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Prepublished online as a Blood First Edition Paper on October 17, 2002; DOI 10.1182/blood-2002-07-2073.
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Blood, 15 February 2003, Vol. 101, No. 4, pp. 1430-1438
IMMUNOBIOLOGY
Histone deacetylase inhibitors: a new class of immunosuppressors
targeting a novel signal pathway essential for CD154
expression
Søren Skov,
Klaus Rieneck,
Lone Frier Bovin,
Kresten Skak,
Søren Tomra,
Birgitte K. Michelsen, and
Niels Ødum
From the Cell Cybernetics Laboratory, Department of
Medical Microbiology and Immunology, The Panum Institute, University of
Copenhagen, Copenhagen, Denmark; the Institute for
Inflammation Research, National University Hospital, Copenhagen,
Denmark; and the Hagedorn Research Institute, Gentofte,
Denmark.
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. Although 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
interleukin 2 (IL-2)-induced CD154 expression on effector T
cells and constitutively expressed CD154 on various tumor cells, events
that were 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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