The general aim of this grant proposal is to understand more about the requirements for B cell activation in aged mice. The inability to activate B cells to produce high affinity antibody and memory B cells to certain antigens currently compromizes the health of the elderly population. Given the recent advances made by my lab in understanding the role of B cell MHC class II molecules in signal transduction and antigen presentation, we are well positioned to explore these issues in aged B cells.
Specific aims are :
Aim 1 : To determine the MHC class II signals eminating from aged B cells following class II ligation. We will measure: increases in intracellular cAMP and Ca2+, tyrosine phosphorylation profiles, upregulation of B7.1, B7.2, CD95, and the ability of aged B cells to enter the cell cycle following signaling through surface Ig, IL-4R and class II.
Aim 2 : A new vaccine modality, anti-class II mAB coupled to the model antigen, hen egg lysozyme (HEL) has shown a remarkable ability to induce a secondary response of IgG and IgA following immunization with small amounts of antigen. The efficacy of this reagent will be tested in aged mice and also in a mouse model that we have recently developed that has impaired class II signaling capability and thus immune responses to antigen that resemble those of aged mice.
| Frleta, D; Demian, D; Wade, W F (2001) Class II-targeted antigen is superior to CD40-targeted antigen at stimulating humoral responses in vivo. Int Immunopharmacol 1:265-75 |
| Desbarats, J; Wade, T; Wade, W F et al. (1999) Dichotomy between naive and memory CD4(+) T cell responses to Fas engagement. Proc Natl Acad Sci U S A 96:8104-9 |
