Cytotoxic T lymphocytes raised against a subdominanl epitope offered as a synthetic peptide eradicate human papillomavirus type 16-induced tumorsPreviously, we have shown that immunization with human papillomavirus (HPV) type 16-derived cytotoxic T lymphocyte (CTL) epitope E7 nned C3 ce3ls and eradicates established O tumors in Bn nude mice, in addition, we show that OTL epitope E7 49-57 is immuno-subdominantJy expressed on C3 cells, inasmuch as CTL raised against C3 cells recognize another naluralK' processed; peptide. The data prestrnled in this study are the first esampJes of CTL-based immunotherapy against established HPVI6-induced tumors, supporting the thought that T cells are involved in the control of cervical cancer. Furthermore, our data stress the feasibility of generating tumor-sp...
Enterovirus infections have been implicated in the development of type I diabetes mellitus. They may cause beta cell destruction either by cytolytic infection in the pancreas or indirectly by contributing to autoimmune reactivity. We sought evidence for these 2 mechanisms in a case of acute-onset diabetes mellitus that occurred during severe echovirus 9 infection. The virus was isolated and administered to cultured human beta cells. No viral proliferation was observed, and no beta cell death was induced, while parallel exposure to Coxsackie B virus serotype 3 resulted in viral proliferation and massive beta cell death. Although the viral protein 2C exhibited a sequence similar to that of the beta cell autoantigen glutamic acid decarboxylase (GAD(65)), no cross-reactive T cell responses were detected. The patient did not develop antibodies to GAD(65) either. Absence of evidence for direct cytolytic action or an indirect effect through molecular mimicry with GAD(65) in the present case raises the possibility of another indirect pathway through which enteroviruses can cause diabetes mellitus.
Aims/hypothesis. In the human pancreas, a close topographic relationship exists between duct cells and beta cells. This explains the high proportion of duct cells in isolated human islet preparations. We investigated whether human duct cells are a source of TNFα-mediated interactions with beta cells and immune cells. This cytokine has been implicated in the development of autoimmune diabetes in mice. Methods. Human duct cells were isolated from donor pancreases and examined for their ability to produce TNFα following a stress-signalling pathway. Ductcell-released TNFα was tested for its in vitro effects on survival of human beta cells and on activation of human dendritic cells. Results. Exposure of human pancreatic duct cells to interleukin-1β (IL-1β) induces TNFα gene expression, synthesis of the 26,000 M r TNFα precursor and conversion to the 17,000 M r mature form, which is rapidly released. This effect is NO-independent and involves p38 MAPK and NF-κB signalling. Duct-cellreleased TNFα contributed to cytokine-induced apoptosis of isolated human beta cells. It also induced activation of human dendritic cells. Conclusions/interpretation. Human pancreatic duct cells are a potential source of TNFα that can cause apoptosis of neighbouring beta cells and initiate an immune response through activation of dendritic cells. They may thus actively participate in inflammatory and immune processes that threaten beta cells during development of diabetes or after human islet cell grafts have been implanted.
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