Modulation of B Cells and Homing Marker on NK Cells Through Extracorporeal Photopheresis in Patients With Steroid-Refractory/Resistant Graft-Vs.-Host Disease Without Hampering Anti-viral/Anti-leukemic Effects

• Published in: Frontiers in immunology 2018-10, Vol.9, p.2207-2207
• Main Authors: Wang, Lei, Ni, Ming, Hückelhoven-Krauss, Angela, Sellner, Leopold, Hoffmann, Jean-Marc, Neuber, Brigitte, Luft, Thomas, Hegenbart, Ute, Schönland, Stefan, Kleist, Christian, Sill, Martin, Chen, Bao-An, Wuchter, Patrick, Eckstein, Volker, Krüger, William, Hilgendorf, Inken, Yerushalmi, Ronit, Nagler, Arnon, Müller-Tidow, Carsten, Ho, Anthony D, Dreger, Peter, Schmitt, Michael, Schmitt, Anita
• Format: Article
• Language: English
• Subjects: ECP; effector cells; GvHD; Immunology; immunomodulation; proinflammatory cytokines; regulatory cells
• ISSN: 1664-3224; 1664-3224
• DOI: 10.3389/fimmu.2018.02207

Graft-vs.-host disease (GvHD), a severe complication of allogeneic hematopoietic stem cell transplantation, significantly affects the post-transplant morbidity and mortality. Systemic steroids remain the gold standard for the initial management of GvHD. However, up to 60% of patients will not sufficiently respond to steroids. Extracorporeal photopheresis (ECP), a cell-based immunotherapy, has shown good clinical results in such steroid-refractory/resistant GvHD patients. Given its immunomodulatory, but not global immunosuppressive and steroid-sparing capacity, ECP constitutes an attractive option. In the case of GvHD, the balance of immune cells is destroyed: effector cells are not any longer efficiently controlled by regulatory cells. ECP therapy may restore this balance. However, the precise mechanism and the impact of ECP on anti-viral/anti-leukemic function remain unclear. In this study, 839 ECP treatments were performed on patients with acute GvHD (aGvHD) and chronic GvHD (cGvHD). A comprehensive analysis of effector and regulatory cells in patients under ECP therapy included multi-parametric flow cytometry and tetramer staining, Luminex -based cytokine, interferon-γ enzyme-linked immunospot, and chromium-51 release assays. Gene profiling of myeloid-derived suppressor cells (MDSCs) was performed by microarray analysis. Immunologically, modulations of effector and regulatory cells as well as proinflammatory cytokines were observed under ECP treatment: (1) GvHD-relevant cell subsets like CD62L NK cells and newly defined CD19 CD20 B cells were modulated, but (2) quantity and quality of anti-viral/anti-leukemic effector cells were preserved. (3) The development of MDSCs was promoted and switched from an inactivated subset (CD33 CD11b ) to an activated subset (CD33 CD11b ). (4) The frequency of Foxp3 CD4 regulatory T cells (Tregs) and CD24 CD38 regulatory B cells was considerably increased in aGvHD patients, and Foxp3 CD8 Tregs in cGvHD patients. (5) Proinflammatory cytokines like IL-1β, IL-6, IL-8, and TNF-α were significantly reduced. In summary, ECP constitutes an effective immunomodulatory therapy for patients with steroid-refractory/resistant GvHD without impairment of anti-viral/leukemia effects.