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.

Agency
National Institute of Health (NIH)
Institute
National Institute on Aging (NIA)
Type
Research Project (R01)
Project #
5R01AG005731-05
Application #
3116488
Study Section
Immunobiology Study Section (IMB)
Project Start
1986-08-01
Project End
1994-07-31
Budget Start
1992-08-01
Budget End
1993-07-31
Support Year
5
Fiscal Year
1992
Total Cost
Indirect Cost
Name
University of Kentucky
Department
Type
Schools of Medicine
DUNS #
832127323
City
Lexington
State
KY
Country
United States
Zip Code
40506
Fallah, Mosoka P; Chelvarajan, R Lakshman; Garvy, Beth A et al. (2011) Role of phosphoinositide 3-kinase-Akt signaling pathway in the age-related cytokine dysregulation in splenic macrophages stimulated via TLR-2 or TLR-4 receptors. Mech Ageing Dev 132:274-86
Dasu, Trivikram; Sindhava, Vishal; Clarke, Stephen H et al. (2009) CD19 signaling is impaired in murine peritoneal and splenic B-1 B lymphocytes. Mol Immunol 46:2655-65
Wu, Hsin-Jung; Bondada, Subbarao (2009) CD72, a coreceptor with both positive and negative effects on B lymphocyte development and function. J Clin Immunol 29:12-21
Dasu, Trivikram; Qualls, Joseph E; Tuna, Halide et al. (2008) CD5 plays an inhibitory role in the suppressive function of murine CD4(+) CD25(+) T(reg) cells. Immunol Lett 119:103-13
Gururajan, Murali; Simmons, Alan; Dasu, Trivikram et al. (2008) Early growth response genes regulate B cell development, proliferation, and immune response. J Immunol 181:4590-602
Garg, M; Kaplan, A M; Bondada, S (1994) Cellular basis of differential responsiveness of lymph nodes and spleen to 23-valent Pnu-Imune vaccine. J Immunol 152:1589-96
Muthukkumar, S; Udhayakumar, V; Bondada, S (1993) Elevation of cytosolic calcium is sufficient to induce growth inhibition in a B cell lymphoma. Eur J Immunol 23:2419-26
Baluyut, A R; Pollok, K E; Bondada, S (1993) Molecular events in B lymphocyte activation: consequences of signals transduced through MHC class II molecules. Cell Immunol 147:353-66
Garg, M; Bondada, S (1993) Reversal of age-associated decline in immune response to Pnu-imune vaccine by supplementation with the steroid hormone dehydroepiandrosterone. Infect Immun 61:2238-41
Muthusamy, N; Bondada, S (1993) Differential regulation of surface immunoglobulin and Lyb2 mediated B cell activation: II. cAMP dependent (prostaglandin E2) and independent (IFN-gamma) mechanisms of regulation of B lymphocyte activation. Int Immunol 5:949-56

Showing the most recent 10 out of 23 publications