90: Photopheresis stimulates the generation of regulatory T cells

Abstract

Extracorporeal photopheresis (ECP) involves the reinfusion of autologous, apoptotic peripheral blood leukocytes treated ex vivo with 8-methoxypsoralen (8-MOP) and UVA light. ECP is approved for the treatment of cutaneous T cell lymphoma. ECP has also shown promise as a treatment for other immune-mediated inflammatory disorders suggesting a common immunologic pathway may be involved in its mechanism of action. Several investigators including ourselves have recently provided in vivo evidence to suggest that the delivery of ECP-treated apoptotic cells modulates immune responses, in part, through the generation of regulatory T cells. In vitro studies have also demonstrated that activation of naive T cells in the presence of antigen presenting cells (APCs) that have previously engulfed ECP-treated apoptotic cells leads to the generation of a T cell population that can suppress syngeneic T cell proliferation and function. In this study, we expand the scope of these original findings by demonstrating that co-incubation of naive CD4+ T cells with ECP-treated peripheral blood mononuclear cells also results in the development of a regulatory T cell phenotype. ECP-mediated generation of regulatory T cells is dependent on APCs and can be reversed by the addition of IL-2. CD25 expression is upregulated on these regulatory T cells and they actively proliferate in response to concanavalin-A (Con A) but do not express increased levels of Foxp3 or IL-10, nor do they secrete significant levels of pro-inflammatory cytokines such as IL-2, IFNγ, IL-4, and TNFα. Transfer of these regulatory T cells to a secondary MLR reaction results in the inhibition of syngeneic responder T cell proliferation. Collectively, these results demonstrate that ECP-treated apoptotic cells are capable of modulating other immune cells, in part, through the generation of regulatory T cells. It is hoped that a better understanding of the mechanism of action behind ECP will help to define more efficacious and cost-effective treatment regimens.