LBH589 enhances T cell activation in vivo and accelerates graft-versus-host disease in mice.
Histone deacetylase inhibitors (HDACis) are a new class of compounds that induce acetylation of histone lysine tails in chromatin and modify gene expression. The Food & Drug Administration approved HDACi, Vorinostat, or suberoylanilide hydroxamic acid (SAHA), has been shown to inhibit tumor cell growth and the production of proinflammatory cytokines. In preclinical allogeneic transplant models, SAHA induces graft-versus-host disease (GVHD) amelioration in treated mice without impairing graft-versus-leukemia. LBH589 (Panobinostat), a structurally novel cinnamic hydroxamic acid class, is an HDACi more potent than SAHA. In the current work, we tested the hypothesis that LBH589 would be highly effective in the prevention of GVHD. Using mouse model of allogeneic bone marrow transplant (BMT), we unexpectedly found that treatment with LBH589 accelerated GVHD, in contrast to the treatment with SAHA that alleviated GVHD. Accelerated GVHD in the recipients treated with LBH589 was associated with elevated Th1 cytokines in recipient serum, enhanced CXCR3 expression on donor T cells, and T cell infiltration in the liver. The current study highlights the distinct effects of pan HDACi on allogeneic BMT and alerts that LBH589 (Panobinostat) could have an adverse effect on GVHD, and possibly on other inflammatory diseases.
Departments of Immunology & Blood and Marrow Transplantation, H. Lee Moffitt Cancer Center and Research Institute, Tampa, FL 33612, USA.
Dapeng
D
Wang
Cristina
C
Iclozan
Chen
C
Liu
Changqing
C
Xia
Claudio
C
Anasetti
Xue-Zhong
XZ
Yu
D000818:Animals; D004195:Disease Models, Animal; D005260:Female; D006086:Graft vs Host Disease / Q000276:immunology* / Q000517:prevention & control*; D056572:Histone Deacetylase Inhibitors / Q000009:adverse effects / Q000494:pharmacology*; D006877:Hydroxamic Acids / Q000009:adverse effects / Q000494:pharmacology*; D007211:Indoles / Q000009:adverse effects / Q000494:pharmacology*; D008213:Lymphocyte Activation / Q000187:drug effects / Q000276:immunology; D051379:Mice; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D000077767:Panobinostat; D013601:T-Lymphocytes / Q000187:drug effects* / Q000276:immunology
D056572:Histone Deacetylase Inhibitors; D006877:Hydroxamic Acids; D007211:Indoles; D000077767:Panobinostat