| dc.description.abstract | Background
Over five million people in the UK are receiving treatment for asthma. Corticosteroids
(steroids) are the mainstay of asthma therapy but some patients do not respond fully to
steroid treatment, they are characterised as being steroid resistant (SR) and are at high
risk of morbidity and mortality. Earlier data from our laboratory has shown evidence
that in vitro treatment with the active form of vitamin D, - 1!,25-dihydroxyvitamin D3
or calcitriol - enhanced responsiveness to steroids for induction of the anti inflammatory
cytokine IL-10. This thesis discusses the results of a proof of concept clinic trial - ‘The
Calcitriol Study’ - which hypothesized that concomitant in vivo treatment with oral
calcitriol improves the clinical responsiveness to systemic steroid (prednisolone)
therapy. The study further allowed investigation of the in vitro cytokine profile of
patients with SR and steroid sensitive (SS) asthma. Th17 cells and their hallmark
cytokine IL-17A are proposed to play a role in the pathology of severe asthma, including
SR asthma, and this work tested the susceptibility of IL-17A and other pro inflammatory
cytokines important in asthma to inhibition by steroids and calcitriol in vivo and in
culture.
Methods
Adult patients with moderate/severe asthma (FEV1 <80% predicted) with demonstrable
reversibility of airways obstruction underwent a two-week, pharmacodynamically
standardised course of oral prednisolone (screening phase) to delineate steroid resistance
a <10% improvement in FEV1. Patients were then randomly assigned to receive
calcitriol (n=12) or indistinguishable placebo (n=11) for four weeks, with a repeat
course of prednisolone during the final two weeks (treatment phase). Changes in lung
function (!FEV1) in response to prednisolone were compared between the placebo and
calcitriol groups in the treatment phase, and within groups between the screening and
treatment phases. Asthma Control Questionnaires and fractional exhaled nitric oxide
(FeNo) were scored and analysed as secondary endpoints. All participants had serum
25(OH)D levels measured at baseline. CD8-depleted PBMCs were isolated from SS and
SR asthmatics and healthy controls and cultured with or without dexamethasone and / or
calcitriol. Cytometric bead array, ELISA, qPCR and intracellular cytokine staining were
used to assess cytokine production.
Results
5
Treatment with calcitriol improved the clinical response to steroids in patients classified
as clinically steroid resistant (SR) in a within group comparison of changes in FEV1.
However, there was no significant difference seen between the two groups from
screening to the end of the trial.
A striking dichotomy was observed between SR and SS asthma patients in terms of their
cytokine profiles; SS patients, who showed the biggest improvement in lung function
after a course of prednisolone had the highest levels of IL-10 in culture in response to
dexamethasone, whereas SR patients, whose lung function failed to improve, had
significantly greater levels of IL-17A. Treatment with steroids appeared to aggravate
production of this pro-inflammatory cytokine but in vitro and in vivo calcitriol not only
resulted in a significant reduction of IL-17A levels but also restored the impaired,
steroid-induced anti-inflammatory IL-10 response in SR patients. Serum 25(OH)D
levels at baseline correlated positively with IL-13 in culture, a Th2 cytokine known to be
associated with steroid responsive asthma.
Conclusion
Calcitriol may have the potential to improve the clinical responsiveness of asthma
patients to systemic steroid therapy in SR asthma. These data identify immunological
pathways that likely underpin the beneficial clinical effects of calcitriol in SR asthma,
by directing the SR cytokine profile towards a more SS type, suggesting strategies to
characterise vitamin D responder immune phenotypes. | en_US |
