Humoral immune reconstitution after allogeneic stem cell transplantation

• Applicant: Professor Dr. Matthias Edinger
• Subject Area: General and Visceral Surgery
• Term: from 2010 to 2017
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 160225957

• Final Report Year: 2018

Final Report Abstract

Graft-versus-host disease (GVHD) is a major complication after allogeneic stem cell transplantation (SCT) and causes prolonged immunodeficiency, which is usually attributed to immunosuppressive therapy. Focusing on the quantitative and functional recovery of the B cell compartment in murine disease models, we now clarified the contribution of GVHD itself to poor immune reconstitution. Our experiments revealed that GVHD not only impairs B cell reconstitution in the periphery via the destruction of secondary lymphoid organs, but also impedes early B cell differentiation in the bone marrow by interfering with the B cell niche. B cell precursors are not direct targets of the alloresponse as they are even eradicated in fully reconstituted SCT recipients after the delayed induction of GVHD using donor T cell transfusions (syngenic to the reconstituted B cells). Importantly, this DLI-induced B cell deficiency depends on Fas/FasL-interactions and is reversible as B cell recovery is observed in GVHD-mice successfully treated with donor Treg cell transfusions.

Publications

• (2011) Regulatory T cells in stem cell transplantation: strategies and first clinical experiences. Curr Opin Immunol. 23:679-684
  Edinger, Matthias & Hoffmann, Petra
  
• (2011) Tryptophan catabolism is associated with acute GVHD after human allogeneic stem cell transplantation and indicates activation of indoleamine 2,3-dioxygenase. Blood 118:6971-6974
  Landfried, Karin; Zhu, Wentao; Waldhier, Magdalena C.; Schulz, Ute; Ammer, Julia; Holler, Barbara; Wolff, Daniel; Edinger, Matthias; Peter, Katrin; Kreutz, Marina; Andreesen, Reinhard; Oefner, Peter J. & Holler, Ernst
  
• (2012) The lack of memory B cells including T cell independent IgM+ IgD+ memory B cells in chronic graft-versus host disease is associated with susceptibility to infection. Transpl Int. 25:87-96
  Hilgendorf, Inken; Mueller-Hilke, Brigitte; Kundt, Günther; Holler, Ernst; Hoffmann, Petra; Edinger, Matthias; Freund, Mathias & Wolff, Daniel
  
• (2011) Whole-body UVB irradiation during allogeneic hematopoietic cell transplantation is safe and decreases acute graft-versus-host disease. J Invest Dermatol. 132:179-187
  Kreutz, Marina; Karrer, Sigrid; Hoffmann, Petra; Gottfried, Eva; Szeimies, Rolf-Markus; Hahn, Joachim; Edinger, Matthias; Landthaler, Michael; Andreesen, Reinhard; Merad, Miriam & Holler, Ernst
  
• (2012) Dominant Th2 differentiation of human regulatory T cells upon loss of FOXP3 expression. J Immunol. 1;188(3):1275-1282
  Hansmann, Leo; Schmidl, Christian; Kett, Janina; Steger, Lena; Andreesen, Reinhard; Hoffmann, Petra; Rehli, Michael & Edinger, Matthias
  
• (2014) A promoter-level mammalian expression atlas. Nature 27;507(7493):462-470
  FANTOM Consortium and the RIKEN PMI and CLST (DGT), Forrest AR, Kawaji H, Rehli M, et al. Sandelin A, Hume DA, Carninci P, Hayashizaki Y
  
• (2014) Langerhans cells promote early germinal center formation in response to Leishmania-derived cutaneous antigens. Eur J Immunol. 44(10):2955-2967
  Zimara, Nicole; Florian, Christian; Schmid, Maximilian; Malissen, Bernard; Kissenpfennig, Adrien; Männel, Daniela N.; Edinger, Matthias; Hutchinson, James A.; Hoffmann, Petra & Ritter, Uwe
  
• (2014) Physiologic TLR9-CpG-DNA interaction is essential for the homeostasis of the intestinal immune system. Inflamm Bowel Dis. 20(1):136-143
  Hofmann, Claudia; Dunger, Nadja; Doser, Kristina; Lippert, Elisabeth; Siller, Sebastian; Edinger, Matthias; Falk, Werner & Obermeier, Florian
  
• (2014) The enhancer and promoter landscape of human regulatory and conventional T-cell subpopulations. Blood 24;123(17):e68-78
  Schmidl, Christian; Hansmann, Leo; Lassmann, Timo; Balwierz, Piotr J.; Kawaji, Hideya; Itoh, Masayoshi; Kawai, Jun; Nagao-Sato, Sayaka; Suzuki, Harukazu; Andreesen, Reinhard; Hayashizaki, Yoshihide; Forrest, Alistair R. R.; Carninci, Piero; Hoffmann, Petra; Edinger, Matthias & Rehli, Michael
  
• (2014) Basophils inhibit proliferation of CD4+ T cells in autologous and allogeneic mixed lymphocyte reactions and limit disease activity in a murine model of graft versus host disease. Immunology 145(2):202-212
  Hermann, Fabian J.; Rodriguez Gomez, Manuel; Doser, Kristina; Edinger, Matthias; Hoffmann, Petra; Schiechl, Gabriela; Talke, Yvonne; Göbel, Nicole; Schmidbauer, Kathrin; Syed, Shahzad N.; Brühl, Hilke & Mack, Matthias
  
• (2015) CD19(+)CD21(low) B Cells and CD4(+)CD45RA(+)CD31(+) T cells correlate with first diagnosis of chronic graft-versus-host disease. Biol Blood Marrow Transplant. 21(2):250-258
  Greinix, Hildegard T.; Kuzmina, Zoya; Weigl, Roman; Körmoczi, Ulrike; Rottal, Arno; Wolff, Daniel; Kralj, Mateja; Kalhs, Peter; Mitterbauer, Margit; Rabitsch, Werner; Edinger, Matthias; Holler, Ernst & Pickl, Winfried F.
  
• (2015). Identification and characterization of the specific murine NK cell subset supporting graft-versus-leukemia- and reducing graft-versus-host-effects. Oncoimmunology 4(1):e981483
  Meinhardt, Kathrin; Kroeger, Irena; Bauer, Ruth; Ganss, Franziska; Ovsiy, Ilja; Rothamer, Johanna; Büttner, Maike; Atreya, Imke; Waldner, Maximilian; Bittrich, Max; Lehmann, Christian HK; Rieger, Michael A; Beilhack, Andreas; Zeiser, Robert; Edinger, Matthias; Dudziak, Diana; Mackensen, Andreas; Rehli, Michael & Ullrich, Evelyn
  
• (2015). Total nodal irradiation in patients with severe treatment-refractory chronic GVHD after allogeneic stem cell transplantation: Response rates and immunomodulatory effects. Radiother Oncol.; 116(2):287-93
  Hautmann, Anke H.; Wolff, Daniel; Hilgendorf, Inken; Fehn, Ute; Edinger, Matthias; Hoffmann, Petra; Herr, Wolfgang; Kölbl, Oliver; Holler, Barbara; Sporrer, Daniela; Holler, Ernst & Hautmann, Matthias G.
  
• (2016). Relation between acute GVHD and NK cell subset reconstitution following allogeneic stem cell transplantation. Front Immunol.;7:595
  Ullrich, Evelyn; Salzmann-Manrique, Emilia; Bakhtiar, Shahrzad; Bremm, Melanie; Gerstner, Stephanie; Herrmann, Eva; Bader, Peter; Hoffmann, Petra; Holler, Ernst; Edinger, Matthias & Wolff, Daniel
  
• (2017). Altered immune reconstitution of B and T cells precedes the onset of clinical symptoms of chronic GVHD and is influenced by the type of onset. Ann Hematol.; 96(2):299-310
  Bohmann, E.-M.; Fehn, U.; Holler, B.; Weber, D.; Holler, E.; Herr, W.; Hoffmann, P.; Edinger, M. & Wolff, D.