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Oral Administration of Antigen-Specific Exosomes Carrying MicroRNA-150 Suppresses Delayed-Type Hypersensitivity (DTH) Underlying Casein Allergy in Mouse Model; Results Suggest Possible Treatment Approach for Patients with Clinical Conditions Like Asthma

A publication in the April 23, 2019 issue of Nutrients presents new data, from the lab group of Philip Askenase (photo), MD, at the Yale University School of Medicine, describes the successful oral administration of suppressor T cell-derived exosomes strongly inhibiting immune inflammation in the skin. Exosomes are nano-sized, membrane-bounded vesicles secreted by cells, often to communicate between cells, mostly by exchange of RNAs. The article, which was included in Nutrients special issue "Cow's Milk and Allergy" is titled "Delayed-Type Hypersensitivity Underlying Casein Allergy Is Suppressed by Extracellular Vesicles Carrying miRNA-150." The results in this study were largely generated by visiting Professors Krzysztof Bryniarski and Katarzyna Nazimek from the Jagellonian College of Medicine in Krakow, Poland. The Askenase group studied allergic CD4pos T cell- and macrophage-orchestrated effector inflammation in the ear skin of mice that was strongly inhibited by oral administration of antigen-specific suppressor CD8pos T cell-derived exosomes delivering miRNA-150. Quantitated skin responses were measured kinetically over five days and the responses were to casein, a common protein of milk allergy. The antigen specificity was due to anti-casein antibody light chains coating the exosomes. This was demonstrated by flow cytometry, which also showed that the suppressive exosomes also expressed CD9, CD63, and CD81 (typical markers of classical exosomes) on their surfaces. The functioning exosomes were definitively identified by specific affinity column fractionation with beads linked to casein antigen and separately to anti-CD9. The exosomes were recovered and tested for function in vivo. The suppressor exosomes were administered systemically in a single physiological dose at the peak of the skin immune inflammatory response to casein.

These miRNA-150pos exosomes produced very strong inhibition of the T-cell-dependent skin inflammation for at least the subsequent four days. In fact, the oral route, reported positively for the first time, produced greater suppression then the also examined and more commonly used intraperitoneal route, and even both the intravenous and intradermal routes, which were also administered as a single dose systemically.

This model system has many advantages to truly test the xeno miRNA dietary delivery hypothesis concerning activity of food exosome miRNA in ingesting mammalian subjects. Also, considering the validity of oral miRNA treatment, this skin immune system administers just exosomes, which only work if they are antigen-specific and require delivery of their miRNA-150 to antigen-presenting cells that regulate the effector CD4pos T cells mediating the immune inflammation.

This Askenase laboratory system is measured quantitatively and kinetically, entirely by in vivo functions; allowing both dose response and time course determinations, with antibody and miRNA markers to be followed, and functioning to likely make epigenetic alterations affecting skin inflammation, that can be measured in a variety of ways.

The authors believe their findings to be very important because, in general, they resemble the clinical situation of treating a patient with a pre-existing and ongoing immune-mediated response. Further, such successful and powerful suppressive exosome administration by the oral route, if translated to the clinical situation, represents a low-impact and high-effect treatment modality that obviously would be appealing to patients; especially children.

Possible application to clinical conditions involving protein Ag-specific delayed-type hypersensitivity-like systems include: asthma, transplantation, cancer immunity, and autoimmunity conditions like multiple sclerosis.

Such protein Ag-specific, possibly universal therapeutic exosomes would be an entirely new, novel, unique, and unprecedented dual Ag-specific and gene-specific approach for therapies, because none currently exists for chosen Ag-specific targeting and simultaneous delivery of selected therapeutic miRNA or RNAi.

[Nutrients abstract]