Enhancement of cutaneous immunity during ageing by blocking p38 MAPkinase induced inflammation

Publication date: Available online 17 November 2017
Source:Journal of Allergy and Clinical Immunology
Author(s): Milica Vukmanovic-Stejic, Emma S. Chambers, Mayte Suarez- Farinas, Daisy Sandhu, Judilyn Fuentes-Duculan, Neil Patel, Elaine Agius, Katie E. Lacy, Carolin T. Turner, Anis Larbi, Veronique Birault, Mahdad Noursadeghi, Neil A. Mabbott, Malcolm H.A. Rustin, James Krueger, Arne N. Akbar
BackgroundImmunity declines with age that leads to re-activation of varicella zoster virus (VZV). In humans, age associated immune changes are usually measured in blood leukocytes however this may not reflect alterations in tissue-specific immunity.ObjectivesWe used a VZV antigen challenge system in the skin to investigate changes in tissue specific mechanisms involved in the decreased response to this virus during ageing.MethodsWe assessed cutaneous immunity by the extent of erythema and induration after intradermal VZV antigen injection. We also performed immune histology and transcriptomic analyses on skin biopsies taken from the site of challenge in young (<40 yrs) and old (>65 yrs) subjects.ResultsOld humans exhibited decreased erythema and induration, CD4⁺ and CD8⁺ T cell infiltration and attenuated global gene activation at the site of cutaneous VZV antigen challenge compared to young subjects. This was associated with elevated sterile inflammation in the skin in the same subjects, related to p38 MAPK-related pro-inflammatory cytokine production (p <0.0007). We inhibited systemic inflammation in old subjects by pre-treatment with an oral small molecule p38 MAP kinase inhibitor (Losmapimod), which reduced both serum C reactive protein (CRP) and peripheral blood monocyte secretion of IL-6 and TNF-α. In contrast, cutaneous responses to VZV antigen challenge was significantly increased in the same individuals (p <0.0006).ConclusionExcessive inflammation in the skin early after antigen challenge retards antigen-specific immunity. However this can be reversed by inhibition of inflammatory cytokine production that may be utilized to promote vaccine efficacy and the treatment of infections and malignancy during ageing.

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Capsule summary: Elevated cutaneous inflammation retards VZV-specific immunity. Inhibiting inflammatory cytokine production with p38 MAPkinase inhibitors enhances VZV-specific cutaneous immunity. Targeting inflammation may be used to promote vaccine efficacy and the treatment of malignancy during ageing.


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