We observed a remarkable synergism of adenoviruses and LPS in triggering the production of TNF in intact animals. We found that in mice pre-exposed to adenoviruses, LPS injections generated extremely high levels of TNF with altered kinetics. The elevated TNF synthesis stemmed mostly from posttranscriptional up-regulation of TNF production, although transcription of the TNF gene was also induced. Adenoviruses and LPS exhibited a significant but less dramatic synergism in the induction of IL-6, IFN-γ, and NO. Only marginal changes were detected in the synthesis of a panel of other cytokines. Different serotypes of the virus showed practically identical effects. As deletion mutants lacking indispensable viral genes or UV inactivated virions exhibited similar activities as the infectious, wild-type virus, it seems unlikely that the viral genome plays any significant role in the phenomenon. Published data indicate that other viruses also show some kind of synergism with LPS, although by different cellular mechanisms. T cells and their IFN-γ production—crucial in the synergism of influenza viruses and LPS—were dispensable in our experiments. We suggest that the phenomenon is probably a general one: an overlap between different molecular mechanisms detecting bacterial and viral pathogens and inducing mediators of nonspecific cell-mediated host defense. The synergism of viruses and LPS (bacteria) could be a concern in medical practice as well as in gene therapy experiments with high doses of recombinant adenoviruses.
A new member of the chicken TNF superfamily has recently been identified, namely receptor activator of NF-κB ligand (RANKL), as have its signalling receptor, RANK, and its decoy receptor, osteoprotegerin (OPG). In mammals, RANKL and RANK are transmembrane proteins expressed on the surface of Th1 cells and dendritic cells (DC) respectively, whereas OPG is expressed as a soluble protein from osteoblasts and DC. Recombinant soluble chicken RANKL (chRANKL) forms homotrimers whereas chicken OPG (chOPG) forms homodimers, characteristic of these molecules in mammals. ChRANKL, chRANK and chOPG are expressed at the mRNA level in most tissues and organs. ChRANKL is transcriptionally regulated by Ca(2+) mobilisation and enhances the mRNA expression levels of pro-inflammatory cytokines in bone marrow-derived DC (BMDC); this is inhibited by both chOPG-Fc and soluble chRANK-Fc. However, chRANKL does not enhance the expression of cell surface markers in either BMDC or BM-derived macrophages (BMM). Furthermore, chRANKL enhances the survival of APC similar to its mammalian orthologue.
Certain HLA class II-specific monoclonal antibodies (mAb) cause up to 90% decrease in the cell surface expression of class II molecules. This down-regulation is isotype-specific, i.e. DR-specific mAb do not affect the expression of DP and DQ molecules. However, antibodies binding to one DR allotype down-regulate both allotypes in heterozygous antigen-presenting cells (APC), indicating that the phenomenon is not a direct consequence of ligation. All down-regulating mAb identified recognize the first (peptide binding) domains of class II heterodimers, and strongly inhibit the activation of class II-restricted human T cells in vitro. Conversely, non-down-regulating mAb fail to inhibit T cell activation, and most of them (four out of five) recognize class II second domains. Down-regulating antibodies are cytotoxic for B lymphoblastoid cell lines and for a small proportion of normal activated B cells. Their F(ab')2 fragments mediate both down-regulation and cytotoxicity, whereas the monovalent Fab fragments are not cytotoxic, but retain the down-regulatory and T cell inhibitory properties. These findings raise the possibility of a class II major histocompatibility complex-specific, antibody-based immunosuppressive therapy without cytotoxic side effects.
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