Investigative ophthalmology & visual science · 2001
Requirement of B7-mediated costimulation in the induction of experimental autoimmune anterior uveitis.
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Shao H, Woon M D, Nakamura S, Sohn J H, Morton P A, Bora N S, Kaplan H J
Аннотация
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-alpha.
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-alpha is inhibited. Abrogation of this costimulatory signal may be an important therapeutic option for 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-alpha.
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-alpha is inhibited. Abrogation of this costimulatory signal may be an important therapeutic option for EAAU.
Предметные рубрики MeSH
AbataceptAdoptive TransferAnimalsAntigens, CDAntigens, DifferentiationAutoantigensAutoimmune DiseasesB7-1 AntigenCD28 AntigensCTLA-4 AntigenCell LineEnzyme-Linked Immunosorbent AssayImmunoconjugatesIncidenceLymphocyte ActivationMaleMelaninsModels, AnimalRatsRats, Inbred LewT-LymphocytesTumor Necrosis Factor-alphaUveitis, Anterior