PLGA nanoparticles loaded with beta-lactoglobulin-derived peptides modulate mucosal immunity and may facilitate cow's milk allergy prevention

Abstract

Beta-lactoglobulin (BLG)-derived peptides may facilitate oral tolerance to whey and prevent cow's milk allergy (CMA). Loading of BLG-peptides in poly(lactic-co-glycolic acid) (PLGA) nanoparticles (Pep-NP) may improve this. Here we studied the uptake of NP and the capacity of NP and Pep-NP to activate bone marrow dendritic cells (BMDC). Furthermore, CMA prevention was evaluated by orally exposing three-week-old female C3H/HeOuJ mice to Pep-NP, NP or free peptides (PepMix) for 6 days before oral sensitization with whole whey protein and effects on the spleen and small intestine lamina propria (SI-LP) were studied. In BMDC, NP and Pep-NP enhanced CD40 expression and IL-6 and TNF-α secretion, while tended to decrease CD80 expression and prevented PepMix-induced IL-12 secretion. In vivo, oral exposure to Pep-NP, but not NP or PepMix, prior to whey sensitization tended to partially prevent the acute allergic skin response to whole whey protein. Splenocytes of NP-pre-exposed mice secreted increased levels of whey-specific IL-6, but this was silenced in Pep-NP-pre-exposed mice which also showed reduced TNF-α and IFN-γ secretion. In the SI-LP, Pep-NP pre-exposure reduced the CD4 T cell frequency in CMA mice compared to PBS pre-exposure. In addition, while NP increased whey-specific IL-6 secretion in the SI-LP, Pep-NP did not and maintained regulatory TGF-β secretion. This study presents a proof-of-concept that PLGA nanoparticles facilitate the capacity of BLG peptides to suppress the allergic response to whole whey protein. Hence, PLGA nanoparticles may be further developed as an adjunct strategy for BLG-peptide-based oral tolerance induction and CMA prevention.

Mechanisms of Particles in Sensitization, Effector Function and Therapy of Allergic Disease

“…Encapsulating allergen in biodegradable polymeric NPs provides a better safety profile during immunizations and activates the uptake by APCs, thus enhancing cellular and humoral responses (242). Poly(lactic-co-glycolic acid) (PLGA)-based drugs are approved by the FDA and the European Medical Agency for subcutaneous, intramuscular and oral administration.…”

“…Liu et al (245) targeted liver sinusoidal endothelial cells with surface-modified PLGA NPs to induce tolerance against ovalbumin in a murine asthma model. In a murine cow's milk allergy model, prophylactic oral applications of beta-lactoglobulin-derived peptides incorporated into PLGA NPs induced tolerance to the whole whey protein after sensitization (242). In SLIT nanoparticles are captured within sublingual mucosa by Langerhans-like dendritic cells (246) and swallowed allergen is later taken up by M cells in Peyer's patches (244).…”

A Solid-in-Oil Nanodispersion System for Transcutaneous Immunotherapy of Cow’s Milk Allergies

“…The ear swelling response tended to be alleviated by the BLG administration using the S/O system. Other promising approaches to deliver vaccines for CMA immunotherapy have recently been developed, including the oral administration of PLGA nanoparticles [29]. However, transcutaneous administration may still be more convenient for patients who are young infants or who have gastrointestinal disorders.…”

Formulations for Allergen Immunotherapy in Human and Veterinary Patients: New Candidates on the Horizon

“…In addition, PLGA-microparticles were used orally with different plant lectins e.g., Aleura aurantia lectin, wheat-germ agglutinin or Ulex europaeus -I, or Vibrio cholerae neuraminidase to target mucosal cells for enhanced uptake ( 100 – 103 ). Other allergens used with PLGA-particles in animal models via different routes are the Chenopodium allergen rChe a 3, as sublingual immunotherapy in a mouse model of allergic rhinitis ( 104 , 105 ), Ole e 1 from olive pollen or T cell epitopes thereof for intranasal prevention ( 106 , 107 ), bee venom allergen PLA2 ( 108 ), pollen-profilin from palm Caryota mitis ( 109 ), Der p 2 from HDM ( 110 ), peanut extract ( 111 ), or beta-lactoglobulin from milk whey ( 112 ). PLGA locally induced a regulatory T cell response via the incorporated mediator substances TGF-beta-1, rapamycin, and IL-2 to prevent a subsequent contact dermatitis reaction ( 113 ).…”