The aim of the proposed study is to investigate whether anti- idiotypic antibodies directed to T cells specific for defined epitopes of a viral protein have merit as vaccines. A murine rabies virus infection will be used as a model system. Initially major T helper cell epitopes of the rabies virus nucleoprotein which has been shown to induce protective immunity to a lethal rabies virus infection will be determined using panels of synthetic peptides. T cell clones to epitopes that are recognized by a significant proportion of rabies virus specific T cells of different genetic backgrounds will be generated, characterized and used to induce antibodies in syngeneic mice. Monoclonal antibodies will be established, their specificity will be identified by binding studies, immunoprecipitation and/or Western blot analysis. Antibodies that specifically bind to idiotopes expressed on the receptor of rabies virus-specific T cells will be used to determine if T cells carry recurrent, dominant idiotopes and if such idiotopes are associated with a given epitope specificity. This will be tested by using a panel of rabies virus-specific T cell clones of different H-2 haplotypes directed to the same or distinct epitopes of the viral nucleoprotein. Anti-idiotypic antibodies especially those which have been identify to recognize public (dominant) idiotopes on virus-specific T cells will be tested initially in vitro for functional activities (i.e. inhibition of an antigen induced T cell response or stimulation of a T cell response in absence of antigen). In vivo the antibodies will be tested for: 1. Induction of a rabies virus-specific T and B cell response in adult mice; 2. Induction of long-term immunological memory to rabies virus; 3. Induction of protective immunity against a subsequent lethal challenge with rabies virus; and 4. Induction of immunity vs. tolerance in neonates. Some of the in vivo studies (induction of T and B cells, protective immunity) will be extended to other species (rabbits and raccoons) to test the efficacy of anti-idiotype vaccines across species barriers.
