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

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 in vivo: C57BL/6 (H-2k^b) donors into lethally irradiated BALB/c (H-2k^d) recipients. SR11302 inhibited alloreactive T cell response in a dose-dependent manner and negatively regulated signal transducer and activator of transcription 3 (STAT3) activation. AP-1 blocking in T cells inhibited the differentiation of Th1 and Th17. Conversely, Foxp3⁺ regulatory T cells (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 in vivo 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⁺ T cell differentiation through modulating transcription factors.