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Hui Shao, Ming-Dar Woon, Satoshi Nakamura, Jeong-Hyeon Sohn, Phillip A. Morton, Nalini S. Bora, Henry J. Kaplan; Requirement of B7-Mediated Costimulation in the Induction of Experimental Autoimmune Anterior Uveitis. Invest. Ophthalmol. Vis. Sci. 2001;42(9):2016-2021.
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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-α.
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-α is inhibited. Abrogation of this costimulatory
signal may be an important therapeutic option for
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