Immune checkpoint-engineered virus-like particles induce antigen-specific immune tolerance and protect against food allergy

1. Ruiter, B. & Shreffler, W. G. The role of dendritic cells in food allergy. J. Allergy Clin. Immunol. 129, 921–928 (2012).

   Google Scholar 

2. Ling, E. M. et al. Relation of CD4 + CD25+ regulatory T-cell suppression of allergen-driven T-cell activation to atopic status and expression of allergic disease. Lancet 363, 608–615 (2004).

   Google Scholar 

3. Stoumpos, A., Heine, G., Saggau, C. & Scheffold, A. The role of allergen-specific regulatory T cells in the control of allergic disease. Curr. Opin. Immunol. 92, 102509 (2025).

   Google Scholar 

4. Torgerson, T. R. et al. Severe food allergy as a variant of IPEX syndrome caused by a deletion in a noncoding region of the FOXP3 gene. Gastroenterology 132, 1705–1717 (2007).

   Google Scholar 

5. Conrad, M. L. et al. Regulatory T cells and their role in allergic disease. Allergy 80, 77–93 (2025).

   Google Scholar 

6. Yamashita, H., Takahashi, K., Tanaka, H., Nagai, H. & Inagaki, N. Overcoming food allergy through acquired tolerance conferred by transfer of Tregs in a murine model. Allergy 67, 201–209 (2012).

   Google Scholar 

7. Rosenzwajg, M. et al. Low-dose IL-2 in birch pollen allergy: A phase-2 randomized double-blind placebo-controlled trial. J. Allergy Clin. Immunol. 155, 650–655 (2025).

   Google Scholar 

8. Bonnet, B. et al. Low-dose IL-2 induces regulatory T Cell-mediated control of experimental food allergy. J. Immunol. 197, 188–198 (2016).

   Google Scholar 

9. Bonnet, B., Vinot, P. A. & Bellier, B. Cibles et immunothérapies innovantes dans le traitement de l’allergie alimentaire. Rev. Franç. Allergol. 57, 327–336 (2017).

   Google Scholar 

10. Laoubi, L. et al. Epicutaneous allergen immunotherapy induces a profound and selective modulation in skin dendritic-cell subsets. J. Allergy Clin. Immunol. 150, 1194–1208 (2022).

    Google Scholar 

11. Lombardi, V. & Akbari, O. Dendritic cell modulation as a new interventional approach for the treatment of asthma. Drug N. Perspect. 22, 445–451 (2009).

    Google Scholar 

12. Xu, J. et al. The role of DC subgroups in the pathogenesis of asthma. Front. Immunol. 15, 1481989 (2024).

    Google Scholar 

13. Nam, J.-H. et al. Functional ambivalence of dendritic cells: tolerogenicity and immunogenicity. Int. J. Mol. Sci. 22, 4430 (2021).

    Google Scholar 

14. Dao Nyesiga, G. et al. Tolerogenic dendritic cells generated in vitro using a novel protocol mimicking mucosal tolerance mechanisms represent a potential therapeutic cell platform for the induction of immune tolerance. Front Immunol. 14, 1045183 (2023).

    Google Scholar 

15. Pallotta, M. T. et al. Indoleamine 2,3-dioxygenase is a signaling protein in long-term tolerance by dendritic cells. Nat. Immunol. 12, 870–878 (2011).

    Google Scholar 

16. An, X. J. et al. Immature dendritic cells expressing indoleamine 2,3-dioxygenase suppress ovalbumin-induced allergic airway inflammation in mice. J. Investig. Allergol. Clin. Immunol. 21, 185–192 (2011).

    Google Scholar 

17. Que, W., Guo, W.-Z. & Li, X.-K. Manipulation of regulatory dendritic cells for induction transplantation tolerance. Front. Immunol. 11, 582658 (2020).

    Google Scholar 

18. Horton, C., Shanmugarajah, K. & Fairchild, P. J. Harnessing the properties of dendritic cells in the pursuit of immunological tolerance. Biomed. J. 40, 80–93 (2017).

    Google Scholar 

19. de Aragão-França et al. Tolerogenic dendritic cells reduce airway inflammation in a model of dust mite-triggered allergic inflammation. Allergy Asthma Immunol. Res 10, 406–419 (2018).

    Google Scholar 

20. Mohammadi, P., Hesari, M., Chalabi, M., Salari, F. & Khademi, F. An overview of immune checkpoint therapy in autoimmune diseases. Int. Immunopharmacol. 107, 108647 (2022).

    Google Scholar 

21. Waterhouse, P. et al. Lymphoproliferative disorders with early lethality in mice deficient in Ctla-4. Science 270, 985–988 (1995).

    Google Scholar 

22. Zheng, Y. et al. A meta-analysis of the association between CTLA-4 genetic polymorphism and susceptibility of asthma. Medicine 97, e11380 (2018).

    Google Scholar 

23. Rudd, C. E. & Schneider, H. Unifying concepts in CD28, ICOS and CTLA4 co-receptor signalling. Nat. Rev. Immunol. 3, 544–556 (2003).

    Google Scholar 

24. Grohmann, U. et al. CTLA-4-Ig regulates tryptophan catabolism in vivo. Nat. Immunol. 3, 1097–1101 (2002).

    Google Scholar 

25. Maazi, H. et al. Cytotoxic T lymphocyte antigen 4-immunoglobulin G is a potent adjuvant for experimental allergen immunotherapy. Clin. Exp. Immunol. 172, 113–120 (2013).

    Google Scholar 

26. Puricelli, C. et al. Cutting-edge delivery systems and adjuvants in tolerogenic vaccines: a review. Pharmaceutics 14, 1782 (2022).

    Google Scholar 

27. Unger, W. W. J., Laban, S., Kleijwegt, F. S., van der Slik, A. R. & Roep, B. O. Induction of Treg by monocyte-derived DC modulated by vitamin D3 or dexamethasone: differential role for PD-L1. Eur. J. Immunol. 39, 3147–3159 (2009).

    Google Scholar 

28. Obregon, C., Kumar, R., Pascual, M. A., Vassalli, G. & Golshayan, D. Update on Dendritic Cell-Induced Immunological and Clinical Tolerance. Front Immunol. 8, 1514 (2017).

    Google Scholar 

29. Engeroff, P. et al. Allergens displayed on virus-like particles are highly immunogenic but fail to activate human mast cells. Allergy: Eur. J. Allergy Clin. Immunol. 73, 341–349 (2018).

    Google Scholar 

30. Brune, K. D. et al. Plug-and-Display: decoration of Virus-Like Particles via isopeptide bonds for modular immunization. Sci. Rep. 6, 19234 (2016).

    Google Scholar 

31. Wojta-Stremayr, D. et al. CD8+ T cell fate and function influenced by antigen-specific virus-like nanoparticles co-expressing membrane tethered IL-2. Plos One 10, e0126034 (2015).

    Google Scholar 

32. Chazal, N. & Gerlier, D. Virus entry, assembly, budding, and membrane rafts. Microbiol. Mol. Biol. Rev. 67, 226–237 (2003).

    Google Scholar 

33. Maldonado, R. & Von Andrian, U. How tolerogenic dendritic cells induce regulatory T cells. Adv. Immunol. 108, 111–165 (2010).

    Google Scholar 

34. Tuettenberg, A., Fondel, S., Steinbrink, K., Enk, A. H. & Jonuleit, H. CD40 signalling induces IL-10-producing, tolerogenic dendritic cells. Exp. Dermatol. 19, 44–53 (2010).

    Google Scholar 

35. Flórez-Grau, G., Zubizarreta, I., Cabezón, R., Villoslada, P. & Benitez-Ribas, D. Tolerogenic dendritic cells as a promising antigen-specific therapy in the treatment of multiple sclerosis and neuromyelitis optica from preclinical to clinical trials. Front. Immunol. 9, 1–10 (2018).

    Google Scholar 

36. Comi, M., Amodio, G. & Gregori, S. Interleukin-10-producing DC-10 is a unique tool to promote tolerance via antigen-specific T regulatory Type 1 cells. Front. Immunol. 9, 682 (2018).

    Google Scholar 

37. Akdis, C. A. & Akdis, M. Mechanisms of immune tolerance to allergens: role of IL-10 and Tregs. J. Clin. Investig. 124, 4678–4680 (2014).

    Google Scholar 

38. Coomes, S. M. et al. CD4 + Th2 cells are directly regulated by IL-10 during allergic airway inflammation. Mucosal Immunol. 10, 150–161 (2017).

    Google Scholar 

39. Platten, M., Wick, W. & Van Den Eynde, B. J. Tryptophan catabolism in cancer: Beyond IDO and tryptophan depletion. Cancer Res. 72, 5435–5440 (2012).

    Google Scholar 

40. Baban, B. et al. IDO activates regulatory T cells and blocks their conversion into Th17-like T cells. J. Immunol. 183, 2475–2483 (2009).

    Google Scholar 

41. Taher, Y. A. et al. Indoleamine 2,3-dioxygenase-dependent tryptophan metabolites contribute to tolerance induction during allergen immunotherapy in a mouse model. J. Allergy Clin. Immunol. 121, 16–18 (2008).

    Google Scholar 

42. Kratzer, B. et al. Prevention of allergy by virus-like nanoparticles (VNP) delivering shielded versions of major allergens in a humanized murine allergy model. Allergy 74, 246–260 (2018).

    Google Scholar 

43. Soneoka, Y. et al. A transient three-plasmid expression system for the production of high-titer retroviral vectors. Nucleic Acids Res 23, 628–633 (1995).

    Google Scholar 

44. Pitoiset, F. et al. Retrovirus-based virus-like particle immunogenicity and its modulation by toll-like receptor activation. J. Virol. 91. (2017).

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