/metabolism , Mice , Mice, Inbred BALB C , Mice, Inbred C57BL , Natural Killer T-Cells/drug effects , Th2 Cells/drug effectsABSTRACT
Two 60+-membered libraries of alpha-galactosylceramides have been prepared by reactions between activated ester resins and two core, fully deprotected galactosylated sphingoid bases. The libraries were evaluated for their ability to stimulate CD1d-restricted NKT cells, using in vitro stimulation of a murine NKT cell hybridoma line and for their ability to induce the expansion of NKT cells from peripheral blood mononuclear cells (PBMC) of a normal human subject. Our results showed that many compounds constructed on a C18-phytosphingosine base had significant stimulatory activity in both assays. Because no product purification was required, this approach is particularly attractive as a method for rapid synthesis of large libraries of potential immunomodulatory glycosylceramides.
Subject(s)
Combinatorial Chemistry Techniques , Galactosylceramides/immunology , Galactosylceramides/pharmacology , Killer Cells, Natural/drug effects , Leukocytes, Mononuclear/drug effects , Lymphocyte Activation/drug effects , Animals , Galactose/chemistry , Galactosylceramides/chemical synthesis , Humans , Killer Cells, Natural/immunology , Killer Cells, Natural/metabolism , Leukocytes, Mononuclear/immunology , Leukocytes, Mononuclear/metabolism , Lymphocyte Activation/physiology , Mice , Models, Chemical , Resins, Synthetic/chemistry , Sphingolipids/chemistry , Sphingosine/analogs & derivatives , Sphingosine/chemistry , Sphingosine/immunology , Sphingosine/metabolismABSTRACT
Activation of CD1d-restricted invariant NKT (iNKT) cells by alpha-galactosylceramide (alphaGalCer) significantly suppresses development of diabetes in NOD mice. The mechanisms of this protective effect are complex, involving both Th1 and Th2 cytokines and a network of regulatory cells including tolerogenic dendritic cells. In the current study, we evaluated a newly described synthetic alphaGalCer analog (C20:2) that elicits a Th2-biased cytokine response for its impact on disease progression and immunopathology in NOD mice. Treatment of NOD mice with alphaGalCer C20:2 significantly delayed and reduced the incidence of diabetes. This was associated with significant suppression of the late progression of insulitis, reduced infiltration of islets by autoreactive CD8(+) T cells, and prevention of progressive disease-related changes in relative proportions of different subsets of dendritic cells in the draining pancreatic lymph nodes. Multiple favorable effects observed with alphaGalCer C20:2 were significantly more pronounced than those seen in direct comparisons with a closely related analog of alphaGalCer that stimulated a more mixed pattern of Th1 and Th2 cytokine secretion. Unlike a previously reported Th2-skewing murine iNKT cell agonist, the alphaGalCer C20:2 analog was strongly stimulatory for human iNKT cells and thus warrants further examination as a potential immunomodulatory agent for human disease.
