J. Emiliano Gómez Medellín, Trevor W. M. Ung, Thomas Wang, Kevin Chang, Alexandra Cassano, Trevin Kurtanich, Joseph W. Reda, Kristen E. Shema, Nikola Stanic, Anna J. Slezak, Ivan Vuong, Bohao Chen, Shijie Cao, Maria-Luisa Alegre, Melody A. Swartz, Jeffrey A. Hubbell
{"title":"肝脏靶向过敏原免疫治疗快速、安全地诱导抗原特异性耐受治疗小鼠过敏性气道疾病","authors":"J. Emiliano Gómez Medellín, Trevor W. M. Ung, Thomas Wang, Kevin Chang, Alexandra Cassano, Trevin Kurtanich, Joseph W. Reda, Kristen E. Shema, Nikola Stanic, Anna J. Slezak, Ivan Vuong, Bohao Chen, Shijie Cao, Maria-Luisa Alegre, Melody A. Swartz, Jeffrey A. Hubbell","doi":"","DOIUrl":null,"url":null,"abstract":"<div >Current asthma treatments manage disease symptoms but fail to address the underlying cause of allergic disease. Allergen immunotherapy holds the promise for durable disease control by establishing allergen-specific tolerance through repeated introduction of native allergens; however, its efficacy can be limited by long interventions, reactions upon administration, and poor patient compliance. Here, we developed a rapid, safe, and effective liver-targeted allergen immunotherapy (LIT) to provide long-term disease control. We developed LIT tolerogens from native respiratory allergens, which induced antigen-specific regulatory T (T<sub>reg</sub>) cells in vivo with only two interventions. Synthetic mannosylation of native allergens prevented antibody-mediated recognition and subsequent life-threatening anaphylaxis upon administration. Protein engineering prevented sensitization events that occurred because of the proteolytic activity of native respiratory allergens, which limit the effectiveness of allergen immunotherapy. In preclinical models of allergic asthma, LIT ameliorated clinical, pathological, and serological features, and protection was dependent on antigen-specific T<sub>reg</sub> cells. In sensitized mice, LIT provided a year-long control of allergic asthma symptoms in the absence of additional intervention. Last, LIT induced antigen-specific T<sub>reg</sub> cells against Der p 1, a major protein in the clinically relevant house dust mite (HDM) respiratory allergen. In mice with established HDM allergy, LIT was well tolerated and provided allergic symptom relief. Together, our data provide a proof of concept that LIT with synthetically mannosylated tolerogens provides a rapid, safe, and effective approach to allergen immunotherapy and holds promise for durable control of allergic asthma.</div>","PeriodicalId":21580,"journal":{"name":"Science Translational Medicine","volume":"17 794","pages":""},"PeriodicalIF":15.8000,"publicationDate":"2025-04-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":"0","resultStr":"{\"title\":\"Liver-targeted allergen immunotherapy rapidly and safely induces antigen-specific tolerance to treat allergic airway disease in mice\",\"authors\":\"J. Emiliano Gómez Medellín, Trevor W. M. Ung, Thomas Wang, Kevin Chang, Alexandra Cassano, Trevin Kurtanich, Joseph W. Reda, Kristen E. Shema, Nikola Stanic, Anna J. Slezak, Ivan Vuong, Bohao Chen, Shijie Cao, Maria-Luisa Alegre, Melody A. Swartz, Jeffrey A. Hubbell\",\"doi\":\"\",\"DOIUrl\":null,\"url\":null,\"abstract\":\"<div >Current asthma treatments manage disease symptoms but fail to address the underlying cause of allergic disease. Allergen immunotherapy holds the promise for durable disease control by establishing allergen-specific tolerance through repeated introduction of native allergens; however, its efficacy can be limited by long interventions, reactions upon administration, and poor patient compliance. Here, we developed a rapid, safe, and effective liver-targeted allergen immunotherapy (LIT) to provide long-term disease control. We developed LIT tolerogens from native respiratory allergens, which induced antigen-specific regulatory T (T<sub>reg</sub>) cells in vivo with only two interventions. Synthetic mannosylation of native allergens prevented antibody-mediated recognition and subsequent life-threatening anaphylaxis upon administration. Protein engineering prevented sensitization events that occurred because of the proteolytic activity of native respiratory allergens, which limit the effectiveness of allergen immunotherapy. In preclinical models of allergic asthma, LIT ameliorated clinical, pathological, and serological features, and protection was dependent on antigen-specific T<sub>reg</sub> cells. In sensitized mice, LIT provided a year-long control of allergic asthma symptoms in the absence of additional intervention. Last, LIT induced antigen-specific T<sub>reg</sub> cells against Der p 1, a major protein in the clinically relevant house dust mite (HDM) respiratory allergen. In mice with established HDM allergy, LIT was well tolerated and provided allergic symptom relief. 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Liver-targeted allergen immunotherapy rapidly and safely induces antigen-specific tolerance to treat allergic airway disease in mice
Current asthma treatments manage disease symptoms but fail to address the underlying cause of allergic disease. Allergen immunotherapy holds the promise for durable disease control by establishing allergen-specific tolerance through repeated introduction of native allergens; however, its efficacy can be limited by long interventions, reactions upon administration, and poor patient compliance. Here, we developed a rapid, safe, and effective liver-targeted allergen immunotherapy (LIT) to provide long-term disease control. We developed LIT tolerogens from native respiratory allergens, which induced antigen-specific regulatory T (Treg) cells in vivo with only two interventions. Synthetic mannosylation of native allergens prevented antibody-mediated recognition and subsequent life-threatening anaphylaxis upon administration. Protein engineering prevented sensitization events that occurred because of the proteolytic activity of native respiratory allergens, which limit the effectiveness of allergen immunotherapy. In preclinical models of allergic asthma, LIT ameliorated clinical, pathological, and serological features, and protection was dependent on antigen-specific Treg cells. In sensitized mice, LIT provided a year-long control of allergic asthma symptoms in the absence of additional intervention. Last, LIT induced antigen-specific Treg cells against Der p 1, a major protein in the clinically relevant house dust mite (HDM) respiratory allergen. In mice with established HDM allergy, LIT was well tolerated and provided allergic symptom relief. Together, our data provide a proof of concept that LIT with synthetically mannosylated tolerogens provides a rapid, safe, and effective approach to allergen immunotherapy and holds promise for durable control of allergic asthma.
期刊介绍:
Science Translational Medicine is an online journal that focuses on publishing research at the intersection of science, engineering, and medicine. The goal of the journal is to promote human health by providing a platform for researchers from various disciplines to communicate their latest advancements in biomedical, translational, and clinical research.
The journal aims to address the slow translation of scientific knowledge into effective treatments and health measures. It publishes articles that fill the knowledge gaps between preclinical research and medical applications, with a focus on accelerating the translation of knowledge into new ways of preventing, diagnosing, and treating human diseases.
The scope of Science Translational Medicine includes various areas such as cardiovascular disease, immunology/vaccines, metabolism/diabetes/obesity, neuroscience/neurology/psychiatry, cancer, infectious diseases, policy, behavior, bioengineering, chemical genomics/drug discovery, imaging, applied physical sciences, medical nanotechnology, drug delivery, biomarkers, gene therapy/regenerative medicine, toxicology and pharmacokinetics, data mining, cell culture, animal and human studies, medical informatics, and other interdisciplinary approaches to medicine.
The target audience of the journal includes researchers and management in academia, government, and the biotechnology and pharmaceutical industries. It is also relevant to physician scientists, regulators, policy makers, investors, business developers, and funding agencies.