Guiding Dyslipidemia Treatment: A Population Pharmacokinetic-Pharmacodynamic Framework for Obicetrapib.

Obicetrapib is a selective inhibitor of cholesteryl ester transfer protein that is currently in phase 3 of development for the treatment of dyslipidemia as adjunct therapy. The purpose of this study was to comprehensively characterize the pharmacokinetic (PK) and pharmacodynamic (PD) disposition of obicetrapib. Data from 7 clinical trials conducted in healthy adults and those with varying degrees of dyslipidemia were included for model development.

Activated macrophages infected with Legionella inhibit T cells by means of MyD88-dependent production of prostaglandins.

To understand how macrophages (Mphi) activated with IFN-gamma modulate the adaptive immune response to intracellular pathogens, the interaction of IFN-gamma-treated bone marrow-derived murine Mphi (BMphi) with Legionella pneumophila was investigated. Although Legionella was able to evade phagosome lysosome fusion initially, and was capable of de novo protein synthesis within IFN-gamma-treated BMphi, intracellular growth of Legionella was restricted. It was determined that activated BMphi infected with Legionella suppressed IFN-gamma production by Ag-specific CD4 and CD8 T cells.

Processing and major histocompatibility complex class II presentation of Legionella pneumophila antigens by infected macrophages.

To better understand interactions between the intracellular pathogen Legionella pneumophila and macrophages (Mphis), host and bacterial determinants important for presentation of antigens on major histocompatibility complex class II molecules (MHC-II) were investigated. It was determined that immune CD4 T-cell responses to murine bone marrow-derived Mphis (BMphis) infected with wild-type L. pneumophila were higher than the responses to avirulent dotA mutant bacteria.

Immunity to vacuolar pathogens: what can we learn from Legionella?

Intracellular pathogens can manipulate host cellular pathways to create specialized organelles. These pathogen-modified vacuoles permit the survival and replication of bacterial and protozoan microorganisms inside of the host cell. By establishing an atypical organelle, intracellular pathogens present unique challenges to the host immune system.

Legionella reveal dendritic cell functions that facilitate selection of antigens for MHC class II presentation.

To understand how adaptive immune responses are generated against bacteria that avoid being delivered to lysosomes, interactions between professional antigen-presenting cells (APCs) and the intracellular pathogen Legionella pneumophila were examined. In contrast to murine bone marrow-derived macrophages (BMMs), we show that dendritic cells (DCs) restrict the growth of intracellular Legionella. Similar to what has been reported in BMMs, phagosomes containing Legionella matured into endoplasmic reticulum (ER)-derived organelles after DC internalization.