AIDSWEEKLY Plus; Monday, December 21, 1998
Daniel J. DeNoon, Senior Editor
It remains unknown how immunologic memory - the ability of the immune system to mount an expedient response to a pathogen it has seen before - is maintained.
The answer isn't Methuselah-aged lymphocytes: these key immune cells turn over many times in a person's lifetime. Two modern theories compete. One is that persistent antigen (or re-exposure to a pathogen) must constantly provide restimulation to the immune system. The second admits that such restimulation can lead to very long- lasting memory, but suggests that it is not necessary for memory to last.
Now a mathematical model offers support for the second theory.
"Our results suggest that, if homeostatic control regulates the total population of memory cells, then for a wide range of parameters immune memory will be long-lived in the absence of persistent antigen (T[1/2]>1 year," concluded Rustom Antia, Sergei S. Pilyugin, and Rafi Ahmed of the Emory Vaccine Center, Emory University, Atlanta, Georgia.
Antia et al. reported their findings in the Proceedings of the National Academy of Sciences ("Models of Immune Memory: On The Role of Cross-Reactive Stimulation, Competition, and Homeostasis in Maintaining Immune Memory," PNAS, 1998;95:14926-31).
For their model, the researchers defined immune memory as maintenance of an elevated pool of immune cells sensitized to a specific antigen. This is the major (but not sole) factor in protective immunity.
Various factors influence immune memory and repertoire: persistence of antigen, cross-reactive stimulation, homeostatic mechanisms, competition between different lymphocyte lineages, and rate of cell turnover. Antia et al. developed mathematical formulae to account for these factors.
"The models we develop incorporate a large repertoire of immune cells, each lineage having distinct antigenic specificities, and describe the dynamics of the individual linages and total population of cells," they wrote.
If it is indeed true that homeostasis maintains the size of the memory compartment, the model shows that antigen-specific immune cells can have a half-life of more than a year - and possibly as much as 100 years. The authors were careful to note, however, that these predictions do not explicitly predict how long the immune repertoire will be able to control new invasions of pathogens.
Their model, Antia et al. observed, supports the hypothesis first put forward by Freitas, Rocha, et al.: that immune memory is governed by homeostatic mechanisms (Freitas, A.A. and Rocha, B.B., Immunol Today, 1993;14:25-9).
The research team led by author Rafi Ahmed, head of Emory's new Vaccine Center, recently reported the revolutionary finding that the size of the initial immune response to a virus determines the strength of long-term immunity (see Vaccine Weekly, April 6, 1998). These findings, too, highlighted the importance of homeostasis to immune function.
Once a virus is cleared, apoptosis deletes more than 90 percent of activated T cells, thereby maintaining T-cell homeostasis. The remaining virus-specific cells are added to the pool of memory cells.
The current study was supported by grants from the National Institutes of Health.
The corresponding author for this study is Rustom Antia, Emory Vaccine Center, Emory University, Atlanta, Georgia 30322. Email: <rantia@biology.emory.edu>.
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