LONG-TERM IMMUNE MEMORY HOLDS CLUES TO VACCINE DEVELOPMENT

CHICAGO--Individuals who acquire immunity to diseases such as measles, yellow fever, polio or rubella, either through exposure to disease or through vaccination are in many cases capable of retaining that immunity for many years or for an entire lifetime despite lack of re-exposure or revaccination. Rafi Ahmed, Ph.D., director of the Emory University Vaccine Center, is working to uncover the specific mechanisms of long-term immune memory that are essential to the development of new, effective vaccines, particularly for diseases like HIV, malaria and tuberculosis.

Dr. Ahmed discussd his recent findings on immune memory during acute and chronic viral infections at the 6th Conference on Retroviruses and Opportunistic Infections in Chicago.

Acute viral infections induce two types of long-term memory ­ humoral immunity, in which B cells produce antibodies to prevent infection by viruses, and cellular immunity, in which T cells activated by specific viral antigens kill the virus infected cells and also produce cytokines, which are proteins that prevent the growth of viruses and make cells resistant to viral infection.

Until recently, scientists have believed that plasma cells, the B cells that produce antibodies, live only a short time and that other factors, such as re-exposure, chronic infection, or cross reactivity with other viruses are necessary to maintain a long-term antibody response. Dr. Ahmed and his colleagues have discovered instead that, although all of these conditions may play a role, an important factor in serum antibody persistence is that plasma cells, at least in mouse models, actually live for quite a long time ­ sometimes for the entire life of an organism. If this is true in humans also, Dr. Ahmed believes it might explain why humoral immunity is capable of such long-term persistence. He and his colleagues have recently received a grant from the National Institutes of Health to extend their studies of immune memory into humans, and to explore what specific signals or mechanisms cause some plasma cells to live longer than others.

The other aspect of immunity ­ the response of T cells to viruses ­ is much different than the B cell response, Dr. Ahmed explains. CD8 T cells, which do not prevent infection but instead kill virus after infection, can be divided into three distinct populations: naïve CD8 T cells, effector CD8 T cells, and memory CD8 T cells. The response to virus by each of these groups of cells is different. Naïve CD8 T cells are activated and become effector cells in the presence of antigen. The effector response lasts for only a few weeks, after which the majority of effector cells die and about 5-10% become memory cells. When memory cells come into contact with the original virus, they are capable of mounting a strong and rapid immune response. The number of effector cells involved in the initial response to disease appears to dictate the number of memory cells remaining, Dr. Ahmed points out. This means that a strong initial response is critical to generating a large pool of memory T cells and maintaining strong, long-term immunity.

Recent research by Dr. Ahmed and his colleagues has shown that the stable maintenance of the pool of total memory cells may be dictated by the principle of homeostatis. Models developed by Rustom Antia, Ph.D., an Emory mathematical biologist, suggests that the total number of cells in the immune system is constant and that the long-term maintenance of cellular immunity may be regulated by competition for space by immune memory cells.

As an individual is exposed to new pathogens, some memory cells may need to make way for new ones. Since the total number of memory cells can be very large, the immune system is normally capable of maintaining immunity to many pathogens at once, especially in the absence of repeated exposures. The impact of new pathogens could govern the loss of existing immune memory cells, however, and might help explain the eventual loss of immune memory to certain viruses.

"Understanding immunological memory is the necessary basis of developing any effective vaccine", says Dr. Ahmed. "No matter what type of vaccine you are working on, or for which disease, you need to understand the mechanisms of immune memory."