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Interestingly, the impact of CMV infection in humans on the efficacy of vaccination, e.g. against influenza depends on the age and the immune status of the individuals [38]. The more subjects are in poor health, the more the antibody titer against CMV is higher and less the vaccination is effective [149]. It is assumed that in old subjects, this should be the case, but in contrast in younger individuals this could be beneficial because of the shorter duration of the CMV infection resulting in a CMV-induced enhancement of the antiviral immunity [150]. Together, CMV infection by modulating the whole immune system may lead to survival advantages in younger age and perhaps in not so younger age also. It seems that age is not the most decisive factor, but the duration of the CMV infection, as chronic infection has a reducing effect on vaccination response of NK cells.

It was very recently shown in a murine model [51], that besides the innate CD8⁺ T cells [151], NK cells were also major producer of IFNγ to activate the adaptive part of the immune system such as CD4⁺ T cells and ultimately B cells [27, 152]. It was shown that after influenza vaccination, early production of IFNγ production was mediated by NK cells under the high level of IFN type I produced by adjacent cells in the lymph nodes such as macrophages. This high production of IFNγ has been shown to be essential for the Th1 differentiation; however, prior to this the very early secretion of IFNγ stimulates various cytokine production, including IL-12 but mainly IL-6 [153]. IL-6 will modulate and further increase the IL-6⁺CD11⁺ DCs which will ultimately regulate the influenza-specific local B cell response via the Th1 response [51]. In this model, the activation of NK cells resulting in various cytokine production and cell-cell interactions was necessary for efficient influenza vaccine protection. However, this seems to be vaccination-dependent as for the vaccinia virus vaccination the main effector seemed to be the inflammasome pathway.

Very few longitudinal studies exist which may distinguish between the effect of aging and CMV infection [73, 74]. It seems that the presence of the late differentiated NK cells is more determined by the CMV infection as their phenotype and number do not significantly change once the infection is installed. Moreover, aging has much less influence on the accumulation of such cells. However, from an evolutionary point of view, the development of these types of cells may be beneficial not only in adults but also in the elderly. Their aggressive elimination might prove detrimental [154, 155].