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Prepublished online as a Blood First Edition Paper on October 17, 2002; DOI 10.1182/blood-2002-07-2073.
Submitted July 15, 2002
Accepted September 15, 2002
Histone deacetylase inhibitors: a new class of immunosuppressors targeting a novel signal-pathway essential for CD154 expression
Soren Skov*, Klaus Rieneck, Lone F Bovin, Kresten Skak, Soren Tomra, Birgitte K Michelsen, and Niels Odum
Department of Medical Microbiology and Immunology, The Panum Institute, University of Copenhagen, Copenhagen, Denmark
Institute for Inflammation Research, National University Hospital, Copenhagen, Denmark
Hagedorn Research Institute, Gentofte, Denmark
* Corresponding author; email: s.skov{at}immi.ku.dk.
Here we report that Histone deacetylase inhibitors (HDAC-i) comprise a new class of immunosuppressive agents.
HDAC-i inhibited CD4 T cell proliferation in a dose dependent manner, which was not caused by apoptosis or decreased viability. While early intracellular signals such as tyrosine kinase activity and elevation of intracellular calcium concentration were not affected, the characteristic aggregation of T cells following activation was completely abrogated. This correlated with diminished activation-induced expression of the adhesion molecules. HDAC-i furthermore inhibited activation-induced CD25 and CD154 expression on CD4 cells, without affecting induction of CD69. HDAC-i inhibited CD154 expression by a mechanism distinctly different from Cyclosporine mediated inhibition. HDAC-i thus inhibited IL-2 induced CD154 expression on effector T cells and constitutively expressed CD154 on various tumor cells, events that was not affected by Cyclosporine. Additional studies showed that HDAC-i treatment inhibited c-Myc expression, which was further shown to be important for CD154 gene activation.
These results demonstrate pronounced T cell inhibitory activity of HDAC-i, which may form the basis of novel therapeutic interventions against autoimmune diseases and allograft rejection.
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