Vaccine efficacy declines significantly with age, yet old baboons immunized with Yersinia pestis LcrV antigen generated vigorous humoral responses [JI 181:109 (2008)] while aged rhesus macaques did not. To assess whether these non-human primate (NHP) species are differentially impacted by immunosenescence, animals were immunized with Y. pestis F1, a plasmid-encoded protein which is known to elicit naïve B and T cell responses. Interestingly, age-associated decreases in antibody titers to F1 were observed in both species. However, defects in T cell proliferative responses were seen only in the macaques; T cell reactivity to both mitogen and antigenic stimulation was similar in the old and young baboons. We therefore asked whether other aspects of immune regulation are affected by age. The loss of naive, relative to memory, T cells was seen, as expected. Moreover, there was a decrease, albeit relatively small, in the production of naive T cells (TRECs). However, several parameters known to change with aging were not affected. For example, AID induction was maintained in most, but not all, old baboons. Moreover, the T cell fine specificity was similar in old and young animals. Lastly, TCR-Vβ spectratype analysis revealed that the age-associated repertoire skewing reported in old rhesus and humans is not seen in baboons, even in the CD8+ T cell subset. Thus, baboons do appear to be less affected by aging and this NHP species may provide novel insights into healthy immune aging.
A better understanding of host defenses against malaria is important, but most studies have traditionally focused on resistance and/or immunological mechanisms that limit parasite burden. Host tolerance mechanisms are thought to minimize physiological damage caused by both the parasite itself and immunopathology without directly affecting parasite burden. On Hawai`i Island, low elevation populations of amakihi (Hemignathus virens) appear to have recently evolved tolerance mechanisms against avian malaria (Plasmodium relictum). Under comparable parasite loads, low elevation amakihi have lower mortality, greater fitness, lower reticulocyte levels and lower heterophil to lymphocyte ratios than high elevation amakihi. Thus, distinct host defense mechanisms are likely operating in low vs. high elevation amakihi. To search for genes involved in host defense, AFLP analysis was completed. Group significance tests (Bionumerics v 2.0) reveal genetic distinction between groups (p = 0.000). Band frequency comparisons between low and high elevation `amakihi (Fisher’s exact test and Pearson’s chi-square test with Yate’s continuity correction, R v 2.11.1) revealed ten band classes with significantly higher (p < 0.05) frequencies in low vs. high elevation birds and 13 band classes with higher frequencies in high vs. low elevation birds. Isolation and sequencing of these candidate bands is underway and may provide a better understanding of host defense mechanisms in natural populations.
The ability to mount effective immune responses declines with age, which correlates clinically with decreased vaccine efficacy and increased susceptibility to infection and cancer. As a result, new vaccines should be tested for efficacy in older individuals. Towards this end, young (5-6 years of age) and old (17-22 years) baboons were immunized with the LcrV candidate vaccine antigen from Yersinia pestis. Surprisingly, older baboons had a strong humoral response [JI 181:109] suggesting either that the baboon immune system is less affected by aging or that LcrV acts like a recall antigen. Thus, a second Y. pestis vaccine antigen, the F1 protein, was tested; F1 is unique to this bacterial species and would be seen as a “new” antigen. The antibody response to F1 did decline with age, but the T cell response did not. Thus, an analysis of the effects of aging on T cell fine specificity was undertaken. T cell proliferation and IFN-γ ELISpots were used to map which of 32 overlapping synthetic F1 peptides stimulated T cells from the immunized baboons. A Th1 response was observed for a few individual animals in response to whole both F1 antigen and specific peptides. ELISpots specific for IL-4 and IL-5 cytokines are currently being used to follow Th2 cells specific for F1. Future efforts will focus on generating F1-specific T cell clones using herpesvirus papio transformed B cell lines as antigen presenting cells.
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