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B- Deficient Mice: Roles of NF-B in the Activation and Differentiation of Autoreactive T Cells1
*
Institute for Human Gene Therapy and Department of Molecular and Cellular Engineering, and
Department of Neurology, University of Pennsylvania School of Medicine, Philadelphia, PA 19104
Experimental autoimmune encephalomyelitis (EAE) is an inflammatory
disease of the CNS, which has long been used as an animal model for
human multiple sclerosis. Development of autoimmune disease requires
coordinated expression of a number of genes that are involved in the
activation and effector functions of inflammatory cells. These include
genes that encode costimulatory molecules, cytokines, chemokines, and
adhesion molecules. Activation of these genes is regulated at the
transcriptional level by several families of transcription factors. One
of these is the NF-
B family, which is present in a variety of cell
types and becomes highly activated at sites of inflammation. To test
the roles of NF-B in the development of autoimmune diseases, we
studied EAE in mice deficient in one of the NF-B isoforms, i.e.,
NF-B1 (p50). We found that NF-B1-deficient mice were
significantly resistant to EAE induced by myelin oligodendrocyte
glycoprotein. The resistance was primarily evidenced by a decrease in
disease incidence, clinical score, and the degree of CNS inflammation.
Furthermore, we established that the resistance to EAE in
NF-B1-deficient mice was associated with a deficiency of myelin
oligodendrocyte glycoprotein-specific T cells to differentiate into
either Th1- or Th2-type effector cells in vivo. These results strongly
suggest that NF-B1 plays crucial roles in the activation and
differentiation of autoreactive T cells in vivo and that blocking
NF-B function can be an effective means to prevent autoimmune
encephalomyelitis.
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