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Proc Natl Acad Sci U S A. 2015 Jan 27;112(4):1125-30. doi: 10.1073/pnas.1409290112. Epub 2015 Jan 12.

Selective NFAT targeting in T cells ameliorates GvHD while maintaining antitumor activity.

Author information

1
Department of Molecular Pathology, Institute of Pathology, and.
2
Department of Medicine II and Center for Interdisciplinary Clinical Research, University Hospital Würzburg, 97078 Würzburg, Germany.
3
Institute of Pathology, and.
4
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.
5
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.
6
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.

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.

KEYWORDS:

NFAT; graft-versus-host disease; graft-versus-leukemia effect; hematopoietic stem cell transplantation; regulatory T cell

PMID:
25583478
PMCID:
PMC4313840
DOI:
10.1073/pnas.1409290112
[Indexed for MEDLINE]
Free PMC Article

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