Androgens protect against development of immune responses to peanut

The National Institute of Allergy and Infectious Diseases awarded the University of Nebraska $127,159 on June 1, 2026, under the Allergy and Infectious Diseases Research program (CFDA 93.855) to characterize how androgens negatively regulate the development of peanut allergy, with particular focus on testosterone's role in weakening innate immune responses to peanut allergen and downstream effects on peanut-specific adaptive immune responses.

The research addresses documented sex differences in food allergies, with females twice as likely to develop peanut allergy as males from childhood into adulthood. The project investigates the immunological mechanisms underlying this disparity and how sex hormones modulate immune responses to peanut exposure through non-oral routes such as skin and airway contact. Understanding these pathways may inform strategies to prevent peanut sensitization and improve public health outcomes as peanut allergy prevalence continues to increase.

Performance occurs in Nebraska. The award funds work through May 31, 2030.

Abstract

SEX differences exist in food allergies. Females report significantly more food allergies than males, mirroring what is seen in asthma following puberty. Recent epidemiological data shows that females, starting in childhood and maintained into adulthood, are twice as likely to develop peanut (PN) allergy than males. The prevalence of PN allergy continues to increase. The reasons behind both the increase in PN allergy and the biological SEX differences observed in disease prevalence remain unclear. Recent clinical trials have shown that eating PN early in life is important to promote tolerance, where the immune system ignores ingested PN. Without eating PN early in life, exposure to PN found in household dust via non-oral routes such as skin or airways likely promotes the development of PN allergy. In fact, mice exposed to PN on their skin or airways develop PN allergy, and the mice even undergo clinical signs of anaphylaxis. While almost two decades (2000- 2017) of recommending parents to avoid feeding PN to children for the first few years of life explains, at least in part, the increase in PN allergy, our knowledge about how the immune system responds to non-oral PN exposure remains incomplete. Even less is known about the biological mechanisms underlying SEX differences in susceptibility to food allergies. Our long-term goal is to dissect the immunological pathways responsible for immune sensitization to PN and these discoveries will allow US to better understand how SEX hormones modulate immune responses to PN. The objective of this grant is to characterize how androgens negatively regulate the development of PN allergy. The central hypothesis is that androgens weaken innate immune responses to PN leading to a decrease downstream in PN-specific adaptive immune responses. Our rationale is that androgens, specifically testosterone, has been shown to decrease airway inflammation in mice. Recently, we showed that female and androgen receptor-deficient mice mount stronger allergic responses to PN than males. Our specific aims will test the following hypotheses: (aim 1) androgens, working through the androgen receptor (AR), weaken the responses of ILC2S, DCS, and mast cells to PN; (aim 2) t cells and b cells activated against inhaled PN are suppressed in their ability to respond by androgens. In aim 1, we will utilize our three-day PN inhalation mouse model in wildtype (WT) male, female, and androgen receptor deficient (artfm) male mice to study how androgens exert negative regulatory control on innate responses against PN. We will use an 11-day inhalation mouse model in WT and artfm mice to study the impact of androgens on t and b cell responses to PN in aim 2. Upon conclusion, we will better understand how androgens exert their control on PN-responsive immune cells to establish SEX differences in PN allergies. This contribution is significant since IT will be the first comprehensive study to pinpoint how androgens regulate the development of allergic immune reactions to PN. The proposed research is innovative because IT will give US crucial insight into the biological mechanisms underlying SEX differences in PN allergy. Such knowledge will prove useful in examining other food allergies.