James W Krempski1, Jyoti K Lama2, Koji Iijima3, Takao Kobayashi3, Mayumi Matsunaga3, Hirohito Kita4. 1. Immunology Program, Mayo Graduate School of Biomedical Sciences, Rochester and Scottsdale; Department of Immunology, Mayo Clinic, Rochester and Scottsdale; Mary H Weiser Food Allergy Center, Department of Pathology, University of Michigan, Ann Arbor, Mich. 2. Immunology Program, Mayo Graduate School of Biomedical Sciences, Rochester and Scottsdale; Department of Immunology, Mayo Clinic, Rochester and Scottsdale. 3. Division of Allergic Diseases, Asthma and Clinical Immunology, and Department of Medicine, Mayo Clinic, Scottsdale. 4. Department of Immunology, Mayo Clinic, Rochester and Scottsdale; Division of Allergic Diseases, Asthma and Clinical Immunology, and Department of Medicine, Mayo Clinic, Scottsdale. Electronic address: kita.hirohito@mayo.edu.
Abstract
BACKGROUND: A human study, Learning Early About Peanut Allergy (LEAP), showed that early introduction of peanut products decreases the prevalence of peanut allergy among children. However, the immunologic mechanisms mediating the protective effects of consuming peanut products are not well understood. OBJECTIVE: The objective was to develop a mouse model that simulates the LEAP study and investigate the underlying mechanisms for the study observations. METHODS: Adult naive BALB/c mice were fed a commercial peanut butter product (Skippy) or buffer control and concomitantly exposed to peanut flour through the airway or skin to mimic environmental exposure. The animals were analyzed for anaphylactic reaction and by molecular and immunologic approaches. RESULTS: After exposure to peanut flour through the airway or skin, naive mice developed peanut allergy, as demonstrated by acute and systemic anaphylaxis in response to challenge with peanut extract. Ingestion of Skippy, however, nearly abolished the increase in peanut-specific IgE and IgG and protected animals from developing anaphylaxis. Skippy-fed mice showed reduced numbers of T follicular helper (Tfh) cells and germinal center B cells in their draining lymph nodes, and single-cell RNA sequencing revealed a CD4+ T-cell population expressing cytotoxic T lymphocyte-associated protein 4 (CTLA-4) in these animals. Critically, blocking CTLA-4 with antibody increased levels of peanut-specific antibodies and reversed the protective effects of Skippy. CONCLUSION: Ingestion of a peanut product protects mice from peanut allergy induced by environmental exposure to peanuts, and the CTLA-4 pathway, which regulates Tfh cell responses, likely plays a pivotal role in this protection.
BACKGROUND: A human study, Learning Early About Peanut Allergy (LEAP), showed that early introduction of peanut products decreases the prevalence of peanut allergy among children. However, the immunologic mechanisms mediating the protective effects of consuming peanut products are not well understood. OBJECTIVE: The objective was to develop a mouse model that simulates the LEAP study and investigate the underlying mechanisms for the study observations. METHODS: Adult naive BALB/c mice were fed a commercial peanut butter product (Skippy) or buffer control and concomitantly exposed to peanut flour through the airway or skin to mimic environmental exposure. The animals were analyzed for anaphylactic reaction and by molecular and immunologic approaches. RESULTS: After exposure to peanut flour through the airway or skin, naive mice developed peanut allergy, as demonstrated by acute and systemic anaphylaxis in response to challenge with peanut extract. Ingestion of Skippy, however, nearly abolished the increase in peanut-specific IgE and IgG and protected animals from developing anaphylaxis. Skippy-fed mice showed reduced numbers of T follicular helper (Tfh) cells and germinal center B cells in their draining lymph nodes, and single-cell RNA sequencing revealed a CD4+ T-cell population expressing cytotoxic T lymphocyte-associated protein 4 (CTLA-4) in these animals. Critically, blocking CTLA-4 with antibody increased levels of peanut-specific antibodies and reversed the protective effects of Skippy. CONCLUSION: Ingestion of a peanut product protects mice from peanut allergy induced by environmental exposure to peanuts, and the CTLA-4 pathway, which regulates Tfh cell responses, likely plays a pivotal role in this protection.
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