Ardeshna, Kirit M.; (2000) Studies into the characteristics and basic biology of dendritic cells and their use in the immunotherapy of malignancy. Doctoral thesis (Ph.D), UCL (University College London).

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Abstract

Dendritic cells (DCs) are the most potent of all antigen presenting cells, playing a central role in initiating and orchestrating immune responses. It has recently become possible to generate large numbers of DCs from either CD34+ haemopoietic progenitor cells or peripheral blood monocytes under the influence of various cytokines. With this advance there has been a great explosion of interest in using ex vivo generated DCs as part of immunotherapy programmes directed towards the treatment of malignancy, chronic infections and autoimmune diseases, as well as in the context of inducing tolerance following allogeneic transplantation. In all these settings the DCs need to be loaded with the appropriate antigens. This can be achieved by several methods, each of which has its advantages and disadvantages. In this thesis a comparison is made between the methods used to generate DCs from either CD34+ progenitor cells or CD14+ monocytes. The morphology, phenotype and functional characteristics of the resulting DCs are reported. Results are presented which demonstrate that the differentiation of monocytes into DCs under the influence of GM-CSF and IL-4 is a non-proliferative process and therefore does not lend itself to retroviral transduction, rendering this method of loading DCs with antigen inapplicable. The signal transduction pathways which are involved in the lipopolysaccharide (LPS)-induced maturation of monocyte derived DCs are also explored. The p38SAPK pathway and NF-KB pathways are shown to be important in regulating some but not all of the phenotypic changes which occur with LPS-induced maturation of DCs. The PI3 kinase pathway is shown to be important in maintaining the viability of LPS stimulated DCs. Finally, a clinically applicable method for generating DCs from CD34+ progenitor cells is described, and preliminary results are presented on two patients with non-Hodgkins Lymphoma treated with DCs generated in this manner and loaded with tumour antigens in the form of an autologous tumour cell lysate.

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