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Biology of blood and marrow transplantation : journal of the American Society for Blood and Marrow Transplantation

Blocking activator protein 1 activity in donor cells reduces severity of acute graft-versus-host disease through reciprocal regulation of IL-17-producing T cells/regulatory T cells.


PMID 24813170

Abstract

Acute graft-versus-host disease (aGVHD) is a major cause of mortality in allogeneic bone marrow transplantation. Here, the diminishing effect of activator protein 1 (AP-1) blocking with a synthetic retinoid (SR11302) on the severity of aGVHD in a murine model was investigated. MHC-mismatched strain combinations were used inxa0vivo: C57BL/6 (H-2k(b)) donors into lethally irradiated BALB/c (H-2k(d)) recipients. SR11302 inhibited alloreactive Txa0cell response in a dose-dependent manner and negatively regulated signal transducer and activator of transcription 3 (STAT3) activation. AP-1 blocking in Txa0cells inhibited the differentiation of Th1 and Th17. Conversely, Foxp3(+) regulatory Txa0cells (Treg) population dramatically expanded. Transfer of SR11302-treated donor splenocytes into lethally irradiated recipients diminished the lethality and clinical severity of aGVHD. In line with these results, AP-1 blocking in donor splenocytes exhibited reduced Th17/Th1 population and enhanced inxa0vivo Treg population. Beneficial Treg expanding property of SR11302 was associated with the induction of Foxp3 and STAT5 transcription factor, where the inhibiting property of Th17 was achieved by suppressing the phosphorylated form of STAT3 and enhancing SOCS3. In conclusion, the preventive potential of AP-1 inhibitor in aGVHD may be accomplished by altering CD4(+) Txa0cell differentiation through modulating transcription factors.