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Title: Immune modulation by dendritic cells as a mechanism of action of extracorporeal photopheresis therapy for graft-versus-host disease after allogeneic haematopoietic stem cell transplantation
Author: Holtick, Udo
ISNI:       0000 0004 2741 4289
Awarding Body: University of Newcastle Upon Tyne
Current Institution: University of Newcastle upon Tyne
Date of Award: 2011
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Extracorporeal Photopheresis (ECP) has been shown to be an effective treatment for graft-versus-host disease (GvHD), the major barrier to successful allogeneic haematopoietic stem cell transplantation. Importantly, ECP results in immunomodulation without affecting relapse or infection rates. The mechanisms of action of ECP described so far include Iymphocyte apoptosis, cytokine modulation and induction of T regulatory cells (Treg). This study attempted to analyse direct and indirect effects of ECP on dendritic cells (DC) using an in vitro model (in vitro PUVA). DC underwent apoptosis after PUVA treatment, which was preceded by partial maturation of DC whereas stimulation through CD40 ligation was abrogated and IL-12 secretion was abolished. PUVA-treated DC skewed naive T cells towards a Th2 response. Employing the human skin explant model as a GvHD model, it was shown that modulation of immature DCs by in vitro PUVA-treated Iymphocytes downregulated GvH reactions. Further experiments demonstrated that activated T cells were more prone to undergo apoptosis after in vitro PUVA treatment. In the last section, blood samples sequentially taken from patients treated with ECP within a Phase II clinical trial in Newcastle were analysed by flow cytometry. Total and relative numbers of Treg increased independently of the response status. Likewise, the number of CCR4-positive CD4 (Th2) cells rose. In conclusion, this study describes direct and indirect effects of ECP/PUVA- treatment on DC and reveals that DC modulation may be an important factor for the altered immune response observed after ECP-treatment. Predominant killing of activated T cells might serve as an explanation of why there is no generalised immunosuppression. The finding of Treg and Th2 cell induction in the course of ECP-treatment generally goes in line with published literature and puts further emphasis on ECP's regulatory impact on the immune response.
Supervisor: Not available Sponsor: Not available
Qualification Name: Thesis (Ph.D.) Qualification Level: Doctoral
EThOS ID:  DOI: Not available