title: Exogenous heat shock protein gp96 ameliorates CD4+CD62L+ T-cell-mediated transfer colitis.
abstract: BACKGROUND
  The heat shock protein gp96 is an endoplasmic reticulum chaperone involved in endoplasmic reticulum stress reactions. gp96 binds antigens and is secreted into extracellular space on cell stress. After reinternalization by antigen presenting cells, antigens can be transferred to major histocompatibility complex molecules. In recent studies, we found induction of gp96 during differentiation of intestinal macrophages, whereas it was absent in intestinal macrophages of patients with Crohn's disease.
  
  
  METHODS
  To study immuno-modulating effects of gp96 in T-cell transfer colitis BALB/c donor mice were injected with 2 × 100 μg gp96. After 1 week, 2.5 × 10(5) CD4+CD62L+ cells were isolated from spleens and injected into severe combined immunodeficiency recipients. Another group received cells from untreated donors and was treated with 100 μg gp96 after transfer. Control groups received cells from untreated donors, or buffer alone.
  
  
  RESULTS
  After transfer of CD4+CD62L+ T cells from gp96-pretreated donors, mice (TBT gp96) showed an initial weight loss, but after 3 weeks, they recovered and reached the starting weight after 5 weeks. Mice treated with gp96 after transfer (TAT gp96) showed a delayed weight loss in comparison with the CD4+CD62L+ group. The histological scores in CD4CD62L mice were 2.6 ± 0.1, in TBT gp96 mice 1.3 ± 0.3 (CD4+CD62L+ versus TBT gp96: P < 0.05) and in mice treated after transfer 1.9 ± 0.1 (CD4+CD62L+ versus TAT gp96: P < 0.05).
  
  
  CONCLUSIONS
  These findings indicate an essential role of gp96 in the maintenance of tolerance against luminal antigens in the intestinal mucosa. The absence of gp96 in intestinal macrophages of patients with Crohn's disease might provoke loss of this tolerance mediating mechanism.
authors.affiliation: *Division of Gastroenterology and Hepatology, University Hospital Zurich, University of Zurich, Zurich, Switzerland; and †Department of Internal Medicine I, University of Regensburg, Regensburg, Germany.
authors.forename: Anne
authors.initials: A
authors.lastname: Fischbeck
authors.forename: Katja
authors.initials: K
authors.lastname: Schreiter
authors.forename: Katharina
authors.initials: K
authors.lastname: Leucht
authors.forename: Isabelle
authors.initials: I
authors.lastname: Frey-Wagner
authors.forename: Silvia
authors.initials: S
authors.lastname: Lang
authors.forename: Martin
authors.initials: M
authors.lastname: Hausmann
authors.forename: Michael
authors.initials: M
authors.lastname: Fried
authors.forename: Werner
authors.initials: W
authors.lastname: Falk
authors.forename: Gerhard
authors.initials: G
authors.lastname: Rogler
mesh_terms: D019264:Adoptive Transfer; D000818:Animals; D000951:Antigens, Neoplasm / Q000378:metabolism*; D015496:CD4-Positive T-Lymphocytes / Q000276:immunology* / Q000378:metabolism / Q000473:pathology; D002454:Cell Differentiation; D002478:Cells, Cultured; D003092:Colitis / Q000276:immunology* / Q000378:metabolism / Q000473:pathology; D005260:Female; D005434:Flow Cytometry; D007249:Inflammation / Q000276:immunology* / Q000378:metabolism / Q000473:pathology; D007413:Intestinal Mucosa / Q000276:immunology* / Q000378:metabolism / Q000473:pathology; D019041:L-Selectin / Q000378:metabolism*; D008264:Macrophages / Q000276:immunology* / Q000378:metabolism / Q000473:pathology; D051379:Mice; D008807:Mice, Inbred BALB C; D016513:Mice, SCID; D013154:Spleen / Q000276:immunology* / Q000378:metabolism / Q000473:pathology
chemical_list: D000951:Antigens, Neoplasm; C052646:sarcoma glycoprotein gp96 rejection antigens; D019041:L-Selectin