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| ■ Immunology |
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T-cell targeted, anti-rheumatic drugs
For decades, considerable efforts have been made to develop immunosuppressive drugs for the
treatment of undesired immune reactions, such as graft rejection and autoimmune diseases. These immunosuppressive
agents include small chemicals, steroids, peptides and proteins. The use of small chemicals, consisting mainly of
anti-metabolites, and steroids is effective in the short term only, however, as these treatments usually result
in quite serious side effects, including bone marrow toxicity, kidney toxicity and a general loss of the
integrity of immune function. These toxic manifestations are due to a lack of
target-specificity. Protein based drugs, including recombinant receptors and
antibodies, are relatively target-specific but are excessively costly to produce. Hence, there is now a need
and an increased demand for anti-rheumatic agents which specifically attack discrete subpopulations of immune
cells.
 MBRI is focusing
on the development of T cell-targeted drugs by screening
natural inhibitors of the molecular interactions between T cell signal transducers. Lck is a Src family protein
tyrosine kinase that plays a principal role in the initiation as well as the propagation of T cell antigen
receptor (TCR)-induced signaling, leading to IL-2 expression and T cell proliferation. Deletion or mutation of
lck results in severe damage to T cell function. Lck transmits TCR stimuli via molecular interaction with
downstream signal transducers, resulting in their subsequent phosphorylation. The Lck protein has a
non-catalytic SH2 domain, which is important for protein-protein interaction and subsequent TCR-induced
signaling.
To screen for natural products that inhibit Lck SH2-mediated molecular interactions, an ELISA system has been
developed to analyze thousands of substances. A compound (Rosmarinic acid) has now been identified from these searches
whose derivatives show strong T cell inhibitory activities in various in vitro assays and also function
in a dual mechanism, i.e., inhibition of T cell antigen receptor-induced activation and apoptosis induction.
Rosmarinic acid (RosA) also induces apoptosis of human peripheral blood mononuclear cells in an Lck-dependent manner, where
RosA kills Lck-expressing T cells and NK cells but not Lck-negative cells such as B cells and monocytes. Most
importantly, RosA-induced apoptosis is limited to actively proliferating T cells
and NK cells but not resting cells. This indicates that T cells contributing to various pathological conditions
such as autoimmune diseases could be eliminated without disrupting the normal T cell repertoire. RosA and its derivatives showed strong anti-rheumatic activity in a collagen-induced arthritis
model. Currently, these compounds are under development as therapeutics against rheumatoid arthritis and other
related diseases.
Publications
Hur, Y. G., Yun, Y. and Won, J. (2004). Rosmarinic acid induces p56lck-dependent apoptosis in Jurkat and
peripheral T cells via mitochondrial pathway independent from Fas/Fas ligand interaction. J. Immunol.
172:79-87.
[PubMed Citation]
Youn, J., Lee, K. H., Won, J., Huh, S. J., Yoon, H. S., Cho, W. G., Paik, D. J. (2003).
Beneficial effects of rosmarinic acid on suppression of collagen-induced arthritis. J. Rheumatology
30:1203-1207
[PubMed Citation]
Yun, S. Y., Hur, Y. G., Kang, M. A., Lee, J. and Won, J. (2003). Synergistic
immunosuppressive effects of rosmarinic acid and rapamycin in vitro and in vivo. Transplantation.
75(10):1758-1760
[PubMed Citation]
Kang, M. A., Yun, S. Y., and Won, J. (2003). Rosmarinic acid inhibits Ca2+-dependent
pathways of T cell antigen receptor-mediated signaling through the inhibition of ITK and PLCg-1 activity.
Blood 101:3534-3542.
[PubMed Citation]
Won, J., Hur, Y. G., Hur, E. M., Park, S., Kang, M. A., Choi, Y., Park, C., Lee, K. H. and
Yun, Y. (2003). Rosmarinic acid inhibits TCR-induced T cell activation and proliferation in an Lck-dependent
manner. Eur. J. Immunol. 33: 870-879
[PubMed Citation]
Park, S. H., Won, J., and Lee, K. H. (2002). Design and characterization of
non-phosphopeptide inhibitors for Src family SH2 domains. Bioorg. Med. Chem. Lett.
12(19):2711-2714
[PubMed Citation] |
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