Biomedical subjects

P E Seiden

Publications and source records attributed to P E Seiden.

6 recordsLinked to original sources

PubMed2000

A systematic approach to vaccine complexity using an automaton model of the cellular and humoral immune system. I. Viral characteristics and polarized responses.

A modern approach to vaccination faces the compound complexity of microorganism behavior and immune response triggering and regulation. Since computational modeling can yield useful guidelines for biological experimentation, we have used IMMSIM(3), a cellular automaton model for simulating humoral- and cell-mediated responses, to explore a wide range of virus-host relations. Sixty-four virtual viruses were generated by an assortment of speed of growth, infectivity level and lethal load. The outcome of the infections, as influenced by the immune response and the bolstering of cures, obtained by vaccine presensitization are illustrated in this first article. The results of the in machina experiments allow us to relate the success rate of responses to certain combinations of viral parameters and by freezing one or the other branch, and to determine that some viruses are more susceptible to humoral, and others to cellular responses, depending either on single parameters or combinations thereof. This finding allows prediction of which infection may be susceptible to polarized ((Th)(1)>Th(2) and Th(1)<Th(2)) responses and will eventually help designing vaccines whose action relies on antagonizing both the specificity and the behavior of the invader. A second, not lesser, result of this study is the finding that humoral and cellular responses, while cooperating, towards the cure of the infected body, also show significant patterns of competition and mutual thwarting.

Animals↗

PubMed1997

A solution to the rheumatoid factor paradox: pathologic rheumatoid factors can be tolerized by competition with natural rheumatoid factors.

Rheumatoid factors (RF) associated with arthritic joint erosion are only seen transiently, if at all, in nondiseased individuals. Therefore, a tolerance mechanism must exist that prevents pathologic RF B cells from expressing Abs. Surprisingly, it has been shown that pathologic RF B cells are not tolerized by any previously established tolerance mechanism such as deletion, receptor editing, anergy, or prevention of memory establishment. How are pathologic RF cells tolerized? By simulating the RF response with a cellular automaton model immune system, we demonstrate that pathologic RFs can be tolerized by the novel mechanism of "competitive tolerance" with natural, nonpathologic RFs. We then demonstrate that competitive tolerance can be broken when a sequestered pool of expanding B cells are inappropriately subjected to chronic stimulation (as appears to occur in MRL/lpr mice and in patients with rheumatoid arthritis).

Animals↗

PubMed1996

Affinity maturation and hypermutation in a simulation of the humoral immune response.

By experimenting with a cellular automaton model of the immune system, we have reproduced affinity maturation of the antibody response, a somatic adaptation to a changing environment. The simulation allowed the isolation of a number of variables, e.g. the fraction of repertoire available, the magnitude of the change in affinity with mutation, the mutation frequency and its focus on the complementarity-determining regions (CDR) of the antibody. Multiple series of immunizations were run in machina where the contribution of each variable was evaluated against the maturation observed. We found that hypermutation is not necessary for affinity maturation if the repertoire of B cell specificities is sufficiently complete, but is essential when the B cell diversity is limited (which happens to be the case in vivo), as it fills the holes in the repertoire and allows selection by antigen. Maturation also depends on the magnitude of the change in affinity with mutation, and we supply some necessary limits on this parameter. For mutations confined to the CDR, the most efficient maturation occurs at mutation rates of 0.2 per paratope and per cell division. When mutations also affect the framework regions, the peak of the most effective CDR mutation rate moves progressively to lower values. A most sensitive parameter is the speed of maturation, which reflects the rate of expansion of mutated clones. Comparing it with biological observations can help to discriminate between alternative hypotheses on the phenomena of hypermutation and affinity.

Antibody Affinity↗

PubMed1995

Modelling thymic functions in a cellular automaton.

Along the lines developed by Celada and Seiden, for simulating an immune system by means of cellular automata, we have constructed a 'thymus' where T cells undergo positive and negative selection. The populations thus 'matured' have been analyzed and their performance has been tested in machina. The key feature of this thymus is to allow chance meeting and possible interaction between newly born T cells and antigen presenting cells. The latter represent both the epithelial and the dendritic cells of the biological organ and are equipped with MHC molecules that can accommodate selected self peptides. All possible specificities are represented among the virgin T cells entering the thymus, but this diversity is drastically reduced by the time they exit as mature elements. In the model organ the fate of T cells, i.e. whether they will undergo proliferation or apoptosis, is governed by their capacity to recognize MHCs and the affinity of this interaction. Crucial parameters turn out to be the concentration of presenting cells, the number of types of MHC per cell, the 'size of self' in terms of the number of different peptides and their prevalence. According to the results, events in the automaton can realize unforeseen cooperations and competitions among receptors, depending upon the interaction order and frequency, and ultimately determine the rescue or the killing of thymocytes. Thus the making of the mature T repertoire has a random component and cannot be completely predicted.

Antigen Presentation↗

PubMed1992

A model for simulating cognate recognition and response in the immune system.

We have constructed a model of the immune system that focuses on the clonotypic cell types and their interactions with other cells, and with antigens and antibodies. We carry out simulations of the humoral immune system based on a generalized cellular automaton implementation of the model. We propose using computer simulation as a tool for doing experiments in machine, in the computer, as an adjunct to the usual in vivo and in vitro techniques. These experiments would not be intended to replace the usual biological experiments since, in the foreseeable future, a complete enough computer model capable of reliably simulating the whole immune would not be possible. However a model simulating areas of interest could be used for extensively testing ideas to help in the design of the critical biological experiments. Our present model concentrates on the cellular interactions and is quite adept at testing the importance and effects of cellular interactions with other cells, antigens and antibodies. The implementation is quite general and unrestricted allowing most other immune system components to be added with relative ease when desired.

Antibodies↗

PubMed1992

A computer model of cellular interactions in the immune system.

The power of modern computers allows the modeling and simulation of complex biological systems. The last decade has seen the emergence of a growing number of simulations of the immune system. In this article, Franco Celada and Philip Seiden present a model that, they suggest, is rich enough to allow computer experiments to be used as practical adjuncts to the usual biological experiments, at a saving of cost and time.

Animals↗