Abstract

Chronic graft-versus-host disease (cGVHD) is a common side effect of allogeneic stem cell transplantation and a major cause of morbidity and mortality in affected patients. Especially skin, eyes and oral mucosa are affected. This can lead to pain and functional impairment. Extracorporeal photopheresis (ECP) is an effective immunomodulatory therapy with minimal side effects but its mode of action is still largely unknown. The objective of the present study was to examine the effects of ECP on neutrophil granulocytes in patients with cGVHD. Analysis of leukocytes from cGVHD patients obtained from the ECP device during treatment showed that neutrophil granulocytes account for the majority of cells treated during ECP. Neutrophils from healthy donors treated in vitro with 8-methoxypsoralen and UVA light as well as neutrophils from buffy coats of patients with cGVHD treated by ECP showed increased apoptosis and decreased half-life. In remaining non-apoptotic cells chemoirradiation resulted in loss of activation markers and reduced effector functions. This was accompanied by an increase in extracellular arginase-1 activity. Additional comparison of neutrophils isolated from blood of cGVHD patients before and 24h after ECP revealed a decreased half-life and reduction of effector functions of post-ECP neutrophils ex vivo. These observations strongly suggest that ECP induces both apoptosis and physiological changes in neutrophils and that these changes also take place in vivo. This study is the first to show that ECP modulates apoptosis and inflammatory activity in neutrophil granulocytes, indicating that neutrophils may significantly contribute to the overall immunomodulatory effects attributed to this treatment.

Highlights

  • Hematopoietic stem cell transplantation (HSCT) is a curative treatment for hematological malignancies

  • We demonstrate that neutrophil granulocytes account for the majority of cells treated during Extracorporeal photopheresis (ECP) and address systematically the effects of this treatment on neutrophil apoptosis and function

  • Analysis of buffy coats from patients with chronic GVHD obtained during ECP showed that the majority of the treated cells belong to the neutrophil fraction

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Summary

Introduction

Hematopoietic stem cell transplantation (HSCT) is a curative treatment for hematological malignancies. Besides relapse of the malignant disease itself GVHD is the most common cause of death for patients who have undergone stem cell transplantation [2]. ECP was applied to heterogeneous patient populations with high response rates [10,11,12,13,14] It is applied in a variety of other clinical settings as e.g. for the treatment of cutaneous T cell-lymphoma [15], allograft rejection after solid organ transplantation and severe autoimmune diseases like scleroderma [16]. An accumulation of neutrophilic myeloid-derived suppressor cells over time has been observed in a subgroup of patients with GVHD treated with ECP [30].

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