Long-Evans Cinnamon (LEC) rats, an inbred strain of a mutant rat isolated from Long-Evans rats, develop hereditary hepatitis. To elucidate the role of copper metabolism in the development of the hepatitis in LEC rats, we examined the copper concentration in the tissues and serum levels of copper and ceruloplasmin. Copper concentration in the liver of LEC rats was over 40 times that of normal Long-Evans Agouti (LEA) rats, while the serum ceruloplasmin and copper concentrations in LEC rats decreased significantly. The hepatocytes of LEC rats show steatosis in cytoplasm and pleomorphism of mitochondria, resembling the histologic features of the liver in Wilson's disease. These findings suggest that the hereditary hepatitis in LEC rats is closely associated with copper toxicity, and may be dealing with a rat form of Wilson's disease. Thus the LEC rats will provide a unique and useful animal model for clarifying the mechanism and for developing treatment strategies for Wilson's disease and other abnormal copper metabolism in humans. (J. Clin. Invest. 1991. 87:1858-1861

QR-32 tumor cells, a clone derived from a murine fibrosarcoma, are poorly tumorigenic and nonmetastatic when injected into syngeneic C57BL/6 mice. However, they are converted to highly malignant ones once they have grown in vivo after being co-implanted in a subcutaneous site with a foreign body, a gelatin sponge. Early phase of inflammation induced by the gelatin sponge participates in the conversion and histological analysis shows predominant infiltration of neutrophils. The objective of this study was to determine whether the depletion of the infiltrating neutrophils has any effect on the tumor progression. Intraperitoneal administration of a monoclonal anti-granulocyte antibody, RB6-8C5 (RB6), depleted neutrophils from both the peripheral blood circulation and the local inflamed site in mice with co-implantation of QR-32 tumor cells and gelatin sponge. The RB6 administration did not inhibit either tumor development or growth of QR-32 tumor cells. In contrast, tumor cell lines established from RB6-administered mice showed a significant decrease in metastatic incidence as compared with the tumor cell lines obtained from the mice with administration of control rat IgG or saline. Metastatic ability was significantly suppressed when RB6 had been administered in the early phase (from day -2 to day 6 after implantation); however, the administration in the middle (from day 6 to day 14) or late (from day 14 to day 22) phase did not affect the metastatic ability. We confirmed the phenomena by using integrin beta(2) knockout mice that had impaired neutrophil infiltration into inflamed sites. In the knockout mice, neutrophils hardly infiltrated into the gelatin sponge and the tumors showed dramatically suppressed metastatic phenotype as compared with those in wild-type mice or nude mice. Immunohistochemical analysis demonstrated that expressions of 8-hydroxy-2'-deoxyguanosine and nitrotyrosine were parallel to those in the presence of neutrophils. These results suggested that inflammation, especially when neutrophils infiltrate into tumor tissue, is primarily important for benign tumor cells to acquire metastatic phenotype.

Although MIF plays multifunctional roles in a broad spectrum of pathophysiological states, little has been done to investigate the role of this protein in association with tumor growth. The current results suggest the possibility that MIF induces tumor cell growth in concert with other growth factors, which encouraged us to investigate a novel approach for tumor therapy using an anti-MIF antibody and an MIF anti-sense plasmid transfection technique.

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There is no standard treatment modality for advanced gastric cancer (GC) at the present time. To develop a new treatment modality, we investigated the immunological responses of advanced GC patients (n = = = =13, 9 non-scirrhous and 4 scirrhous types) vaccinated with peptides to a regimen under which pre-vaccination peripheral blood mononuclear cells (PBMCs) were screened for their reactivity in vitro to each of 14 peptides on HLA-A24 or 16 peptides on -A2 allele, then only the reactive peptides (maximum: 4) were administered in vivo. This regimen was generally well tolerated, although grade I levels of fever and local skin reactions were observed in several patients. astric cancer (GC), a leading cause of cancer-related death worldwide throughout the past century, now ranks second only to lung cancer, with an estimated 750,000 new cases diagnosed annually around the world. 1) Except in Japan and a few East Asian countries, the prognosis of GC remains poor, and the overall 5-year survival rate ranges from 5 to 15% despite many clinical trials of chemotherapy and other new therapies. In particular, there is no current treatment modality for disseminated GC histologically of the scirrhous type.2) Therefore, development of a new treatment modality is needed, and one such modality could be specific immunotherapy, given that recent advances in tumor immunology have resulted in identification of many tumor antigens and epitopes recognized by HLA-class-I-restricted cytotoxic T lymphocytes (CTLs) from various cancers, including GC.3-6) However, clinical trials with these peptides have rarely obtained major clinical responses.7-9) This failure could have been due to an insufficient induction of antitumor responses by these vaccine regimens, since peptide-specific memory T cells were not measured in pre-vaccination peripheral blood mononuclear cells (PBMCs). We speculated that vaccination based on pre-vaccination measurement of peptidespecific CTLs in the circulation might be able to induce potent anti-tumor immune responses in cancer patients. [8][9][10][11][12][13] In this report, we describe the safety of such a regimen and the immune responses to peptides and tumor cells in advanced GC patients vaccinated with peptides based on pre-existing cellular response.