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CTLs recognize peptide epitopes which are proteolytically generated by the proteasome and presented on MHC class I molecules. According to the defective ribosomal product (DRiP) hypothesis, epitopes originate from newly synthesized polypeptides which are degraded shortly after their translation. The DRiP hypothesis would explain how epitopes can be generated from long-lived proteins. We examined whether neosynthesis is required for presentation of the immunodominant epitope NP118 of the lymphocytic choriomeningitis virus nucleoprotein, which has a half-life of >3 days. Two days after nucleoprotein biosynthesis was terminated in a tetracycline-regulated transfectant, the presentation of the NP118 epitope ceased. This indicates that NP118 epitopes are generated from newly synthesized nucleoproteins rather than from the long-lived pool of nucleoproteins in the cell. Therefore, the lymphocytic choriomeningitis virus nucleoprotein is the first substrate for which a major prediction of the DRiP hypothesis, namely the requirement for neosynthesis, is shown to hold true.

The proteasome is critically involved in the production of MHC class I-restricted T cell epitopes. Proteasome activity and epitope production are altered by IFN-gamma treatment, which leads to a gradual replacement of constitutive proteasomes by immunoproteasomes in vitro. However, a quantitative analysis of changes in the steady state subunit composition of proteasomes during an immune response against viruses or bacteria in vivo has not been reported. Here we show that the infection of mice with lymphocytic choriomeningitis virus or Listeria monocytogenes leads to an almost complete replacement of constitutive proteasomes by immunoproteasomes in the liver within 7 days. Proteasome replacements were markedly reduced in IFN-gamma(-/-) mice, but were only slightly affected in IFN-alphaR(-/-) and perforin(-/-) mice. The proteasome regulator PA28alpha/beta was up-regulated, whereas PA28gamma was reduced in the liver of lymphocytic choriomeningitis virus-infected mice. Proteasome replacements in the liver strongly altered proteasome activity and were unexpected to this extent, since an in vivo half-life of 12 days had been previously assigned to constitutive proteasomes in the liver. Our results suggest that during the peak phase of viral and bacterial elimination the antiviral cytotoxic T lymphocyte response is directed mainly to immunoproteasome-dependent T cell epitopes, which would be a novel parameter for the design of vaccines.

The complete inhibition of proteasome activities interferes with the production of most MHC class I peptide ligands as well as with cellular proliferation and survival. In this study we have investigated how partial and selective inhibition of the chymotrypsin-like activity of the proteasome by the proteasome inhibitors lactacystin or epoxomicin would affect Ag presentation. At 0.5-1 microM lactacystin, the presentation of the lymphocytic choriomeningitis virus-derived epitopes NP118 and GP33 and the mouse CMV epitope pp89-168 were reduced and were further diminished in a dose-dependent manner with increasing concentrations. Presentation of the lymphocytic choriomeningitis virus-derived epitope GP276, in contrast, was markedly enhanced at low, but abrogated at higher, concentrations of either lactacystin or epoxomicin. The inhibitor-mediated effects were thus epitope specific and did not correlate with the degradation rates of the involved viral proteins. Although neither apoptosis induction nor interference with cellular proliferation was observed at 0.5-1 microM lactacystin in vivo, this concentration was sufficient to alter the fragmentation of polypeptides by the 20S proteasome in vitro. Our results indicate that partial and selective inhibition of proteasome activity in vivo is a valid approach to modulate Ag presentation, with potential applications for the treatment of autoimmune diseases and the prevention of transplant rejection.

This review article aims to discuss the modalities of oesophageal resection, to define the categories of patients who are most likely to benefit from oesophagectomy with extensive lymph node clearance, and to analyse the eventual contribution of nonsurgical neo-adjuvant or adjuvant therapies to improving long-term survival rates achieved by surgery alone. Both the review of the literature devoted to potentially curative treatment of oesophageal cancer and the authors' own experience indicate that resection of the oesophageal tube en bloc with the locoregional lymph nodes provides patients with the best chance of long-term survival and cure. This is true, even though some of the resected Lymph nodes are metastatic. Most phase III comparative studies fail to shown any overall survival improvement following multimodal therapy in comparison with surgery alone, so that there is now no scientific reason for systematic addition of radio- and/or chemotherapy to extensive surgery in potentially resectable neoplastic processes. However, neo-adjuvant radio- and/or chemotherapy is indicated in suspected non-resectable T4 tumors for downstaging and subsequent oesophageal resection in good responders. The benefit in terms of long-term survival and cure that can be expected from adjuvant chemo- and/or radiotherapy after radical resection of a neoplastic process having already spread into a large number of loco-regional lymph node requires objective evaluation by prospective, randomized studies.

In the Western world, the incidence of adenocarcinoma of the lower esophagus has risen almost 10% per year since the mid- 1970s and now accounts for over 40% of esophageal carcinomas in males [1]. The estimated relative risk of developing adenocarcinoma of the lower esophagus in patients with "Barrett's epithelium" is increased 40-50 fold compared to the normal population...

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