The microbiome modulates host immunity and aids the maintenance of tolerance in the gut, where microbial and food-derived antigens are abundant. Yet modern dietary factors and the excessive use of antibiotics have contributed to the rising incidence of food allergies, inflammatory bowel disease and other non-communicable chronic diseases associated with the depletion of beneficial taxa, including butyrate-producing Clostridia. Here we show that intragastrically delivered neutral and negatively charged polymeric micelles releasing butyrate in different regions of the intestinal tract restore barrier-protective responses in mouse models of colitis and of peanut allergy. Treatment with the butyrate-releasing micelles increased the abundance of butyrate-producing taxa in Clostridium cluster XIVa, protected mice from an anaphylactic reaction to a peanut challenge and reduced disease severity in a T-cell-transfer model of colitis. By restoring microbial and mucosal homoeostasis, butyrate-releasing micelles may function as an antigen-agnostic approach for the treatment of allergic and inflammatory diseases.
The only FDA-approved oral immunotherapy for a food allergy provides protection against accidental exposure to peanuts. However, this therapy often causes discomfort or side effects and requires long-term commitment. Better preventive and therapeutic solutions are urgently needed. We have developed an inverse vaccine technology that utilizes glycopolymer-conjugated antigens to induce antigen-specific non-responsiveness. The glycopolymer conjugates were administered intravenously (i.v.) or subcutaneously (s.c.) and were found to traffic to the liver or lymph nodes, respectively, leading to preferential internalization by antigen-presenting cells, educating the immune system to respond in an innocuous way. In a mouse model of cow's milk allergy, treatment with glycopolymer-conjugated β-lactoglobulin (BLG) was effective in preventing the onset of allergy. In addition, s.c. administration of glycopolymer-conjugated BLG showed superior safety and potential in treating existing allergies in combination with an anti-CD20 co-therapy. This platform may provide an antigen-specific immunomodulatory strategy to prevent and treat food allergies.
The only FDA-approved oral immunotherapy for a food allergy provides protection against accidental exposure to peanuts. However, this therapy often causes discomfort or side effects and requires long-term commitment. Better preventive and therapeutic solutions are urgently needed. We have developed a technology for inverse vaccination using glyco-polymerized antigens to induce antigen-specific non-responsiveness. We have demonstrated that following subcutaneous (SC) administration, glyco-polymer conjugates traffic to draining lymph nodes (LNs) and are preferentially internalized by antigen presenting cells, educating the immune system to respond to these antigens in an innocuous way. Here, we tested SC administration of glyco-polymerized β-lactoglobulin (BLG) in a murine model of cow’s milk allergy. Two doses of glyco-polymerized BLG given one week apart (prior to sensitization) prevented an allergic response to BLG upon intragastric challenge as measured by reductions in BLG-specific IgG, IgG1, and IgE production as well as BLG-specific type 2 T helper cell (Th2) responses in vitro. We further explored the therapeutic potential of glyco-polymerized BLG. Unlike unmodified BLG, two SC injections of glyco-polymerized BLG after sensitization did not cause anaphylactic reactions in allergic mice and inhibited cellular Th2 cytokines upon BLG restimulation. Since pre-existing humoral immunity inhibited the therapeutic effect of our glyco-polymerized BLG, we introduced a co-therapy (anti-CD20) to blunt the humoral response and observed ameliorated anaphylactic responses following glyco-polymerized BLG therapy. This platform may provide a potential T cell-modulating strategy to prevent and treat food allergies. This work was supported in part by seed funding from the Chicago Immunoengineering Innovation Center at the University of Chicago as well as the Food Allergy Fund.
Regulatory T cells (Tregs) play essential roles in maintaining immune homeostasis and preventing autoimmunity and allergy. Peripherally derived Tregs are induced most efficiently in the lymph nodes (LNs), yet current therapies are not effectively delivered to these sites. The short-chain fatty acid butyrate facilitates extrathymic differentiation of Tregs and has been considered a promising therapeutic candidate. However, there are challenges to its use, including its foul odor, quick metabolism, and low efficiency with traditional oral delivery. Herein, we designed butyrate-prodrug micelles that deliver butyrate to peripheral LNs through subcutaneous (SC) administration. We have developed two polymeric micelles, one with a neutral charge (termed NtL-ButM) and one with a negative charge (termed Neg-ButM), which both contain 28 wt% butyrate and have similar sizes of ~40 nm. In a biodistribution study, we observed that Neg-ButM, not NtL-ButM, accumulated in draining LNs for over one month. At the cellular level, the Neg-ButM were taken up mostly by the macrophages and dendritic cells in the LNs and inhibited LPS-induced activation of those cells. In antibiotic-treated mice, three weekly doses of Neg-ButM significantly increased the numbers of CD25+ Foxp3+ CD4+ Tregs in draining LNs compared to either PBS or NtL-ButM treatment. Furthermore, we demonstrated that, when combined with intragastrically administered peanut proteins, the SC-injected Neg-ButM protected from anaphylactic responses in a mouse model of peanut allergy. This approach provides a potential Treg-based therapy against food allergies. Supported by a seed grant from the Chicago Immunoengineering Innovation Center of the University of Chicago.
The gut microbiome modulates the body’s response to food antigens1. Beneficial taxa, specifically butyrate-producing Clostridia, are depleted in food-allergic individuals2,3. Although butyrate is known to play important roles in regulating gut immunity and maintaining epithelial barrier function4–6, its clinical translation is challenging due to its offensive odor and quick absorption in the upper gut. Here, we developed two polymeric micelle systems, one with a neutral charge (NtL-ButM) and one with a negative charge (Neg-ButM), that release butyrate from their polymeric core in the ileum or the cecum, respectively. Treatment with NtL-ButM in germ-free (and thus butyrate-depleted) mice up-regulated genes expressing antimicrobial peptides in the ileal epithelium. We show that these butyrate-containing micelles, used in combination, restore a barrier-protective response in mice treated with either dextran sodium sulfate or antibiotics. Treatment with the micelles protects peanut-allergic mice from an anaphylactic reaction to peanut challenge and rescues their dysbiosis by increasing the abundance of Clostridium Cluster XIVa. By restoring microbial and mucosal homeostasis, these butyrate-prodrug polymeric micelles may function as a new, antigen-agnostic approach to the treatment of food allergy.
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