The overall goal of this research proposal is to define the mechanistic basis of the age associated decline in the immune response.
The specific aims are to study the effect of age on the function of B lymphocytes and to develop methods to enhance the immune responses of the aged. We will focus on the inability of B cells from the aged mice to respond to stimulation with some T helper cells or with pneumococcal antigens. The growth and differentiation responses of B cells will be measured. Mechanistic basis of this B cell defect will be investigated in terms of early versus late signaling events and responses to lymphokines. The role of genes and gene products implicated in the movement of cells from the G1 state of the cell cycle into S phase will be evaluated in the context of the proliferation defect in the aged mouse derived B cells. In particular, we will test the hypothesis that the suppressor oncogene products like p53 or the retinoblastoma protein may not be modified appropriately in these B cells and thus prevent their progression into the cell cycle. The biochemical status of these genes and proteins and will be examined using the techniques of agarose and polyacrylamide gel electrophoresis and immunoprecipitation with specific antibodies. The nature of the cellular defect leading to reduced responses of the aged to pneumococcal polysaccharide antigens will be investigated. Methods will be developed to augment the responses of the aged mice to pneumococcal antigens. We will determine if oral immunization will be more effective in obtaining good immune responses to Pneumovax in the older individuals. An animal model of human immune system will be developed by reconstituting mice bearing severe combined immunodeficiency (scid) with lymphocytes form young and aged volunteers. This animal model (scid-hu) will be employed to study the immune responses of the B cells from aged humans to the pneumococcal vaccine and to evaluate potential agents that augment the responses of the elderly humans to the vaccine.
Showing the most recent 10 out of 23 publications
