The Immune System in the Elderly: A Fair Fight Against Diseases?

Anis Larbi; Paulina Rymkiewicz; Anusha Vasudev; Ivy Low; Nurhidaya Binte Shadan; Seri Mustafah; Shamini Ayyadhury; Tamas Fulop

Disclosures

Aging Health. 2013;9(1):35-47. 

In This Article

Restoring Immunity

Many strategies such as caloric restriction, hormone therapy, cytokine therapy or stem cell approaches have been demonstrated to restore immunity in animal models, but may prove difficult to perform in humans due to lack of consensus.[74] For example, while some studies show the benefits of caloric restriction in nonhuman primates,[75] mice with dietary restriction show higher mortality during influenza infection due to lack of reserves.[76] To be able to operate rejuvenation of immunity, it is critical to first fully understand the mechanism identified to be faulty, which is still rarely the case, except for vaccination and thymic involution.

Vaccinations are a reliable and cost-effective method for prevention of infections. With the decline in immune function with age, elderly individuals are not able to respond optimally to challenges to the immune system. In this regard, vaccinations could be of great importance in prevention of immune diseases. Influenza is a leading cause for morbidity and mortality in the elderly, owing to their reduced capacity to fight infections and, thus, there have been many studies on the efficacy of influenza vaccines in the elderly. The aging population has been shown to have poor response to vaccination due to reduced thymic output of naive T cells. Although there is an increase in the number of memory T cells in the elderly, these cells are shown to have undergone replicative senescence.[77] A combination of these factors can render an aged individual unable to successfully respond to vaccination. In another study, it was shown that in a cohort of elderly individuals who do not produce specific antibodies 1 month after influenza vaccination, there was an increase in the number of autoreactive CD8+CD28 T-cell clones, and also IFN-γ production, driving the polarization of T cells towards a Th1 response.[29] This suggests that the imbalance between pro- and anti-inflammatory cytokines could contribute to hyporesponsiveness to vaccination in the aging population. Apart from changes in T cells that influence the response to influenza vaccination, other supporting factors such as latent CMV infection and frailty also impact on the outcome of influenza vaccinations. Physical frailty such as slow walking speed, low physical activity and weight loss have been associated with reduced antibody response to vaccination and postvaccination influenza infection.[78] More in-depth investigations in specific groups such as frail individuals are needed to better understand the link between immune robustness, health and longevity. Reduced response to vaccinations in the elderly calls for more strategies to improve the effectiveness of vaccines in elderly individuals. Some of these strategies include using adjuvant for influenza vaccination. For example, the TLR-4 agonist, glucopyranosyl lipid adjuvant stable emulsion, improved the antigen-presenting capacity of dendritic cells by improving T-cell immune response by increasing the production of proinflammatory cytokines when added to influenza split-virus vaccine.[79] Other methods of improving the efficacy of vaccination include broadening the cross-reactivity of strains, such as in the use of MF59 adjuvenated vaccine, that offers a broader range of protection for multiple strains.[80] It also includes changing the route of delivery for vaccines as intradermal injection has improved immunogenicity in elderly individuals.[81]

Since immunosenescence is primarily characterized by changes in T-cell phenotype and a reduced number of naive T cells in the periphery that are required to fight infections, reversing thymic involution might be of considerable gain in improving the immune system of the elderly. There have been studies in murine models where the exogenous administration of keratinocyte growth factor induces the production of IL-7 on thymic epithelial cells, thereby increasing thymic output.[82,83] Recently, it has also been found that following in vivo administration of FGF-7 in involuted thymus, the senescence-associated gene Ink4a can be repressed to allow for the generation of T-cell progenitor populations.[82] Therefore, strategies for reversing thymic involution and increasing thymopoiesis in the elderly might be effective in tuning the immune system to fight diseases. The limitation resides in the use of animal models, as shown by the marked difference in naive T-cell history in aged mice versus elderly.[84] The pool of naive cells (~90%) in elderly individuals consists primarily of naive cells that underwent homeostatic proliferation. However, in mice, most of the peripheral naive T cells are recently emigrant cells, as shown by CD31 expression and T-cell receptor excision circle quantification. The fraction of newly emigrant naive T cells in the elderly was estimated to be 10%, which matches the size of the thymic extracellular space at this age.[84] This suggests that human aging is very particular, and that only human studies may enable us to understand to what extent the immune system, as well as other systems (e.g., cardiovascular, respiratory and CNS) age. Thus, the earlier findings on rejuvenation of the thymus have to be re-evaluated in view of this recent discovery.

One marker often association with aging, senescence and inflammatory diseases in the elderly is CD28. T cells lacking this coreceptor are often considered as senescent, although they retain certain functionality, mainly because of loss of proliferative capacity. There have been several attempts to restore T-cell functions by activating cells by alternative routes than CD28 that still provide a sufficient costimulation to enhance T-cell activation. Promoting 4–1BB, or blocking PD-1 and supplementing with cytokine cocktails, are probably the most successful. Studies have shown that blockade of 4–1BB highly reduced the production of key cytokines such as IFN-γ and TNF-α.[85] This also demonstrated efficiency also for tumor-infiltrating T cells that were less susceptible to cell death during ex vivo expansion and enhanced cytotoxic activity.[86] This is of major importance to retain T-cell functionality for adoptive cell transfer therapy. A study showed that taken as a whole, T cells expand similarly following stimulation with CD3/CD28/4–1BB, but tumor-reactive T-cell expansion was significantly higher compared with CD3/CD28 stimulation alone without loss of functionality.[87] Cytokines were also shown to play a pivotal role in T-cell survival, homeostasis and activation. Early studies have shown that CD28null T cells retain proliferative capacities compared with CD28+ T cells when stimulated with IL-15.[88] Recent updates showed that IL-15 preferentially supports proliferation of CD28null CD4+ T cells over the CD28+CD4+ T cells. IL-15 not only supports proliferation, but enhances the cytotoxic activity in a short-term manner by increased IFN-γ, granzyme B and perforin production.[89] Other studies supported the differential susceptibility of CD28null versus CD28+ T cells to other stimuli including cytokines such as IL-12 that may drive Th1 versus Th2 responses. For instance, further studies are necessary to understand the impact of different cytokine cocktails on other T-cell subsets and not only on CD28null T cells.[90]

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