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Induction of the IL-12 family of cytokines during the innate immune response to viruses.
Dr. Petro presently has funding from the National Multiple Sclerosis Society to investigate a mouse model of human MS in which a viral infection is the primary trigger. His laboratory is focusing upon the innate immune response to the Theiler's Murine Encephalomyelitis Virus (TMEV). The innate immune response to viral infection is dependent to a large extent upon the induction of Type I interferons (IFN) alpha/beta, IL-12, and IFN-gamma. Type I interferons create an antiviral state in which the cytotoxic capabilities of NK and NKT cells against virus-infected cells are increased. On the other hand, IL-12 and IFN-gamma increase the proliferation of NK and NKT cells and bring about the expression of inducible nitric oxide synthase (NOS2) and thus nitric oxide, which has potent anti-viral properties. Interestingly, innate anti-viral immunity is internally regulated by Type I interferon control of the IL-12/IFN-gamma/NOS2 nexus and nitric oxide control of Type I interferon expression. Therefore, it is possible that one or the other system will dominate an innate anti-viral immune response.

The immune response to viruses is considered necessary for the control of viral replication within the human body. The innate immune response to the virus often is dominated by one nexus that leads to a persistent viral infection. In addition, the tissue destruction brought about by the virus sometimes leads to an autoimmune disease such as MS. It is not completely clear what triggers MS, but production of the IL-12 family of proteins precedes and dominates many of these autoimmune responses. We have found in an experimental mouse model that the production of the prototypical IL-12 family member, IL-12p35/p40, is necessary for a successful anti-TMEV innate immune response that does not lead to MS-like disease. On the other hand, if IL-12 p40/p40 dominates, the unsuccessful innate anti-TMEV immune response, then MS-like disease ensues. The molecular mechanism by which the IL-12 family of proteins is expressed at the gene level is not known and is the subject of our research.

Cytokine Expression
Cytokines produced by cells of the bone microenvironment are being recombined with in vitro and in vivo bone turnover systems to define more clearly their resorption/apposition effects. Inflammatory mediator gene promoter constructs are being transfected into primary cells and cell lines from the bone microenvironment to study mechanisms of gene activation and anabolic/catabolic cytokine production, particularly as influenced by bacterial antigens, estrogen levels, maturity, and tobacco products. Long-term goals include defining gene signalling factors which could be manipulated to direct cytokine production. Novel cytokines that influence bone turnover also are being sought. Cell lines from individuals also could be developed which could be used to reseed periodontal defects and stimulate bone regeneration.

Regulation of Cytokine Production
It is quite clear that CD4 T cell and APC cytokine production is induced by appropriate ligation of cell membrane proteins, transmembrane signalling cascades, and activation of cytokine-specific transcriptional factors interacting with promoters of cytokine genes. The BRG is committed to the elucidation of these pathways and counter-measures that control cytokine expression. This information could be used to direct the immune response against microbial insult down a more protective path. In order to achieve these goals, BRG will explore the use of unique immunological adjuvants and therapies to manipulate these signalling systems.

Last modified: April 2, 2007 6:14 PM