A humanized model of experimental autoimmune uveitis in HLA class II transgenic mice

Giuseppina Pennesi, Mary J. Mattapallil, Shu Hui Sun, Dody Avichezer, Phyllis B. Silver, Zaruhi Karabekian, Chella S. David, Paul A. Hargrave, J. Hugh McDowell, W. Clay Smith, Barbara Wiggert, Larry A. Donoso, Chi Chao Chan, Rachel R. Caspi

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64 Scopus citations

Abstract

Experimental autoimmune uveitis (EAU) is a disease of the neural retina induced by immunization with retinal antigens, such as interphotoreceptor retinoid-binding protein (IRBP) and arrestin (retinal soluble antigen, S-Ag). EAU serves as a model for human autoimmune uveitic diseases associated with major histocompatibility complex (HLA) genes, in which patients exhibit immunological responses to retinal antigens. Here we report the development of a humanized EAU model in HLA transgenic (TG) mice. HLA-DR3, -DR4, -DQ6, and -DQ8 TG mice were susceptible to IRBPinduced EAU. Importantly, HLA-DR3 TG mice developed severe EAU with S-Ag, to which wild-type mice are highly resistant. Lymphocyte proliferation was blocked by anti-HLA antibodies, confirming that antigen is functionally presented by the human MHC molecules. Disease could be transferred by immune cells with a Th1-like cytokine profile. Antigen-specific T cell repertoire, as manifested by responses to overlapping peptides derived from S-Ag or IRBP, differed from that of wild-type mice. Interestingly, DR3 TG mice, but not wild-type mice, recognized an immunodominant S-Ag epitope between residues 291 and 310 that overlaps with a region of S-Ag recognized by uveitis patients. Thus, EAU in HLA TG mice offers a new model of uveitis that should represent human disease more faithfully than currently existing models.

Original languageEnglish (US)
Pages (from-to)1171-1180
Number of pages10
JournalJournal of Clinical Investigation
Volume111
Issue number8
DOIs
StatePublished - Apr 2003

ASJC Scopus subject areas

  • Medicine(all)

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    Pennesi, G., Mattapallil, M. J., Sun, S. H., Avichezer, D., Silver, P. B., Karabekian, Z., David, C. S., Hargrave, P. A., McDowell, J. H., Smith, W. C., Wiggert, B., Donoso, L. A., Chan, C. C., & Caspi, R. R. (2003). A humanized model of experimental autoimmune uveitis in HLA class II transgenic mice. Journal of Clinical Investigation, 111(8), 1171-1180. https://doi.org/10.1172/JCI15155