Impressive advances in computer technology have opened the way to the simulation in machina of complex biological systems. In immunology, this has proven helpful as it can foster both critical phases of generating and testing novel hypotheses. At variance with """"""""conventional"""""""" models based upon differential equations, the applicant has reproduced the dynamics of the humoral response by means of cellular automata, where discrete entities cooperate and develop according to elementary local rules. The success of this model in tackling several """"""""hot"""""""" aspects currently debated among immunologists signals that the time is ripe for the exploration of the complex and challenging cell-mediated immunity. The subject of this proposal is a computer simulation of the immune response to viral infection and to foreign cells. This requires an extensive upgrading of our IMMSIM code, including the introduction of infective antigens, target cells, dendritic cells, CD8 T cell receptors and class I MHCs. The body is represented by a bi-dimensional space subdivided into sites where all interactions take place in discrete time steps. Interactions are probablistic occurrences between cells that take place via their receptors, on the basis of complementarity between binary bit strings. These interactions may lead to destruction, presentation, stimulation or tolerance. As in the living organism, a virus-specific Tc precursor will become anergic by meeting a Class I-bearing infected target cell but will mature to a serial killer upon binding to a DC that has attracted a Th cell, whose lymphokines will act on both Tc and DC. The outcome of each event depends on a number of parameters of largely unknown biological weight. Their effects will be tested experimentally by running the same response serially, varying one parameter at a time, and comparing the results to ascertained immunological behaviors. This will allow us to identify the critical nodes of the virus/response progress and then to use the model to challenge further fundamental aspects, such as viral mutation, lymphoid cell infection, and, ultimately, the cooperative/competitive interplay between the cellular and humoral response against the same invader.
|Kohler, B; Puzone, R; Seiden, P E et al. (2000) A systematic approach to vaccine complexity using an automaton model of the cellular and humoral immune system. I. Viral characteristics and polarized responses. Vaccine 19:862-76|