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Allergen-encoding bone marrow transfer inactivates allergic T cell responses, alleviating airway inflammation
Jane AL-Kouba, … , Philip M. Hansbro, Raymond J. Steptoe
Jane AL-Kouba, … , Philip M. Hansbro, Raymond J. Steptoe
Published June 2, 2017
Citation Information: JCI Insight. 2017;2(11):e85742. https://doi.org/10.1172/jci.insight.85742.
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Research Article Immunology Stem cells

Allergen-encoding bone marrow transfer inactivates allergic T cell responses, alleviating airway inflammation

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Abstract

Memory Th2 cell responses underlie the development and perpetuation of allergic diseases. Because these states result from immune dysregulation, established Th2 cell responses represent a significant challenge for conventional immunotherapies. New approaches that overcome the detrimental effects of immune dysregulation are required. We tested whether memory Th2 cell responses were silenced using a therapeutic approach where allergen expression in DCs is transferred to sensitized recipients using BM cells as a vector for therapeutic gene transfer. Development of allergen-specific Th2 responses and allergen-induced airway inflammation was blocked by expression of allergen in DCs. Adoptive transfer studies showed that Th2 responses were inactivated by a combination of deletion and induction of T cell unresponsiveness. Transfer of BM encoding allergen expression targeted to DCs terminated, in an allergen-specific manner, Th2 responses in sensitized recipients. Importantly, when preexisting airway inflammation was present, there was effective silencing of Th2 cell responses, airway inflammation was alleviated, and airway hyperreactivity was reversed. The effectiveness of DC-targeted allergen expression to terminate established Th2 responses in sensitized animals indicates that exploiting cell-intrinsic T cell tolerance pathways could lead to development of highly effective immunotherapies.

Authors

Jane AL-Kouba, Andrew N. Wilkinson, Malcolm R. Starkey, Rajeev Rudraraju, Rhiannon B. Werder, Xiao Liu, Soi-Cheng Law, Jay C. Horvat, Jeremy F. Brooks, Geoffrey R. Hill, Janet M. Davies, Simon Phipps, Philip M. Hansbro, Raymond J. Steptoe

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Figure 1

Expression of allergen in DC prevents sensitization.

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Expression of allergen in DC prevents sensitization.
(A–D) DC.OVA or non...
(A–D) DC.OVA or nontransgenic (non-Tg) littermates were sensitized with OVA323-339/alum i.p. (OVAp/alum; d0, d14) or sham sensitized with PBS/alum (sham-sens). Seven days later, spleens were collected and restimulated with OVA323-339, and supernatant cytokines were measured by ELISA. (E–G) DC.OVA or non-Tg littermates were sensitized with OVA/alum i.p. or sham sensitized with PBS/alum (sham-sens). Seven days later, spleen cells were restimulated with OVA323-339 and supernatant cytokines measured (E and F), or the frequency of IL-4–producing cells (IL-4 SFU) was determined by ELISpot (G). Data show values for individual mice pooled from 3 experiments, with box and whisker plots showing median, quartiles, and range. ANOVA/Newman-Keuls post-test. Dotted line denotes detection limit of ELISA.

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