New Investigator Symposium Presentation 49th Annual Scientific Meeting of the Australian and New Zealand Society for Immunology 2021

How does allergen immunotherapy 'switch-off' allergy? (#65)

Anya Jones 1 , Denise Anderson 1 , Niamh Troy 1 , Dominic Mallon 2 , Rochelle Hartmann 2 , Michael Serralha 1 , Barbara Holt 1 , Anthony Bosco 1 , Patrick Holt 1 3
  1. Telethon Kids Institute, University of Western Australia, Subiaco, WA, Australia
  2. Department of Clinical Immunology, Fiona Stanley Hospital, Perth, WA, Australia
  3. Child Health Research Centre, The University of Queensland, Brisbane, QLD, Australia

Background: Multiple regulatory mechanisms have been identified that contribute to outcomes of allergen-specific immunotherapy. Allergen-induced immune responses are thought to involve thousands of genes functioning within complex networks, and how these operate/integrate to maintain immunological homeostasis is incompletely understood.

Aim: To identify allergen-specific immunotherapy induced changes to Th-memory responses employing systems-level gene co-expression network analysis.

Methods: Genome-wide allergen-induced Th-cell responses were profiled prospectively during 24 months subcutaneous immunotherapy (SCIT) in 25 rhinitis. Molecular profiles of Th-cells were interrogated employing upstream regulator, pathways and co-expression network analysis.

Results: Prior to immunotherapy, mite-induced Th-cell response networks consisted of multiple discrete co-expression networks; Type1-IFN-, Th2-, Inflammation-, and FOXP3/IL2-associated signalling. A 109 gene signature correlated with symptom scores relating to cytokine signalling/T-cell activation-associated pathways. Upstream drivers demonstrated activation of key Th1/Th2- and Inflammation-associated genes. At 3.5mths SCIT updosing, symptoms reduced by 32.5% and minimal changes to pathway/upstream regulator profiles were detected. In contrast, network changes were evident, displaying merging of FOXP3/IL2- with Inflammation- and Th2-associated modules. By 12mths SCIT, symptoms had reduced by 41%, whilst pathway/upstream regulator/network profiles remained unchanged. At 24mths of SCIT, symptoms stabilised at 47% of baseline, and the Type1-IFN-associated network module merged into the Th2/FOXP3/IL2/Inflammation module.

Conclusions: Stabilisation of the clinical effectiveness of SCIT underlies progressive rewiring of mite-induced Th-cell-associated Th2-, FOXP3/IL2-, Inflammation- networks and Type1-IFN-signalling subnetwork. Importantly, integration only occurs following 24mths of SCIT treatment. The recruitment of Th2-antagonist Type1-IFN signalling into a coordinated expression network may be central to stabilising the clinical effects of SCIT.