ABSTRACT
The administration of Th2 cytokines or immune deviation to a Th2 phenotypic response has been shown to protect against the autoimmune pathology of experimental autoimmune encephalomyelitis (EAE). To better understand the function of Th2 cytokines in the induction stage of EAE in the absence of an overt Th2 response, we immunized IL-4 receptor alpha-deficient (IL-4Ralpha(-/-)) mice, which are unable to respond to either IL-4 or IL-13. Contrary to expectations, mice lacking IL-4Ralpha had a lower incidence of EAE and a delayed onset compared to WT BALB/c mice; however, this delay did not correlate to an alteration in the Th1/Th17 cytokine balance. Instead, IL-4Ralpha-responsive macrophages were essential promoters of disease as macrophage-specific IL-4Ralpha-deficient (LysM(cre)IL-4Ralpha(-/lox)) mice were protected from EAE. The protection afforded by IL-4Ralpha-deficiency was not due to IL-10-, IFN-gamma-, NO- or IDO-mediated suppression of T-cell responses but was dependent upon the presence of regulatory T cells (Tregs). This investigation highlights the importance of macrophages and Tregs in regulating central nervous system inflammation and demonstrates that macrophages activated in the absence of Th2 cytokines can promote disease suppression by Tregs.
Subject(s)
Encephalomyelitis, Autoimmune, Experimental/prevention & control , Macrophages/physiology , Macrophages/transplantation , Receptors, Cell Surface/genetics , T-Lymphocytes, Regulatory/physiology , Adoptive Transfer/methods , Age of Onset , Animals , Cytokines/metabolism , Encephalomyelitis, Autoimmune, Experimental/epidemiology , Encephalomyelitis, Autoimmune, Experimental/genetics , Encephalomyelitis, Autoimmune, Experimental/immunology , Incidence , Lymph Nodes/metabolism , Macrophages/immunology , Macrophages/metabolism , Mice , Mice, Inbred BALB C , Mice, Knockout , Phenotype , Receptors, Cell Surface/metabolism , Signal Transduction/genetics , Spleen/metabolismABSTRACT
We develop a simple mathematical model for forced flow of culture medium through a porous scaffold in a tissue-engineering bioreactor. Porous-walled hollow fibres penetrate the scaffold and act as additional sources of culture medium. The model, based on Darcy's law, is used to examine the nutrient and shear-stress distributions throughout the scaffold. We consider several configurations of fibres and inlet and outlet pipes. Compared with a numerical solution of the full Navier-Stokes equations within the complex scaffold geometry, the modelling approach is cheap, and does not require knowledge of the detailed microstructure of the particular scaffold being used. The potential of this approach is demonstrated through quantification of the effect the additional flow from the fibres has on the nutrient and shear-stress distribution.
