title: Chronic pancreatitis is associated with disease-specific regulatory T-cell responses.
abstract: OBJECTIVE
  Chronic pancreatitis is characterized by alternating phases of acute inflammation and quiescent disease. Involvement of T-cell responses has been suggested, but pancreatitis-specific T cells have not been described.
  
  
  METHODS
  We characterized T-cell responses against pancreatitis, pancreatic carcinoma-associated antigens, and tetanus toxoid in the bone marrow, blood, and/or pancreatitis lesions of patients with pancreatitis, pancreatic cancer, and healthy individuals. T cells were functionally characterized by antigen-dependent secretion of interferon (IFN)-gamma, interleukin (Il)-4, and IL-10, which indicate type 1, type 2, or regulatory T-cell responses, respectively. Regulatory T cells were characterized by multicolor flow cytometry. Isolated regulatory T cells were tested for their capacity to recognize pancreatitis-associated antigens and to suppress conventional T cells in an antigen-dependent manner. T cell-derived cytokines in tissue lesions were quantified by enzyme-linked immunosorbent assay.
  
  
  RESULTS
  Chronic pancreatitis patients showed similar to pancreatic cancer patients and healthy individuals type 1 T-cell responses against tetanus toxoid; however, they exhibited strong IL-10-based T-cell responses against pancreatitis-associated but not pancreatic carcinoma-associated antigens. T cells from pancreatic cancer patients responded to pancreatic cancer-associated but not pancreatitis-associated antigens with IFN-gamma secretion. Pancreatitis-specific IL-10 responses were mediated by IL-10(+)IFN-gamma(-)FoxP3(+) regulatory T cells, which were expanded in the blood, bone marrow, and pancreatitis lesions and possessed the potential to suppress the proliferation of autologous conventional T cells in an antigen-specific manner. Pancreatitis lesions, in comparison with pancreatic carcinomas, contained increased concentrations of IL-10 and reduced levels of IFN-gamma, suggesting pancreatitis-specific activity of regulatory T cells in situ.
  
  
  CONCLUSIONS
  Chronic pancreatitis is associated with disease-specific regulatory T-cell responses.
authors.affiliation: Department of Visceral Surgery, University Hospital of Heidelberg, Heidelberg, Germany.
authors.forename: Hubertus
authors.initials: H
authors.lastname: Schmitz-Winnenthal
authors.forename: Dong-Ho Kim
authors.initials: DH
authors.lastname: Pietsch
authors.forename: Simon
authors.initials: S
authors.lastname: Schimmack
authors.forename: Andreas
authors.initials: A
authors.lastname: Bonertz
authors.forename: Florian
authors.initials: F
authors.lastname: Udonta
authors.forename: Yingzi
authors.initials: Y
authors.lastname: Ge
authors.forename: Luis
authors.initials: L
authors.lastname: Galindo
authors.forename: Sebastian
authors.initials: S
authors.lastname: Specht
authors.forename: Christine
authors.initials: C
authors.lastname: Volk
authors.forename: Kaspar
authors.initials: K
authors.lastname: Zgraggen
authors.forename: Moritz
authors.initials: M
authors.lastname: Koch
authors.forename: Markus W
authors.initials: MW
authors.lastname: Büchler
authors.forename: Jürgen
authors.initials: J
authors.lastname: Weitz
authors.forename: Philipp
authors.initials: P
authors.lastname: Beckhove
mesh_terms: D000951:Antigens, Neoplasm / Q000276:immunology; D001854:Bone Marrow Cells / Q000276:immunology*; D002277:Carcinoma / Q000276:immunology*; D002478:Cells, Cultured; D004797:Enzyme-Linked Immunosorbent Assay; D005434:Flow Cytometry; D051858:Forkhead Transcription Factors / Q000378:metabolism; D006801:Humans; D007150:Immunohistochemistry; D007156:Immunologic Memory; D007371:Interferon-gamma / Q000378:metabolism; D016753:Interleukin-10 / Q000378:metabolism; D015847:Interleukin-4 / Q000378:metabolism; D010179:Pancreas / Q000276:immunology*; D010190:Pancreatic Neoplasms / Q000276:immunology*; D050500:Pancreatitis, Chronic / Q000276:immunology*; D050378:T-Lymphocytes, Regulatory / Q000276:immunology*; D013745:Tetanus Toxoid / Q000276:immunology
chemical_list: D000951:Antigens, Neoplasm; C418974:FOXP3 protein, human; D051858:Forkhead Transcription Factors; C508598:IL4 protein, human; D013745:Tetanus Toxoid; D016753:Interleukin-10; D015847:Interleukin-4; D007371:Interferon-gamma