       Document 0731
 DOCN  M9610731
 TI    Mechanisms of immune tolerance induction through the thymic expression
       of a peripheral tissue-specific protein.
 DT    9601
 AU    Antonia SJ; Geiger T; Miller J; Flavell RA; Department of Immunobiology,
       Yale University School of Medicine,; New Haven, CT 06510, USA.
 SO    Int Immunol. 1995 May;7(5):715-25. Unique Identifier : AIDSLINE
       MED/96053535
 AB    A major process through which the immune system becomes tolerant to self
       proteins involves the deletion of self reactive cells in the thymus.
       However, T cells reactive to peripheral tissue-specific proteins can
       escape this deletion and become tolerized in the periphery by a variety
       of mechanisms. We report here, contrary to expectation, that the
       pancreas-specific protein, elastase I, is also expressed at a low level
       in the thymus, and that this thymic expression contributes to tolerance
       induction. To study the mechanism of this tolerance induction, we
       utilized a double transgenic mouse model. In these mice the expression
       of a model protein, SV40 T antigen, is directed by the elastase I
       promoter and hence parallels elastase I expression in the pancreas and
       thymus. These mice were crossed with mice transgenic for a TCR specific
       for T antigen, so the majority of thymocytes and T cells in these mice
       express the transgene. In double transgenic mice we find that thymic
       expression of T antigen results in anergic thymocytes which also show a
       reduction of Th1 activity with no decrease in Th2 activity. These
       functional characteristics persist in peripheral T cells, but there is
       also a depletion in the number of T antigen reactive T cells in lymph
       nodes. Chimeras were constructed which directly demonstrated that the
       thymus is the site of tolerance induction and that the tolerizing
       element is thymic epithelium. We propose that the loss of Th1 activity
       as a consequence of the thymic epithelium being encountered by
       tissue-specific proteins results in the functional tolerization of CTL
       in vivo, despite the fact that CTL are fully functional in vitro. In
       this way autoimmune destruction is contained. Thymic expression of
       peripheral proteins may therefore be an additional way in which
       tolerance to peripheral proteins can be achieved.
 DE    Animal  Antigens, Polyomavirus Transforming/*IMMUNOLOGY
       Autoimmunity/GENETICS  Base Sequence  Cell Division/IMMUNOLOGY
       Chimera/IMMUNOLOGY  Crosses, Genetic  CD8-Positive
       T-Lymphocytes/IMMUNOLOGY  *Immune Tolerance  Lymph Nodes/IMMUNOLOGY
       Mice  Mice, Transgenic  Molecular Sequence Data
       Pancreas/ENZYMOLOGY/IMMUNOLOGY/METABOLISM
       Pancreatopeptidase/IMMUNOLOGY/METABOLISM
       Peptides/GENETICS/*IMMUNOLOGY/PHYSIOLOGY  Polyomavirus
       macacae/*IMMUNOLOGY  Receptors, Antigen, T-Cell/GENETICS/IMMUNOLOGY
       Thymus Gland/ENZYMOLOGY/*IMMUNOLOGY/METABOLISM  Tumor Cells, Cultured
       JOURNAL ARTICLE

       SOURCE: National Library of Medicine.  NOTICE: This material may be
       protected by Copyright Law (Title 17, U.S.Code).

