Date of Award

January 2011

Document Type

Open Access Thesis

Degree Name

Medical Doctor (MD)

Department

Medicine

First Advisor

Richard Edelson

Subject Area(s)

Immunology

Abstract

We hypothesized that activated platelets induce monocyte-to-dendritic cell (DC) differentiation. The aims of this study were to: (1) determine the role that platelets play, if any, in the signaling of monocyte to DC differentiation; (2) determine the mechanism of action by which platelets induce monocyte-to-DC differentiation. (3) Use this knowledge to advance cancer immunotherapy.

To achieve these ends: (1) parallel-plate flow chambers were designed to deliver monocytes a controlled level of platelet exposure, with phenotype and genotype assessed following overnight incubation; (2) blocking antibodies and proteins were used to assess for the significance of particular monocyte-platelet interactions in the mechanism; (3) additional experiments and mathematical modeling was performed to extrapolate our new mechanistic knowledge to enhance extracorporeal photochemotherapy (ECP), an immunotherapy in clinical use.

Results showed direct correlation between platelet exposure and level of DC differentiation following overnight incubation (p < 0.0001). A detailed mechanism was determined involving p-selectin and other proteins expressed by activated platelets. This mechanistic knowledge permitted intelligent modification of ECP.

We conclude that platelets induce monocyte to DC differentiation. The rapidity and efficiency of this induction suggests the possibility that this is a physiologic mechanism employed in-vivo for DC differentiation. Possible exploitation of this mechanism may prove beneficial in cancer immunotherapy.

Comments

This is an Open Access Thesis.

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