Over 50 different autoimmune diseases have been identified, some of which are common (eg rheumatoid arthritis) while other are very rare. According to some analysts, new therapeutic approaches will drive the market for autoimmune disorders to grow at a rate of over 15%, to a value of over $21 billion by 2006.
The regulation of thymocyte survival/death through T-cell receptor (TCR) activation plays a key role in establishing a functional T-cell repertoire. Control over this repertoire prevents the development of autoimmunity while facilitating host defense. The clonal deletion of auto-reactive T cells in thymus is essential for the discrimination between self and non-self and hence immature T cells that recognize self-peptide-MHC complexes with high affinity/avidity are driven towards apoptosis (negative selection). Therapeutics that bolster this negative selection process may be of benefit to patients with diverse autoimmune disorders.
Among the molecules implicated in T-cell apoptosis is Nur77 (also known as NGFI-B or TR3), a member of the orphan nuclear receptor super-family. Nur77 was originally identified as an immediate early gene transiently induced by serum, growth factors and nerve growth factor. It has also been shown that Nur77 and Nor-1, a related member of the Nur77 family, are induced during TCR-mediated apoptosis. Expression of a dominant-negative Nur77 blocks activation-induced cell death in T-cell hybridomas as well as negative selection in transgenic mice. Conversely, transgenic mice that express wild type Nur77 or Nor-1 exhibit massive apoptosis and a reduction in thymocyte numbers.
Post-translational modification of Nur77 has been previously demonstrated thereby introducing a system of control to the process of T cell apoptosis. This is consistent with the observation that expression of Nur77 does not necessarily correlate with induction of apoptosis. This and other studies suggest the existence of a mechanism that inhibits the proapoptotic function of Nur77. The phosphatidylinositol 3-kinase (PI3-K)-Akt pathway is activated in response to TCR activation and is implicated in mediating survival signals in T cells.
More recently it has been demonstrated that transcription can also be regulated by histone plasticity. This phenomenon centers on the now generally accepted view that chromatin structure is plastic and that histone (de)acetylation regulates genome structure and hence expression. Modifying this process by histone deacetylase (HDAC) inhibitors can therefore regulate, potentially in a highly specific manner, transcription. Information relating to histone deacetylation is emerging with breathtaking rapidity with over 1 new article currently being published every day. In response to this activity we recently published a comprehensive dossier of the pharmaceutical potential of HDAC inhibitors (Click here
HDAC7 was first identified as HDAC-D in 1999 and then classified as HDAC7, a member of the class II histone deacetylase family in 2001. Since its discovery, the functional significance of HDAC7 has remained unclear however as described in Lead Discovery's Daily Updates Bulletin www.leaddiscovery.co.uk/PubMed-dailyupdates.html
and then elaboarted upon in Therapeutic Advances www.leaddiscovery.co.uk/target-discovery/
, UCSF researchers have recently taken a major step forward in this respect demonstrating that it is highly expressed in certain thymocytes. Furthermore HDAC7 was shown to inhibit the expression of Nur77 via the transcription factor MEF2D. HDAC7 is exported from the nucleus during T cell receptor activation, leading to Nur77 expression and hence the facilitation of apoptosis. The UCSF group has demonstrated that a mutant HDAC7 that is not exported from the nucleus in response to TCR activation suppresses TCR-mediated apoptosis. On the other hand, inhibition of HDAC7 expression by RNA interference causes increased apoptosis in response to TCR activation. These observations define HDAC7 as a regulator of Nur77 and apoptosis in developing thymocytes and offer excellent proof of concept data to support the development of HDAC7 inhibitors as modulators of the T-cell repertoire. Such inhibitors therefore deserve investigation as candidates for the treatment of autoimmune disorders. One concept described in our HDAC dossier is that specificity may be conferred to HDAC inhibitors by blocking their interaction with binding proteins rather that inhibiting HDAC activity per se
. In this respect, molecules able to interfere with HDAC7:MEF2D interactions may be of particular therapeutic benefit.
For further information please see Dequiedt et al, 2003 (Immunity. 2003 May;18(5):687-98), click here