title: Selective NFAT targeting in T cells ameliorates GvHD while maintaining antitumor activity.
abstract: Graft-versus-host disease (GvHD) is a life-threatening immunological complication after allogenic hematopoietic stem cell transplantation (allo-HCT). The intrinsic graft-versus-leukemia (GvL) effect, however, is the desirable curative benefit. Patients with acute GvHD are treated with cyclosporine A (CsA) or tacrolimus (FK506), which not only often causes severe adverse effects, but also interferes with the anticipated GvL. Both drugs inhibit calcineurin, thus at first suppressing activation of the nuclear factor of activated T cells (NFAT). Therefore, we explored the specific contribution of individual NFAT factors in donor T cells in animal models of GvHD and GvL. Ablation of NFAT1, NFAT2, or a combination of both resulted in ameliorated GvHD, due to reduced proliferation, target tissue homing, and impaired effector function of allogenic donor T cells. In contrast, the frequency of Foxp3(+) regulatory T (Treg) cells was increased and NFAT-deficient Tregs were fully protective in GvHD. CD8(+) T-cell recall response and, importantly, the beneficial antitumor activity were largely preserved in NFAT-deficient effector T cells. Thus, specific inhibition of NFAT opens an avenue for an advanced therapy of GvHD maintaining protective GvL.
authors.affiliation: Department of Molecular Pathology, Institute of Pathology, and.
authors.forename: Martin
authors.initials: M
authors.lastname: Vaeth
authors.affiliation: Department of Medicine II and Center for Interdisciplinary Clinical Research, University Hospital Würzburg, 97078 Würzburg, Germany.
authors.forename: Carina A
authors.initials: CA
authors.lastname: Bäuerlein
authors.affiliation: Department of Molecular Pathology, Institute of Pathology, and.
authors.forename: Tobias
authors.initials: T
authors.lastname: Pusch
authors.affiliation: Department of Molecular Pathology, Institute of Pathology, and.
authors.forename: Janina
authors.initials: J
authors.lastname: Findeis
authors.affiliation: Department of Medicine II and Center for Interdisciplinary Clinical Research, University Hospital Würzburg, 97078 Würzburg, Germany.
authors.forename: Martin
authors.initials: M
authors.lastname: Chopra
authors.affiliation: Institute of Pathology, and.
authors.forename: Anja
authors.initials: A
authors.lastname: Mottok
authors.affiliation: Institute of Pathology, and Center for Interdisciplinary Clinical Research, University Hospital Würzburg, 97078 Würzburg, Germany Comprehensive Cancer Center Mainfranken, Julius Maximilian University of Würzburg, 97080 Würzburg, Germany; and.
authors.forename: Andreas
authors.initials: A
authors.lastname: Rosenwald
authors.affiliation: Department of Medicine II and Center for Interdisciplinary Clinical Research, University Hospital Würzburg, 97078 Würzburg, Germany Comprehensive Cancer Center Mainfranken, Julius Maximilian University of Würzburg, 97080 Würzburg, Germany; and.
authors.forename: Andreas
authors.initials: A
authors.lastname: Beilhack
authors.affiliation: Department of Molecular Pathology, Institute of Pathology, and Center for Interdisciplinary Clinical Research, University Hospital Würzburg, 97078 Würzburg, Germany Comprehensive Cancer Center Mainfranken, Julius Maximilian University of Würzburg, 97080 Würzburg, Germany; and path230@mail.uni-wuerzburg.de.
authors.forename: Friederike
authors.initials: F
authors.lastname: Berberich-Siebelt
mesh_terms: D064591:Allografts; D000818:Animals; D018414:CD8-Positive T-Lymphocytes / Q000276:immunology* / Q000473:pathology; D065095:Calcineurin Inhibitors / Q000494:pharmacology; D049109:Cell Proliferation / Q000187:drug effects / Q000235:genetics; D016572:Cyclosporine / Q000494:pharmacology; D004195:Disease Models, Animal; D006086:Graft vs Host Disease / Q000235:genetics / Q000276:immunology* / Q000473:pathology; D020544:Graft vs Leukemia Effect / Q000235:genetics / Q000276:immunology*; D018380:Hematopoietic Stem Cell Transplantation; D051379:Mice; D018345:Mice, Knockout; D050778:NFATC Transcription Factors / Q000235:genetics / Q000276:immunology*; D050378:T-Lymphocytes, Regulatory / Q000276:immunology* / Q000473:pathology; D016559:Tacrolimus / Q000494:pharmacology
chemical_list: D065095:Calcineurin Inhibitors; D050778:NFATC Transcription Factors; C494005:Nfatc1 protein, mouse; C494007:Nfatc2 protein, mouse; D016572:Cyclosporine; D016559:Tacrolimus
keywords: NFAT; graft-versus-host disease; graft-versus-leukemia effect; hematopoietic stem cell transplantation; regulatory T cell