Cytotoxic cells are activated in cellular infiltrates of alcoholic chronic pancreatitis

Hunger, RE; Mueller, Christoph; Z’graggen, Kaspar; Friess, Helmut; Büchler, MW

doi:10.1016/s0016-5085(97)70048-9

Cited by 116 publications

(66 citation statements)

References 3 publications

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“…There is growing evidence that immunological mechanisms play a crucial role in the pathogenesis of chronic pancreatitis and the progressive fibrogenesis [10][11][12][13]. Using a rat pancreatitis model, we have recently shown that activated lymphocytes expressing Th1 cytokines are essentially involved in the perpetuation of inflammation associated with the deposition of components of extracellular matrix proteins (ECM) [13].…”

Section: Jcmm Jcmmmentioning

confidence: 99%

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Adenovirus-mediated gene transfer of interleukin-4 into pancreatic stellate cells promotes interleukin-10 expression

Brock

Sparmann

Ritter

et al. 2006

Journal of Cellular and Molecular Medicine

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Pancreatic stellate cells (PSC) are crucially involved in the development of fibrosis, a hallmark of chronic pancreatitis. Therefore, PSC represent an attractive target for the modulation of cellular functions providing the prerequisite for the establishment of novel therapeutic strategies like transfer of genetic material to the cells. Based on recent studies suggesting that the chronic course of pancreatitis is associated with immune deviation towards a Th1 cytokine profile, we have investigated the applicability of primary PSC to an adenovirus-mediated transfer of the cDNA encoding the Th2 cytokine interleukin (IL) 4 and the autocrine-acting effects of IL 4 on the cells in vitro. The trans-duction of primary PSC with a replication-incompetent adenovirus type 5 vector carrying the cDNA encoding rat IL-4 resulted in a distinct expression of the cytokine on mRNA and protein level for two weeks. Similar to recombinant IL 4, effects of the endogenously synthesized cytokine were mediated by the signal transducer and activator of transcription (STAT)6. Interestingly, beside the increase of PSC proliferation, IL 4 transduction was accompanied by an up-regulation in the endogenous expression of the anti-inflammatory cytokine IL 10. In summary, our data suggest that PSC are suitable targets for gene therapy modulating cellular interactions in the pancreas.

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Section: Jcmm Jcmmmentioning

confidence: 99%

“…1 μg of total RNA was reversely transcribed (RT) into cDNA using Oligo(dT) [12][13][14][15][16][17][18] primer and reverse transcriptase Superscript II. Competitive polymerase chain reaction (PCR) was performed according to Brock et al [21] using a synthetic DNA control fragment (CF) as internal standard.…”

Section: Competitive Rt-pcrmentioning

confidence: 99%

Adenovirus-mediated gene transfer of interleukin-4 into pancreatic stellate cells promotes interleukin-10 expression

Brock

Sparmann

Ritter

et al. 2006

Journal of Cellular and Molecular Medicine

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“…Although the antigens involved are unknown, alyϪ/Ϫ mice and MRL/lpr mice spontaneously develop pancreatitis in which the effector cells are also Th1-type CD4ϩ T cells (Mustafa et al, 1998;Tsubata et al, 1996). Recent observations also suggest a functional role of T lymphocytes, such as cytotoxicity (Hunger et al, 1997) or neuroimmune interactions in chronic pancreatitis (Keith et al, 1985). In mice with cerulein-induced experimental pancreatitis, CD4ϩ T cells are required for complete development of pancreatic lesions (Demols et al, 2000).…”

Section: Uchida Et Almentioning

confidence: 99%

Experimental Immune-Mediated Pancreatitis in Neonatally Thymectomized Mice Immunized with Carbonic Anhydrase II and Lactoferrin

Uchida

Okazaki

Nishi

et al. 2002

Laboratory Investigation

109

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SUMMARY:We previously reported that autoantibodies against carbonic anhydrase II and lactoferrin are frequently identified in patients with autoimmune-related pancreatitis. To clarify the role of carbonic anhydrase II and lactoferrin, we created animal models of autoimmune pancreatitis by immunizing neonatally thymectomized mice with carbonic anhydrase II and lactoferrin and also by transferring immunized spleen cells to nude mice. Neonatally thymectomized BALB/c mice were immunized with carbonic anhydrase II or lactoferrin followed by three booster injections

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“…Furthermore, foci of lymphohistiocytic infiltrates are commonly found and are also associated with regressing parenchyma (Bockman, 1997). These infiltrates were shown to contain activated cytotoxic T cells (Hunger et al, 1997), suggesting a role of the immune system in the pathogenesis of acinar atrophy and local scarring. Induction of HLA-DR molecules was observed in parenchymal areas affected by chronic pancreatitis (Bedossa et al, 1990;Jalleh et al, 1993) and transcripts for MCP-1 chemokine have been detected in areas of early stage of chronic pancreatitis (Saurer et al, 2000).…”

mentioning

confidence: 99%

Differential and Mutually Exclusive Expression of CD95 and CD95 Ligand in Epithelia of Normal Pancreas and Chronic Pancreatitis

Hasel

Rau

Perner

et al. 2001

Laboratory Investigation

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SUMMARY:Acinar regression in chronic pancreatitis may be due to immune attack in parenchymal areas neoexpressing HLA-DR molecules. CD4 ϩ Th1 cytotoxic T cells induce apoptosis of their targets via oligomerizing CD95 (APO-1/Fas) death receptors on target cells by their CD95 ligand (CD95L). We determined the expression of CD95 and CD95L in epithelia of normal and chronically inflamed pancreatic tissues. We applied RT-PCR and Western blotting for CD95L expression profiles, serial frozen section immunohistochemistry to detect CD95, CD95L, and HLA-DR molecules, CD3, CD4, CD11c, and S-100 protein (S100p). Normal pancreases and chronic pancreatitis contain CD95L message and protein. Immunohistochemistry revealed a mutually exclusive expression of CD95 and CD95L. Physiologically, acini were CD95 Ϫ /CD95L ϩ , ducts were CD95 Ϫ /CD95L Ϫ , and islets were CD95 Ϫ /CD95L ϩ . In areas of lymphohistiocytic infiltration, mainly consisting of CD3 ϩ CD4 ϩ T cells and CD11c ϩ , CD4 ϩ/Ϫ , S100p ϩ interstitial dendritic cells, and in areas of initial fibrosis, acini and ducts were HLA-DR ϩ , acini CD95 ϩ /CD95L Ϫ , and ducts CD95 ϩ /CD95L Ϫ . Islet cells were CD95 Ϫ /CD95L ϩ in both conditions. IFN␥ levels in protein lysates, as measured by an immunoassay, were significantly higher in chronic pancreatitis than in normal pancreas (p Ͻ 0.0003). In vitro, IFN␥ downmodulated CD95L message and protein in ASPC1 and BxPc3 pancreatic carcinoma cells. In conclusion, pancreatic epithelia differentially express CD95 and CD95L in a mutually exclusive manner. In chronic pancreatitis the CD95 Ϫ /CD95L ϩ status is conserved in islet cells even in the vicinity of lymphohistiocytic infiltrates, whereas it is lost in acini coexpressing HLA-DR. As a potential consequence, and possibly triggered by local release of IFN␥, CD4 ϩ Th1 cells may cognately interact with and successfully attack exocrine cells by triggering CD95 on their target without being killed by epithelial, CD95L-mediated, counterattack. (Lab Invest 2001, 81:317-326).C hronic pancreatitis is characterized by a progressive loss and fibrosis of exocrine parenchyma whereas the endocrine part of the organ remains structurally intact for a prolonged period of time (Bockman, 1997;Klöppel and Maillet, 1993;Sarles, 1991). The disease is often accompanied by duct ectasia and might be initiated by ductal obstruction or distortion (Klöppel and Maillet, 1993). Furthermore, foci of lymphohistiocytic infiltrates are commonly found and are also associated with regressing parenchyma (Bockman, 1997). These infiltrates were shown to contain activated cytotoxic T cells (Hunger et al, 1997), suggesting a role of the immune system in the pathogenesis of acinar atrophy and local scarring. Induction of HLA-DR molecules was observed in parenchymal areas affected by chronic pancreatitis (Bedossa et al, 1990;Jalleh et al, 1993) and transcripts for MCP-1 chemokine have been detected in areas of early stage of chronic pancreatitis (Saurer et al, 2000). Local expression of T cell tropic chemokines may recruit T cell...

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Cytotoxic cells are activated in cellular infiltrates of alcoholic chronic pancreatitis

Cited by 116 publications

References 3 publications

Adenovirus-mediated gene transfer of interleukin-4 into pancreatic stellate cells promotes interleukin-10 expression

Adenovirus-mediated gene transfer of interleukin-4 into pancreatic stellate cells promotes interleukin-10 expression

Experimental Immune-Mediated Pancreatitis in Neonatally Thymectomized Mice Immunized with Carbonic Anhydrase II and Lactoferrin

Differential and Mutually Exclusive Expression of CD95 and CD95 Ligand in Epithelia of Normal Pancreas and Chronic Pancreatitis

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