Date of Award

January 2014

Document Type

Thesis

Degree Name

Medical Doctor (MD)

Department

Medicine

First Advisor

Richard L. Edelson

Second Advisor

Robert E. Tigelaar

Subject Area(s)

Medicine

Abstract

Extracorporeal photochemotherapy (ECP) is a cellular therapy that is FDA approved for the treatment of a variety of T cell mediated diseases, including cutaneous T cell lymphoma, graft-versus-host disease, and solid organ transplantation rejection. Its ability to selectively suppress and stimulate immunity while causing minimal to no side effects in patients distinguishes it from other therapies including pharmacologic agents. Despite the clinical success of ECP, the exact mechanism by which ECP generates immunotolerance and immunogenicity in patients has been elusive. Since monocytes interact with platelets and serum proteins in the ECP chamber to undergo differentiation into dendritic cells (DCs), we examined whether 8-methoxypsoralen (8-MOP) and ultraviolet A (UVA) treatment modified the phenotypic and functional properties of these DCs in a laboratory model of ECP. In a dose-dependent fashion, 8-MOP/UVA treatment of ECP-induced antigen presenting cells induced the expression of glucocorticoid-induced leucine zipper (GILZ), a molecule shown to be both necessary and sufficient for tolerogenic DC phenotype and function. These GILZ expressing cells demonstrated a tolerogenic phenotype and down-regulated the expression of several co-stimulatory molecules including CD80, CD86, and ICAM1. Since the exposure of 8-MOP/UVA on ECP-induced dendritic antigen presenting cells is not uniform, a spectrum of DC is generated from the procedure. The dose-dependent induction of GILZ by 8-MOP/UVA may help to provide a molecular and mechanistic explanation of how ECP is capable of inducing immunosuppression and immunity with GILZ high DCs and GILZ low DCs respectively.

Share

COinS