Monocyte And Dendritic Cell Development And Trafficking

Niaid Extramural Activities

Investigators

Linked publications & trials

Abstract

The ongoing investigations in my laboratory are focused on delineating immunomodulatory mechanisms of innate and adaptive immune responses. The aim of this project is to develop a practical model of myeloid cell mediated immune surveillance to investigate the trafficking signals used by these cells at rest and during infectious, allergic, and inflammatory disease state. I have developed a novel ex vivo system for proliferating and differentiating large numbers of functional dendritic cells, from Sca-1+Lin- hematopoietic progenitor cells (HPC). Using a combination of myeloid and stromal growth factors the murine bone marrow derived HPC used in these experiments average 613 plus/minus 65 fold expansion. The resulting cells are a fairly homogeneous population of cells that express moderate to high levels of surface and intracellular molecules that are characteristic of immature myeloid dendritic cells. Unlike immature dendritic cells however, these Sca-1+Lin- derived myeloid dendritic cell precursors are refractory to maturation in response to bacterial lipopolysaccharide (LPS) stimulation, do not secrete immunomodulatory cytokines and are devoid of allogeneic T- lymphocyte stimulatory activity in mixed leukocyte reactions. In the presence of additional immunomodulatory cytokines the myeloid dendritic cell precursors mature into efficient lymphocyte stimulators. In parallel experiments I have successfully transduced the HPC with a retroviral vector, and successfully culture the cells as indicated above into myeloid dendritic cell precursors. This model can be used for the in vivo trafficking of the various dendritic cell subsets. Also part of this project is a related initiative to study the role of nicotinamide adenine dinucleotide phosphate (NADPH) oxidase in the development of chronic inflammatory disease states.