Mechanisms of endogenous and therapeutic immune modulation by G-CSF

Abstract

The granulocyte colony-stimulating factor (G-CSF) combines hematopoietic and anti-inflammatory properties. This makes it an interesting therapeutic option to leverage the immune response by exploiting natural endogenous mechanisms. This strategy may be employed to prime the immune system before an insult or to reactivate the burnt-out immune system, i.e. in the prevention of infections, the treatment of sepsis or immune reconstitution in HIV disease.In this thesis, two methods, i.e. whole blood staphylococcal enterotoxin B (SEB)-induced lymphokine release and lipopolysaccharide (LPS)-induced eicosanoid release, were established to complement LPS-induced cytokine release as measures of immune function. These methods were employed to characterize immunomodulation by G-CSF and GM-CSF. Further, the immune stimulatory properties of lipoteichoic acid (LTA), the counterpart to Gram-negative LPS, were investigated further with regard to its ability to activate neutrophils and to stimulate the release of G-CSF as well as chemokines. Lastly, the effect of heterozygous polymorphisms of the receptors for LPS and LTA, i.e. TLR4 and TLR2, on the immune response were investigated.