Yong, Kwee Lan; (1993) The effect of myeloid growth factors on phagocyte-endothelium interactions. Doctoral thesis (Ph.D), UCL (University College London).

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Abstract

The myeloid growth factors, granulocyte colony-stimulating factor (G-CSF), granulocyte-macrophage colony-stimulating factor (GM-CSF) and macrophage colony-stimulating factor (M-CSF) were initially defined by their effects on the proliferation and differentiation of haemopoietic progenitor cells, but are now recognised to play an important part in enhancing the functions of mature effector cells. This thesis explores and defines the effect of these growth factors on the adhesive properties of phagocytic cells, with particular emphasis on the interaction of neutrophils with endothelium, and the role of the different leucocyte adhesion molecules. GM-CSF and G-CSF produced upregulation of phagocyte surface CD11b/CD18 both in vitro and in vivo, but induced shedding of the L-selectin receptor on neutrophils only in vitro. In vitro, GM-CSF enhanced the adhesion of neutrophils to cultured human umbilical vein endothelial cells, while G-CSF was without effect. GM-CSF also demonstrated greater proadhesive effects in vivo: Systemic administration of GM-CSF led to a rapid neutropenia, with a much slower recovery of peripheral cell counts than was seen with G-CSF. Histological analysis using a non-human primate (cynomolgus) model showed that GM-CSF increased neutrophil adhesion to pulmonary vascular endothelium in vivo. In vitro, GM-CSF had differential effects on the transendothelial migration of neutrophils, depending on the conditions of endothelial activation. Neutrophils stimulated with GM-CSF showed enhanced migration across unstimulated endothelium, but impaired migration across cytokine activated endothelium. Monoclonal antibodies to CD11b and to CD18 did not inhibit GM-CSF induced neutrophil margination in vivo; and a patient with a congenital deficiency of the CD11/CD18 receptors (leucocyte adhesion deficiency) demonstrated a normal margination response to GM-CSF, confirming that the CD11/CD18 receptor plays a minimal role in GM-CSF induced adhesion in vivo. In spite of this, the same antibodies blocked GM-CSF induced neutrophil adhesion and transendothelial migration in vitro. Neutrophil migration in vitro was not blocked by monoclonal antibodies to L-selectin, and migrated cells expressed lower levels of L-selectin than nonmigrated cells. Finally, the possible direct effect of these growth factors on endothelial cells was studied. in vitro, GM-CSF and G-CSF had no effect on the proliferation of, or the expression of procoagulant or fibrinolytic activites by, cultured human endothelial cells. However, systemic administration of GM-CSF produced a rise in plasma tissue plasminogen activator activity in vivo, an effect which may relate to the enhanced neutrophil adhesion to endothelium. These studies emphasize the role of the myeloid growth factors, in particular GM-CSF, as inflammatory mediators which regulate the immune responses of phagocytic cells, including the cellular adhesive interactions which underly phagocyte recruitment into inflammatory areas.

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