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1 From the Department of Ophthalmology and Vision Sciences, Washington University Medical School, St. Louis, Missouri; 2 Department of Ophthalmology and Visual Sciences, University of Louisville Medical School, Louisville, Kentucky; 3 Department of Ophthalmology, Yokohama City University School of Medicine, Yokohama, Japan; and 4 Discovery Oncology, G. D. Searle/Monsanto, St. Louis, Missouri.
PURPOSE. To study the role of costimulatory signaling through the CD28-B7 interaction in experimental autoimmune anterior uveitis (EAAU).
METHODS. Naive Lewis rats were immunized with insoluble melanin-associated antigen (MAA) derived from bovine iris and ciliary body. CTLA4-Fc, a recombinant protein comprised of the extracellular domain of human CTLA4 bound to mouse IgG2a Fc, was used to block the CD28-B7 interaction. A mutant version (CTLA4-Fc-mutant) was used as a control. The effect of CTLA4-Fc on the in vivo induction of disease with MAA was studied. Subsequently, the mechanism by which CTLA4-Fc blocked the interaction of CD28 and B7 was investigated in vivo, using the adoptive transfer of T cells derived from CTLA4-Fc–treated rats, and in vitro, using the proliferative response and cytokine production of MAA-T cells in the presence of CTLA4-Fc.
RESULTS. CTLA4-Fc markedly reduced the incidence and severity of EAAU in Lewis
rats after sensitization with MAA. The adoptive transfer of sensitized
T cells from CTLA4-Fc–treated donors did not induce EAAU in naive
recipients. CTLA4-Fc inhibited the expansion of antigen-specific MAA-T
cells and the production of TNF-
.
CONCLUSIONS. The costimulatory signal delivered through CD28-B7 is required for the
induction and pathogenesis of EAAU. In the absence of this signal,
antigen-specific expansion of MAA reactive T cells as well as
production of TNF- is inhibited. Abrogation of this costimulatory
signal may be an important therapeutic option for
EAAU.
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