Behring Institute Mitteilungen最新文献

The cell surface molecule APO-1/Fas(CD95), a member of the Tumor Necrosis Factor (TNF) receptor/Nerve Growth Factor (NGF) receptor superfamily mediates apoptosis upon cross-linking by agonistic antibodies or its ligand. Recent findings suggest that APO-1/Fas(CD95) and its ligand are the key molecules for antigen receptor-induced apoptosis in activated mature T cells. Here we propose a mechanism for antigen receptor-induced apoptosis of activated T cells via APO-1 ligand mediated autocrine suicide. This mechanism may also contribute to the depletion of CD4+ T cells in AIDS.

IL-4 and IL-10 are both produced by activated TH2 cells as well as basophil/mast cells. In addition, IL-10 is secreted by activated B cells, monocytes/macrophages and keratinocytes. IL-4 and IL-10 act in concert to induce activated B lymphocytes to grow, switch isotype and ultimately differentiate into antibody producing plasma cells. Both IL-4 and IL-10 inhibit the secretion of proinflammatory cytokines by monocytes/macrophages and neutrophils. While IL-4 enhances the presentation of antigen by monocytes/macrophages and dendritic cells, IL-10 inhibits it. IL-4 and IL-10 can either stimulate or inhibit T cell proliferation. While both cytokines may prove useful in the management of inflammatory disorders, IL-4 is presently used in clinical trials that relate to its antitumor effects.

Interleukin-4 is a major regulator of the immune system, directing e.g. induction of a TH2 phenotype in T-cells, activation of B-cells and synthesis of IgE type antibodies, which are associated with allergic responses. Site-directed mutagenesis has revealed two sites important for receptor interaction on IL-4: site I mediates binding to the IL-4 receptor alpha subunit, and site II is involved in signal transduction through the receptor complex. Specific mutations in site II produced a series of ligands which bound to the receptor with high affinity, but had little or no agonistic activity and inhibited effects of wild type IL-4. The closely related cytokine IL-13, also a mediator of allergic processes, is antagonized as well. Antagonistic site II mutants of human IL-4 are therefore effective inhibitors with therapeutic potential for IL-4 associated diseases like type I hypersensitivity and asthma.

Despite the availability of an efficient live-attenuated measles virus vaccine about 1.5 million annual deaths from measles infections and their complications are recorded worldwide. Particularly in developing countries measles remains an unsolved problem and a new vaccine seems necessary. In our animal model of measles virus infection in rats we studied a candidate vaccine based on infectious replication incompetent (E1A-) adenovirus (RAd) where measles virus genes are expressed under the control of the cytomegalovirus immediate early promoter. The aim of the study was to characterize the cell mediated and humoral immunity after immunization with RAd and its protective effect. After challenge with a lethal dose of measles virus no signs of disease or histopathological changes were detected in RAd68-immunized rats. The elimination of measles virus was successful within a few days. The results demonstrate that defective recombinant adenovirus vectors can induce complete protection from experimental measles infection in rats.

T-cells have a major role both as helper cells for efficient antibody production and as inducers and effector cells in antibody-independent malaria immunity. Thus, antigens to be included into a subunit vaccine must contain T-cell epitopes to become effectively immunogenic. The P. falciparum blood stage vaccine antigen Pf155/RESA has been shown to contain T-helper epitopes inducing T-dependent anti-malarial antibodies in vitro. We have also shown that synthetic peptides representing sequences from the amino-acid repeat regions of Pf155/RESA stimulate T-cells from P. falciparum primed donors to proliferate, to release IFN-gamma and/or IL-4. In individual donors there was no correlation between these different activities. Rather, they were frequently negatively associated. However, IL-4 secretion could be induced in T-cells from donors who had elevated concentrations of serum antibodies to the same peptide as used for T-cell activation. Taken together the results support the occurrence of malaria-specific CD4+ T-cell subsets (e.g. TH1 and TH2) in humans similar to what has been found in mice and suggest the involvement of TH2-type helper cells in the induction of some important P. falciparum specific antibodies. CD4+ T-cells recognize the antigen in the context of MHC class II molecules. However, in human outbred populations no consistent MHC restrictions of anti-Pf155/RESA immune responses could be demonstrated. This is not surprising in view of the extensive polymorphism of the HLA system. Neither were there any obvious MHC class II restrictions seen when antibody- and t-cell responses were measured in naturally primed monozygotic twins.(ABSTRACT TRUNCATED AT 250 WORDS)

In order to facilitate the identification of T-cell epitopes as useful components of synthetic vaccines, we investigated the role of MHC molecules as the restriction element for the recognition of epitopes by the alpha beta receptor of T cells. MHC molecules are able to present thousands of different peptides to T cells, with all the peptides presented by one distinct type of MHC sharing common structural features. Our group analyzed these common characteristics concerning peptide length (only MHC I ligands) and anchor positions (MHC I and II ligands) occupied by a small set of closely related amino acids. Until now, for more than fifty MHC proteins allele-specific "peptide motifs" have been defined. The exact knowledge of MHC I peptide motifs allows for a prediction of CTL epitopes, and this kind of prediction has been successful in many cases over the last three years.

We describe a plasmid system which allows the secretion of foreign antigens in attenuated Salmonella aroA strains by the secretion apparatus of E. coli hemolysin. The gene (or gene fragment) encoding the antigen is inserted in frame into a residual position of the hlyA gene, encoding the HlyA secretion signal (HlyAs). Generally, the fused gene is efficiently expressed and the synthesized antigen is in part secreted into the culture supernatant and in part exposed on the surface of the producing Salmonella strain. The successful use of this approach is demonstrated with two antigens of Salmonella typhimurium, PagC and SlyA, both of which are potent virulence factors but produced only in small amounts under in vitro culture conditions and two virulence proteins of Listeria monocytogenes, p60 and listeriolysin. Interestingly the listeriolysin fusion protein proved to be cytolytically active and allowed, when expressed in Salmonella, the escape of these bacteria into the cytoplasm of infected macrophages.