Alderman, Charles Jason John; (2001) The role of oxidative stress in the regulation of dendritic cell function. Doctoral thesis (Ph.D.), University College London.

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Abstract

The archetypal view of the immune system is that it has evolved primarily to distinguish between non-infectious "self' and infectious "non-self'. However, this view has been superseded by the paradigm that the immune system is based on the recognition of a "danger" signal. The key to this signal is thought to be activation of dendritic cells (DC), which is a critical step in the initiation of adaptive immune responses. However, there is little experimental evidence to support the role of "danger" signals in the activation of DC. Perhaps the most noteworthy hypothesis is that oxidative stress may constitute a common denominator pathway for the activation of DC. This hypothesis has yet to be investigated in detail, and is the subject of this thesis. Human DC were differentiated from monocytes by seven days of culture in the presence of granulocyte/macrophage colony-stimulating factor (GM-CSF) and interleukin (IL)-4. When supplemented to purified cell populations, non-toxic concentrations of reactive oxygen species (ROS) were unable to induce the maturation of DC. In addition, ROS were found not to represent prerequisite activation signals for DC in vitro. It was hypothesised subsequently that the effects of oxidative stress on DC may be mediated indirectly via the actions of oxidised protein and lipid derivatives. Thus, either advanced oxidation protein products (AOPP) or oxidised low-density lipoproteins (LDL) could be representative of the fundamental mechanism for the identification of damaged-"self ' by DC. AOPP were found to increase the T-cell stimulatory capacity of DC (as assessed by oxidative mitogenesis assays) without inducing their conventional maturation, whilst oxidised LDL were shown to cause both phenotypic and functional maturation of DC. Furthermore, native LDL caused DC aggregation, and oxidised LDL caused DC apoptosis. In conclusion, oxidised derivatives of "self' may play an important contribution to physiological and pathophysiological responses involving DC maturation.

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