Patel, Neil Pradip; (2018) Investigating strategies to boost cutaneous varicella zoster virus-specific immune responses in ageing humans. Doctoral thesis (Ph.D), UCL (University College London).

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Abstract

The age-related decline in the immune system, known as immunosenescence, predisposes old individuals to increased mortality and morbidity from infectious diseases (such as shingles, caused by reactivation of varicella zoster virus, VZV) and is associated with impaired vaccine responses. While multiple age-related changes have been identified in circulating memory T cells, little is known about the effects of ageing on memory T cells within peripheral tissues. T cells within human skin were characterised, and surprisingly neither their numbers, differentiation markers or effector functions were altered during ageing. VZV-specific CD4+ T cells were more frequent in the skin than in the blood, and their frequency in the skin did not decline with age. Increased PD-1 expression on T cells and an increased frequency of regulatory T cells in ageing skin consolidated evidence that old skin represents an inhibitory microenvironment. Vaccination of old individuals with the shingles vaccine Zostavax® did not alter the total number of T cells, or frequency of VZV-specific T cells, in the skin but did boost the frequency of circulating VZV-specific T cells. This was associated with a heightened delayed type hypersensitivity (DTH) response to VZV antigen, and with an upregulation of genes involved in T cell migration and activation. It is proposed here that Zostavax® prevents shingles by enhancing the recruitment of circulating VZV-specific memory T cells to sensory nerves during episodes of silent VZV reactivation. Increased early expression of p38 MAPK-associated pro-inflammatory genes has been observed in VZV- or saline-challenged old skin and was associated with poor DTH responses to VZV antigen. In an experimental medicine study, pre-treatment of ageing individuals with the p38 MAPK inhibitor losmapimod effectively restored robust VZV-specific DTH responses. Ageing of the population necessitates improved vaccination strategies, and p38 MAPK inhibition prior to vaccine administration presents a potential therapeutic opportunity to achieve this.

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