Chronic pancreatitis is associated with disease-specific regulatory T-cell responses.
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.
Schmitz-Winnenthal
Hubertus
H
Department of Visceral Surgery, University Hospital of Heidelberg, Heidelberg, Germany.
Pietsch
Dong-Ho Kim
DH
Schimmack
Simon
S
Bonertz
Andreas
A
Udonta
Florian
F
Ge
Yingzi
Y
Galindo
Luis
L
Specht
Sebastian
S
Volk
Christine
C
Zgraggen
Kaspar
K
Koch
Moritz
M
Büchler
Markus W
MW
Weitz
Jürgen
J
Beckhove
Philipp
P
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
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