Application): The drug thalidomide was frequently administered in the 1960's as a sedative for morning sickness, but its use was discontinued due to tetratogenicity. However, this agent has experienced a resurgence in interest in its non-sedative and non-embryonic effects, namely its immunomodulatory activity. Thalidomide, an anti-tumor necrosis factor alpha agent, has been described as being effective in the treatment of autoimmune disorders such as leprosy, the treatment of disorders due to HIV injection such as aphthous ulcerations and cachexia, and the inhibition of HIV-1 replication and AIDS progression. Several researchers have described contradictory immunomodulatory effects of this potentially important therapeutic is still unclear. Therefore, the focus of the proposed study is to determine the effects of thalidomide in normal C57BL/6 mice and hTNF-alpha transgenic C57BL/6 mice. The hypothesis of these proposed series of experiments is that the anti-TNF alpha activity of thalidomide mediates the immunomodulatory effects and will alter the function of the immune system at the cellular level.
The aims of the proposed study include: (1) to determine any side effects to the use of the thalidomide in a normal murine model; (2) to observe and determine if thalidomide induces a significant alleviation of symptoms in arthritis-prone hTNF- alpha transgenic mice; (3) to determine if thalidomide alters the immunocompetence of T and beta lymphocytes in normal and transgenic mice; and (4) to assess the effect of thalidomide on leukocyte cell-cell interactions and programmed cell death and apoptosis. The data generated from the proposed study will supply important information on the action of thalidomide at the cellular level. Additionally, these experiments will allow the observation of the activity of this drug on an animal model for one the most common human autoimmune diseases, arthritis. Finally, the elucidation of the method by which this anti-TNF-alpha agent works may be applied to the treatment of other autoimmune disorders and HIV/AIDS diseases.
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