Abstract
<h3>Introduction</h3> A short pre-seasonal course of grass subcutaneous immunotherapy (SCIT) using MicroCrystalline Tyrosine (MCT) and Monophosphoryl Lipid A showed a significant improvement in combined symptom and medication scores (CSMS) in an exploratory field study (PQGrass309). Moreover, molecular mechanisms associated clinical benefit remain to be fully determined. <h3>Methods</h3> Peripheral blood mononuclear cells were obtained from participants, who underwent subcutaneous grass immunotherapy or placebo with MCT at baseline, end of treatment and end of grass pollen season (GPS). A panel of 58 genes was profiled. Ingenuity Pathway Analysis was deployed to elucidate molecular signature and functional relationships for observed gene expression. <h3>Results</h3> CSMS was significantly decreased (-33%) following grass SCIT compared to placebo with MCT. Transcriptome profiling showed transient upregulation of Th2/Th2A and Th17 signature cytokines at the start of GPS and steady downregulation at the end of GPS. Immune modulation towards Th1/Treg at pre-GPS and post-GPS with upregulation of IFNγ, IL-12A, EBI3 (IL-35), IL-27, IL-10, TGFβ was indicative of immune tolerance induction. T helper cell differentiation was one of the most significantly enriched pathways with Th17 mapped as a top enriched canonical pathway, which was transiently upregulated at the start of GPS and downregulated at the end of GPS. Upstream regulator analysis predicted IL-4, IL17A/IL17F, IL-13 and IFNγ as top upstream regulators at pre-GPS and IFNγ, IL-12A, IL-27 at post-GPS. <h3>Conclusion</h3> A distinct immunomodulatory profile of grass SCIT induced responses revealed clusters of differentially expressed genes, which supports restoration of the Th1/Th2 balance and provides the underpinning mechanisms associated with the robust clinical efficacy outcome.
Published Version
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