Inducing Tolerance in Allergy (ITA)
Research type
Research Study
Full title
TARGETING HUMAN SKIN TO INDUCE LONG-LASTING TOLERANCE IN ALLERGY
IRAS ID
199244
Contact name
Marta E Polak
Contact email
Duration of Study in the UK
4 years, 6 months, 31 days
Research summary
Research Summary - Allergy is a chronic disease that is expected to affect more than 50% of all Europeans in 10 years' time. Recent break-through results demonstrate the correct administration of peanut to high-risk children significantly decreases their likelihood of developing allergy. We have demonstrated that cutaneous immune programming determines the systemic immune responses to allergens and identified a subset of immune cells residing in the epidermis, called “Langerhans’ cells (LCs)” playing a central role in the regulation of immunity and tolerance. Here we aim to investigate how the function human skin residing immune cells is altered in allergic skin disease, and whether we can use them to induce long-lasting tolerance to allergens.
We plan to investigate this process in skin samples collected from paediatric and adult patients, after obtaining an informed consent, and apply laboratory, clinical and computational methodologies to comprehensively characterise them. The clinical and immunological parameters will be correlated using the state-of-the –art computational tools, and the molecular targets key to the induction of allergen-specific responses or tolerance will be identified. These targets will be subsequently validated in laboratory experiments. By focusing on a key control element of immune regulation by human LCs, this work will define the molecular basis for the induction of immunotolerance, and identify targets for immune intervention in allergy.
Lay Summary - We have fulfilled the study aims, identifying the molecular networks activated in atopic skin upon exposure to allergens (results published Sirvent et al 2023, Nature Communications, 14, 2880: https://gbr01.safelinks.protection.outlook.com/?url=https%3A%2F%2Fclick.pstmrk.it%2F3ts%2Fwww.nature.com%252Farticles%252Fs41467-023-38588-1&data=05%7C02%7Cbrightonandsussex.rec%40hra.nhs.uk%7Cc9451416b1d541c4e06c08dd4b4c772c%7C8e1f0acad87d4f20939e36243d574267%7C0%7C0%7C638749513965923148%7CUnknown%7CTWFpbGZsb3d8eyJFbXB0eU1hcGkiOnRydWUsIlYiOiIwLjAuMDAwMCIsIlAiOiJXaW4zMiIsIkFOIjoiTWFpbCIsIldUIjoyfQ%3D%3D%7C0%7C%7C%7C&sdata=S7Xxza7Go%2BxfZyV5cex0E2JUtPi1SJiiuaCP7XMPr3A%3D&reserved=0)/NBTI/XFS7AQ/AQ/43e8006e-41a1-428b-9e82-4e1800f09d0a/2/wqjtB81OYE and described molecular switches regulating activation of Langerhans cells in healthy skin (results published Sirvent et al 2020, Nature Communications 11, 313: https://gbr01.safelinks.protection.outlook.com/?url=https%3A%2F%2Fclick.pstmrk.it%2F3ts%2Fwww.nature.com%252Farticles%252Fs41467-019-14125-x%253B%2FNBTI%2FXFS7AQ%2FAQ%2F43e8006e-41a1-428b-9e82-4e1800f09d0a%2F3%2FSTkE7ai35b&data=05%7C02%7Cbrightonandsussex.rec%40hra.nhs.uk%7Cc9451416b1d541c4e06c08dd4b4c772c%7C8e1f0acad87d4f20939e36243d574267%7C0%7C0%7C638749513965936154%7CUnknown%7CTWFpbGZsb3d8eyJFbXB0eU1hcGkiOnRydWUsIlYiOiIwLjAuMDAwMCIsIlAiOiJXaW4zMiIsIkFOIjoiTWFpbCIsIldUIjoyfQ%3D%3D%7C0%7C%7C%7C&sdata=PhHzZFCKyQykspau4GDZpYiVWq5kKv8ApGaAKoEZdCs%3D&reserved=0 Davies et al Frintiers in Immunology, 2021, 12: https://gbr01.safelinks.protection.outlook.com/?url=https%3A%2F%2Fclick.pstmrk.it%2F3ts%2Fdoi.org%252F10.3389%252Ffimmu.2021.665312%253B%2FNBTI%2FXFS7AQ%2FAQ%2F43e8006e-41a1-428b-9e82-4e1800f09d0a%2F4%2F6oSk35Reg5&data=05%7C02%7Cbrightonandsussex.rec%40hra.nhs.uk%7Cc9451416b1d541c4e06c08dd4b4c772c%7C8e1f0acad87d4f20939e36243d574267%7C0%7C0%7C638749513965948642%7CUnknown%7CTWFpbGZsb3d8eyJFbXB0eU1hcGkiOnRydWUsIlYiOiIwLjAuMDAwMCIsIlAiOiJXaW4zMiIsIkFOIjoiTWFpbCIsIldUIjoyfQ%3D%3D%7C0%7C%7C%7C&sdata=lOhl8eMVtbNyE%2FSODuaz%2BKWfyGygOewsk5gepnMoCf8%3D&reserved=0 Davies et a Frontiers in Immunology, 2022, 13: doi.org/10.3389/fimmu.2022.892254). Langerhans cells activation status in paediatric skin did not correlate with subsequent development of allergy in paediatric cohort. We have however observed significant expansion of Langerhans cells in peri-natal skin, opening a window of opportunity for programming of immune responses in human. These results are published in Science Immunology, Appios et al, 2024, https://gbr01.safelinks.protection.outlook.com/?url=https%3A%2F%2Fclick.pstmrk.it%2F3ts%2Fwww.science.org%252Fdoi%252Fabs%252F10.1126%252Fsciimmunol.adp0344.%2FNBTI%2FXFS7AQ%2FAQ%2F43e8006e-41a1-428b-9e82-4e1800f09d0a%2F5%2F8SnOWUu8uP&data=05%7C02%7Cbrightonandsussex.rec%40hra.nhs.uk%7Cc9451416b1d541c4e06c08dd4b4c772c%7C8e1f0acad87d4f20939e36243d574267%7C0%7C0%7C638749513965961070%7CUnknown%7CTWFpbGZsb3d8eyJFbXB0eU1hcGkiOnRydWUsIlYiOiIwLjAuMDAwMCIsIlAiOiJXaW4zMiIsIkFOIjoiTWFpbCIsIldUIjoyfQ%3D%3D%7C0%7C%7C%7C&sdata=UwOUXtmGTJSy60m%2BmWXhhm%2Fb9Ikblb2YONySGxBlZFo%3D&reserved=0
All transcriptomics data are deposited in public repositories, and available to the community (data from paediatric cohort is still under embargo, until manuscript publication).REC name
London - Brighton & Sussex Research Ethics Committee
REC reference
16/LO/0999
Date of REC Opinion
3 Aug 2016
REC opinion
Further Information Favourable Opinion