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 M and Hoffmann P
  (See online at https://doi.org/10.1016/j.coi.2011.06.006)
• (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 K, Zhu W, Waldhier MC, Schulz U, Ammer J, Holler B, Wolff D, Edinger M, Peter K, Kreutz M, Andreesen R, Oefner PJ, Holler E
  (See online at https://doi.org/10.1182/blood-2011-06-357814)
• (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 M, Karrer S, Hoffmann P, Gottfried E, Szeimies RM, Hahn J, Edinger M, Landthaler M, Andreesen R, Merad M, Holler E
  (See online at https://doi.org/10.1038/jid.2011.255)
• (2012) Dominant Th2 differentiation of human regulatory T cells upon loss of FOXP3 expression. J Immunol. 1;188(3):1275-1282
  Hansmann L, Schmidl C, Kett J, Steger L, Andreesen R, Hoffmann P, Rehli M, Edinger M
  (See online at https://doi.org/10.4049/jimmunol.1102288)
• (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 I, Mueller-Hilke B, Kundt G, Holler E, Hoffmann P, Edinger M, Freund M, Wolff D
  (See online at https://doi.org/10.1111/j.1432-2277.2011.01388.x)
• (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
  (See online at https://doi.org/10.1038/nature13182)
• (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 FJ, Rodriguez Gomez M, Doser K, Edinger M, Hoffmann P, Schiechl G, Talke Y, Göbel N, Schmidbauer K, Brühl H, Mack M
  (See online at https://doi.org/10.1111/imm.12436)
• (2014) Langerhans cells promote early germinal center formation in response to Leishmania-derived cutaneous antigens. Eur J Immunol. 44(10):2955-2967
  Zimara N, Florian C, Schmid M, Malissen B, Kissenpfennig A, Männel DN, Edinger M, Hutchinson JA, Hoffmann P, Ritter U
  (See online at https://doi.org/10.1002/eji.201344263)
• (2014) Physiologic TLR9-CpG-DNA interaction is essential for the homeostasis of the intestinal immune system. Inflamm Bowel Dis. 20(1):136-143
  Hofmann C, Dunger N, Doser K, Lippert E, Siller S, Edinger M, Falk W, Obermeier F
  (See online at https://doi.org/10.1097/01.MIB.0000436276.19755.c1)
• (2014) The enhancer and promoter landscape of human regulatory and conventional T-cell subpopulations. Blood 24;123(17):e68-78
  Schmidl C, Hansmann L, Lassmann T, Balwierz PJ, Kawaji H, Itoh M, Kawai J, Nagao-Sato S, Suzuki H, Andreesen R, Hayashizaki Y, Forrest AR, Carninci P, Hoffmann P, Edinger M, Rehli M; FANTOM consortium
  (See online at https://doi.org/10.1182/blood-2013-02-486944)
• (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 HT, Kuzmina Z, Weigl R, Körmoczi U, Rottal A, Wolff D, Kralj M, Kalhs P, Mitterbauer M, Rabitsch W, Edinger M, Holler E, Pickl WF
  (See online at https://doi.org/10.1016/j.bbmt.2014.11.010)
• (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 K, Kroeger I, Bauer R, Ganss F, Ovsiy I, Rothamer J, Büttner M, Atreya I, Waldner M, Bittrich M, Lehmann CH, Rieger MA, Beilhack A, Zeiser R, Edinger M, Dudziak D, Mackensen A, Rehli M, Ullrich E
  (See online at https://doi.org/10.4161/2162402X.2014.981483)
• (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 AH, Wolff D, Hilgendorf I, Fehn U, Edinger M, Hoffmann P, Herr W, Kölbl O, Holler B, Sporrer D, Holler E, Hautmann MG
  (See online at https://doi.org/10.1016/j.radonc.2015.07.035)
• (2016). Relation between acute GVHD and NK cell subset reconstitution following allogeneic stem cell transplantation. Front Immunol.;7:595
  Ullrich E, Salzmann-Manrique E, Bakhtiar S, Bremm M, Gerstner S, Herrmann E, Bader P, Hoffmann P, Holler E, Edinger M, Wolff D
  (See online at https://doi.org/10.3389/fimmu.2016.00595)
• (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 EM, Fehn U, Holler B, Weber D, Holler E, Herr W, Hoffmann P, Edinger M, Wolff D
  (See online at https://doi.org/10.1007/s00277-016-2881-x)