Public Release: 

Discovering new regulators of the immune system

BioMed Central

London, U.K. and South San Francisco, CA, 15th September 2003. In an attempt to find new regulators of the immune system, a team of researchers at Rigel Pharmaceuticals, Inc. have created a successful method for discovering molecules that are involved in signalling pathways. As published this week in the Journal of Biology, the team conducted a functional genome-wide screen and discovered novel modulators of T-cell receptor signalling that could aid in the development of drugs that target the immune response.

T cells are an integral part of the immune response. Helper T cells encourage antibody-producing B cells to replicate and secrete antibodies, and play a role in the inflammatory response. Cytotoxic T cells identify and kill cells that have been infected with viruses. As all these functions are initiated by T-cell receptors, each response must be determined by the particular set of downstream signalling components that are activated. Until now, identifying novel components of these pathways has been slow. As the article notes, the researchers believe that this study demonstrates, "a successful approach for discovering and validating, in a functionally relevant context, important immune regulators on a genome-wide scale."

The research team, led by Dr. Charlene Liao, as part of a collaboration with Novartis, used retroviruses to carry into cells lymphoid genes that regulate T-cell receptor signalling when expressed. Normally, a cell surface marker called CD69 is up regulated when T-cell receptors are activated. However, the researchers selected cells that, when given a new gene to express, failed to up regulate this protein. They then checked that this repression was caused by the introduced gene and was not a side effect of the procedure. After three rounds of selection, 33 individual genes were cloned. Some of these were already known to play a role in the immune response, some already had unrelated functions assigned to them, and others were completely novel.

The Rigel team carried out additional experiments on three of the genes that were identified in the screen to verify their functional relevance. These experiments confirmed that the genes EDG1, PAK2, and the previously unidentified TRAC-1 were normally expressed in the lymphoid system and that truncated versions of the proteins they produce could repress T-cell receptor signalling in T-cells.

The authors write: "This approach provides a tool for functional cloning of regulators in numerous signal transduction pathways. [...] Importantly, the outlined strategy, which requires no prior sequence information of the players involved, does not bias the search to previously known signalling molecules, molecules flagged by DNA-array technologies or signalling molecules discovered in other contexts."

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Once published, this article will be freely available online, in keeping with BioMed Central's policy of open access to research articles:

Systematic Identification of Regulator Proteins Critical for T Cell activation
Peter Chu, Jorge Pardo, Haoran Zhao, Connie C Li, Erlina Pali, Mary M Shen, Kunbin Qu, Simon X Yu, Betty C B Huang, Peiwen Yu, Esteban S Masuda, Frank Kolbinger, Gregorio Aversa, Jan de Vries, Donald G Payan and X Charlene Liao.
Journal of Biology 2:21
http://jbiol.com/content/2/3/21
Published 15th September 2003

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Contact Dr. Donald G. Payan Rigel's CSO and Executive Vice President (dgpayan@rigel.com) for further information about this research.

Alternatively contact Gemma Bradley by email at press@biomedcentral.com or by phone on 44-207-323-0323.

Journal of Biology (http://jbiol.com) is published by BioMed Central (http://www.biomedcentral.com), an independent online publishing house committed to providing immediate free access to peer-reviewed biological and medical research. This commitment is based on the view that open access to research is essential to the rapid and efficient communication of science. In addition to open-access original research, BioMed Central also publishes reviews and other subscription-based content.

About Rigel Pharmaceuticals, Inc. (www.rigel.com)
Rigel's mission is to become a source of novel, small-molecule drugs to meet large, unmet medical needs. Rigel has identified three lead product development programs: mast cell inhibition to treat immunologic diseases such as asthma/allergy and autoimmune disorders, antiviral agents to treat hepatitis C, and ligases, a new class of cancer drug targets. Rigel has begun clinical testing of its first product candidate, R112, for allergic rhinitis, and plans to begin clinical trials of three additional drug candidates, for the treatment of hepatitis C, rheumatoid arthritis, and asthma by the end of 2004.

This press release contains "forward-looking" statements, including statements about research and development projects. Any statements contained in this press release that are not statements of historical fact may be deemed to be forward-looking statements. Words such as "plans", "intends" and similar expressions are intended to identify these forward-looking statements. There are a number of important factors that could cause Rigel's results to differ materially from those indicated by these forward-looking statements, including risks associated with the timing and success of research projects, clinical trials and the commercialization of product candidates, as well as other risks, detailed from time to time in Rigel's SEC reports, including its Quarterly Report on Form 10-Q for the quarter ended June 30, 2003 and Annual Report on Form 10-K, as amended, for the year ended December 31, 2002. Rigel does not undertake any obligation to update forward-looking statements.

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