Date of Award

January 2011

Document Type

Open Access Thesis

Degree Name

Medical Doctor (MD)

Department

Medicine

First Advisor

Richard Edelson

Second Advisor

Carole Berger

Subject Area(s)

Immunology

Abstract

Extracorporeal photochemotherapy (ECP), a cellular therapy involving a light activated drug, is FDA approved for the treatment of Cutaneous T-cell lymphoma (CTCL) and used for reversal of Graft-versus-Host Disease (GHVD) and solid organ transplant rejection. The mechanism by which ECP functions as an immunomodulating treatment is unknown, although work by our lab and others suggests ECP generates functional Dendritic cells (DC) that may be involved in tolerization. Both radiation and chemotherapy have been shown to be involved in generation of tolerizing DC, and so we hypothesized that UVA activated chemotherapy 8-Methoxypsoralen (8MOP) exposure induces a tolerizing phenotype in ECP generated DC. In this study, normal donor peripheral blood mononuclear cells (PBMC) were treated in an in vitro model of the ECP apparatus, and collected (no8MOP/UVA sample) or treated with 8MOP (100ng/ml), UVA (2J/cm2) (8MOP/UVA sample). We measured phenotype and functionality of generated cells by two-color flow cytometry and functional assays. In all populations, we noted a statistically significant increase in percentage of cells staining double positive for DC markers (HLA-DR+/CD83+) 18 hours post treatment. 8MOP/UVA treatment reduced expression of mature DC markers (membrane HLA-DR/CD83) and co- stimulatory molecules (CD80/CD86) when compared to no8MOP/UVA and positive control DC, and failed to stimulate CD4+Tcells in antigen presenting assay. These data suggest 8MOP/UVA exposure during ECP inhibits DC maturation and induces a tolerizing phenotype. These tolerizing DC may play a role in the immunosuppressive effects of ECP in the treatment of GVHD and solid organ transplant rejection.

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