Increasing age brings an enhanced susceptibility to viral and bacterial infections and to certain types of cancer. Similarly, vaccine protocols are much less efficacious in the elderly. This is partly due to an age-associated loss in the ability to generate an immune response to a """"""""new"""""""" antigen. Studies have shown that old animals generate less vigorous antibody (B cell) responses to antigens encountered for the first time than do younger animals and a decline in the effectiveness of T cell """"""""help"""""""" is at least partly responsible. On the other hand, although the ability to respond to a """"""""new"""""""" antigen is profoundly diminished in the elderly, we and others have shown that immune responses to """"""""recall"""""""" antigens (antigens first encountered in youth) are not severely affected by aging. In other words, memory B and T cells do survive during aging and are capable of responding vigorously if their antigen is re-encountered in old age. Given that memory T cells generated at a young age survive aging, a novel scheme to exploit these cells to generate effective antibody (B cell) responses to """"""""new"""""""" antigens first seen in older animals is now proposed. It is hypothesized that a chimeric protein, comprised of a """"""""recall"""""""" antigen (one that re-activates memory T cells) fused to a """"""""new"""""""" antigen (one that invokes a response by """"""""old"""""""" naive T and B cells) would be more immunogenic in the elderly. The recall antigen would stimulate """"""""youthful"""""""" memory T cells and these T cells could provide the robust """"""""bystander help"""""""" to naive B cells responding to a newly introduced antigen. To test this protocol, young mice will be immunized with an antigen known to provoke a strong response (the acetylcholine receptor from an electric ray, Torpedo californica, (T-AChR)). The mice will be rested until they are old, and then re-exposed to the antigen. For the """"""""recall"""""""" in old age, T-AChR will be linked to an antigen not previously seen by the animal (the tetanus toxoid fragment C (TTFC)). The working hypothesis is that the memory T cells to T-AChR will provide """"""""bystander"""""""" T cell help and will enhance B cell production of antibodies to TTFC (the""""""""new"""""""" antigen). Two schemes for delivering the chimeric antigen, T-AChR-TTFC, will be tested.
In Aim I, the old mice will be immunized with a chimeric protein and in Aim II, the old mice will be given a DNA vaccine encoding the same T-AChR-TTFC immunogen. This will allow comparison of the quality of immune """"""""recall"""""""" responses stimulated by protein versus DNA immunization. Importantly, these initial studies could have significant implications for future enhancement of vaccine efficacy in the elderly.
| Stacy, Sue; Williams, Earlanda L; Standifer, Nathan E et al. (2010) Maintenance of immune tolerance to a neo-self acetylcholine receptor antigen with aging: implications for late-onset autoimmunity. J Immunol 184:6067-75 |
| Stacy, Sue; Pasquali, Amanda; Sexton, Valerie L et al. (2008) An age-old paradigm challenged: old baboons generate vigorous humoral immune responses to LcrV, a plague antigen. J Immunol 181:109-15 |
