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Division of Immunology and Rheumatology, Departments of Medicine and
Pediatrics, Stanford University School of Medicine, Stanford, CA 94305
CD4+ T cells are believed to play a central role in the
initiation and perpetuation of autoimmune diseases such as multiple
sclerosis. In the murine model for multiple sclerosis,
experimental autoimmune encephalomyelitis, pathogenic T cells exhibit a
Th1-like phenotype characterized by heightened expression of
proinflammatory cytokines. Systemic administration of "regulatory"
cytokines, which serve to counter Th1 effects, has been shown to
ameliorate autoimmune responses. However, the inherent problems of
nonspecific toxicity limit the usefulness of systemic cytokine delivery
as a potential therapy. Therefore, we used the site-specific
trafficking properties of autoantigen-reactive CD4+ T cells
to develop an adoptive immunotherapy protocol that provided local
delivery of a Th1 cytokine antagonist, the p40 subunit of IL-12. In
vitro analysis demonstrated that IL-12 p40 suppressed IFN-
production in developing and effector Th1 populations, indicating its
potential to modulate Th1-promoted inflammation. We have previously
demonstrated that transduction of myelin basic protein-specific
CD4+ T cells with pGC retroviral vectors can result in
efficient and stable transgene expression. Therefore, we adoptively
transferred myelin basic protein-specific CD4+ T cells
transduced to express IL-12 p40 into mice immunized to develop
experimental autoimmune encephalomyelitis and demonstrated a
significant reduction in clinical disease. In vivo tracking of
bioluminescent lymphocytes, transduced to express luciferase, using
low-light imaging cameras demonstrated that transduced CD4+
T cells trafficked to the central nervous system, where histological
analysis confirmed long-term transgene expression. These studies have
demonstrated that retrovirally transduced autoantigen-specific
CD4+ T cells inhibited inflammation and promoted
immunotherapy of autoimmune disorders.
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