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Transgenic overexpression of anti‐apoptotic FLIP on lymphocytes inhibits resolution of granulomatous experimental autoimmune thyroiditis (G‐EAT)
Author(s) -
Fang Yujiang,
BraleyMullen Helen
Publication year - 2008
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fasebj.22.1_supplement.669.11
Subject(s) - flip , apoptosis , autoimmune thyroiditis , splenocyte , cd8 , thyroglobulin , transgene , inflammation , genetically modified mouse , immunology , cancer research , microbiology and biotechnology , biology , chemistry , immune system , endocrinology , thyroid , thyroiditis , biochemistry , gene
G‐EAT isinduced by transfer of mouse thyroglobulin (MTg)‐primed in vitro activated splenocytes. We recently showed that transgenic FLIP expressed on thyroid epithelial cells (TEC) promotes earlier resolution of G‐EAT by protecting TEC from Fas‐mediated apoptosis. We hypothesized that if transgenic FLIP were expressed on lymphocytes, CD4+ effectors would be protected from Fas‐mediated apoptosis, and resolution would be inhibited resulting in chronic inflammation. Transgenic (Tg) mice overexpressing FLIP under the CD2 promoter were generated. Transgenic FLIP was expressed on all CD4+ and CD8+ T cells and B cells. Tg+ mice and Tg‐ littermates were immunized with MTg and adjuvant, and donor CD8+ T cells were depleted. Splenocytes were activated in vitro with MTg and IL‐12, and transferred to syngeneic recipients. Recipients of both Tg+ and Tg‐ donor cells developed severe G‐EAT (4–5+) 20 days later. Thyroid lesions in recipients of Tg‐ donor cells were resolving or had begun to resolve at day 60, but lesions in recipients of Tg+ cells did not resolve. Studies are in progress to determine if transgenic FLIP protects T cells from apoptosis and if expression of FLIP on T cells alters cytokine profiles in thyroids. The results indicate that a single anti‐apoptotic molecule can determine if an autoimmune inflammatory response resolves or becomes chronic depending on where it is expressed (TEC or lymphocytes) (NIH DK35527).