This proposal concerns the second stage development of a computer model of the immune system and its use in performing in ma china experiments on cell cooperation, affinity maturation, self recognition and regulation of the response. The applicant has constructed the basic system using the cellular automaton concept. It incorporates a number of consensus features of the immune system, e.q., A cells, B cells and T cells, diversity of receptors in the individual and of the MHC class II in the population, negative and positive selection of T cells in the thymus, competitive cell-antigen and cell-immune complex interaction, antigen processing by A and B cells, presentation of peptides to T cells in the context of MHC, clonal growth of B and T cells resulting in memory. The applicant states that it has been possible to develop a realistic calibration of interaction parameters, such that the model responds to the introduction of antigen as a credible, if minimal, immune system. The computer model was also shown to display adaptability and the capacity to learn from experience. The model shows promise of becoming a novel tool in the hands of immunologists. The applicant states that although the simulations may not substitute for biological work, they may guide and verify it. Moreover, the applicant argues that some general hypotheses could be tested where no biological verification is at hand for technical or economic reasons. In the proposed project the applicant intends to reproduce a limited number of immunological scenarios and to test the recent hypotheses prevailing in each case. This will be done by introducing, for each case, modifications of the basic model and by running experiments according to the hypothesis. This will be done in close interactions with the authors or proposers of the experimental systems.
The specific aims of the proposal are to study the following: a) the factors involved in the affinity maturation of the immune response, in particular assessing separately and then together the impact of clonal selection by antigen binding and by hypermutation of the V genes; b) the concept of dominance/crypticity of peptides potentially immunogenic for T cells, and the expected effect of this property in thymic selection of auto- aggressive cells and autoimmunity; c) the production and regulation of rheumatoid factor during normal immune responses according to the hypothesis that anti-Fc B-lymphocytes can present foreign peptides to T cells after binding immune complexes, and thus enjoy putative help for clonal growth. The simulation should also indicate the consequences and the probable regulatory factors to prevent generalized autoimmunity.
| Shifrin, V I; Anderson, P (1999) Trichothecene mycotoxins trigger a ribotoxic stress response that activates c-Jun N-terminal kinase and p38 mitogen-activated protein kinase and induces apoptosis. J Biol Chem 274:13985-92 |
| Stewart, J J; Agosto, H; Litwin, S et al. (1997) A solution to the rheumatoid factor paradox: pathologic rheumatoid factors can be tolerized by competition with natural rheumatoid factors. J Immunol 159:1728-38 |
| Celada, F; Seiden, P E (1996) Affinity maturation and hypermutation in a simulation of the humoral immune response. Eur J Immunol 26:1350-8 |
