Sheasby, Christopher Edmund; (2001) An investigation into the immunostimulatory effects of Lipopolysaccharide on lymphocytes and dendritic cells in vivo. Doctoral thesis (Ph.D), UCL (University College London).

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Abstract

Protein antigens alone are poorly immunogenic and require adjuvants to generate a vigorous immune response. Poor adjuvanticity may contribute to some vaccines conferring a relatively short duration of protection compared with natural infection. At present, there are few adjuvants available for use in human vaccines. The best experimental adjuvants include components of microorganisms, the activity of which is likely to be related to their ability to mimic natural infection. In this regard, Lipopolysaccharide (LPS) has long been known to act as an adjuvant. However, the mechanism by which LPS enhances the generation of effector and memory T cells during the immune response remains undetermined. We have examined whether the immunostimulatory activity of LPS is associated with effects on both naive lymphocytes and antigen presenting cells. We have primarily focused on the possibility that LPS may act in part through the alteration of cell adhesion and co-stimulatory molecules on naive T cells or antigen presenting cells (APC), altering their ability to respond to, or present specific antigen respectively. In this thesis we report that T cells and antigen presenting cells (DC) isolated from LPS-injected mice had increased cell surface expression of a number of activation markers, including Ly6A/E, CD54, CD95 and CD86. The activation was transient, and for DC was followed by extreme cell loss in the spleen mirrored by a 4-fold increase in the lymph nodes. The phenotypic changes exhibited by T cells were induced indirectly by LPS and could be mimicked by LPS-induced cytokines or supernatant harvested from LPS-stimulated dendritic cells. The data raise the possibility that non-specific "partial" activation of T cells and DC by LPS may affect the generation of an antigen-specific response.

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