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

Lei Wang, Ming Ni, Angela Hückelhoven-Krauss, Leopold Sellner, Jean Marc Hoffmann, Brigitte Neuber, Thomas Luft, Ute Hegenbart, Stefan Schönland, Christian Kleist, Martin Sill, Bao An Chen, Patrick Wuchter, Volker Eckstein, William Krüger, Inken Hilgendorf, Ronit Yerushalmi, Arnon Nagler, Carsten Müller-Tidow, Anthony D. HoPeter Dreger, Michael Schmitt, Anita Schmitt

Research output: Contribution to journalArticlepeer-review

Abstract

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, LuminexTM-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 CD19hiCD20hi 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+CD38hi 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.

Original languageEnglish
Article number2207
JournalFrontiers in Immunology
Volume9
Issue numberOCT
DOIs
StatePublished - 8 Oct 2018
Externally publishedYes

Keywords

  • Anti-leukemic effect
  • Anti-viral effect
  • ECP
  • Effector cells
  • GvHD
  • Immunomodulation
  • Proinflammatory cytokines
  • Regulatory cells

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