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Clinical and Immunological Outcomes after Randomized Trial of Baked Milk Oral Immunotherapy for Milk Allergy

ABSTRACT: BACKGROUND. Cow’s milk allergy (CMA) is the most common food allergy in young children. Treatment with oral immunotherapy (OIT) has shown efficacy but also high rates of adverse reactions. We sought to determine if baked milk (BM) OIT could reduce adverse reactions while still inducing desensitization, and to identify immunological correlates of successful BMOIT. METHODS. This phase II, randomized trial evaluated the safety and efficacy of BMOIT in children age 3-18 years. After the initial placebo-controlled first year of treatment, placebo-treated participants crossed over to active BMOIT for year two. Double-blind, placebo-controlled food challenges (DBPCFC) were conducted to BM after year one and to both BM and unheated milk (UM) after year two. IgG/IgE antibodies were measured along with cow’s milk (CM)-specific CD4 memory T cell populations, profiled using flow cytometry and scRNA-Seq. RESULTS. Twenty-one of 30 (70%) reached the primary endpoint of tolerating 4044mg of BM protein at month-24, and 11/30 tolerated ≥2000mg of UM. Dosing symptoms were common, but >98% were mild with no severe reactions. Immunological changes associated with desensitization included increased CM IgG4, CM+ FOXP3+ cells, and Tregs and corresponding decreases in CM IgE, CM+ Th2A cells, and CD154+ cells. T cell and antibody measurements were combined to build a model that predicted UM oral food challenge (OFC) outcomes. CONCLUSION. BMOIT was well tolerated and induced a substantial level of desensitization to baked and unheated milk. This desensitization corresponded to significant redistribution within antigen specific antibody and T cell compartments that provide novel insight into the mechanistic changes that occur with OIT treatment.

ORGANISM(S): Homo sapiens

PROVIDER: GSE280063 | GEO | 2025/01/13

REPOSITORIES: GEO

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Project description:Cow milk (CM) allergy is the most prevalent food allergy in young children in the US and Great Britain. Current diagnostic tests are either unreliable (IgE, skin prick test), or resource-intensive with risks (food challenges). Here we set out to determine if allergen-specific T cells in cow milk allergic (CMA) patients have a distinct quality and/or quantity that could potentially be used as a diagnostic marker. Starting from cow milk extract, we mapped T cell responses to a set of reactive epitopes that we compiled in a peptide pool. This pool induced cytokine responses in in vitro cultured cells distinguishing allergic from non-allergic subjects. Using single-cell RNA and paired TCR sequencing we detected significant changes in the transcriptional program and clonality of cow milk antigen-specific (CM+) T cells elicited by the pool in allergic vs. non-allergic subjects ex vivo. CM+ T cells from allergic subjects had increased percentages of FOXP3+ over FOXP3- cells. FOXP3+ cells are often equated with regulatory T cells (Tregs) that have suppressive activity, but CM+ FOXP3+ cells from allergic subjects showed significant expression of interferon-responsive genes and dysregulated chemokine receptor expression compared to non-allergic subjects, suggesting that these are not conventional Tregs. The CM+ FOXP3+ cells were also more clonally expanded than the FOXP3- population. We were further able to utilize surface markers (CD25, CD127, CCR7) in combination with our peptide pool stimulation to quantify these CM+ FOXP3+ cells by a simple flow cytometry assay. We show increased percentages of CM+ CD127-CD25+ cells from CMA subjects in an independent cohort, which could be used for diagnostic purposes. Looking specifically for Th2 cells normally associated with allergic diseases, we found a small population of clonally expanded CM+ cells that were significantly increased in CMA subjects and that had high expression of Th2 cytokines and pathogenic Th2/Tfh markers. Overall, these findings suggest that there are several differences in the phenotype of CM+ T cells with CM allergy and that the increase in CM+ FOXP3+ cells is a potential diagnostic marker of an allergic state. Such markers have promising applications in monitoring natural disease outgrowth and/or the efficacy of immunotherapy that will need to be validated in future studies.

Project description:Human ingestion of microplastics (MPs) is common and inevitable due to the widespread contamination of food items, but implications on the gastric digestion of food proteins are still unknown. In this study, the interaction between pepsin and polystyrene (PS) MPs was uncovered by investigating its effect on enzyme activity and conformation while in a simulated human gastric environment. The impact on food digestion was also determined by monitoring the kinetics of protein hydrolysis through static in vitro gastric digestion of cow’s milk contaminated with PS. The binding of pepsin to PS showed that surface chemistry of MPs dictates binding affinity. The key contributor to pepsin adsorption seems to be π−π interactions between the aromatic residues and the PS phenyl rings. During quick exposure (10 minutes) of pepsin to increasing concentrations (222, 2219, 22188 particles/mL) of 10 μm PS (PS10) and 100 μm PS (PS100), total enzymatic activities were not affected remarkably. However, upon prolonged exposure at 1 and 2 hours, preferential binding of pepsin to the small, low zeta-potential PS caused structural changes in the protein which led to a significant reduction of its activity. Digestion of cow’s milk mixed with PS10 resulted in transient accumulation of larger peptides (10-35 kDa) and reduced bioavailability of short peptides (2-9 kDa) in the gastric phase. This, however, was only observed at extremely high PS10 concentration (0.3 mg/mL or 5.46E+05 particles/mL). The digestion of milk peptides, bound preferentially over pepsin on the hard corona around PS10, was delayed up to 15 minutes in comparison to bulk protein digestion. Intact caseins, otherwise rapidly digested, remained bound to PS10 in hard corona for up to 15 minutes. This work presents valuable insights regarding the interaction of MPs, food proteins, and pepsin, and their dynamics during gastric digestion which provides new knowledge and understanding on the potential risks of MPs to human health.

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Clinical and Immunological Outcomes after Randomized Trial of Baked Milk Oral Immunotherapy for Milk Allergy

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