Thymic stromal lymphopoietin rather than IL-33 drives food allergy after epicutaneous sensitization to food allergen.

BACKGROUND: A major route of sensitization to food allergen is through an impaired skin barrier. IL-33 and thymic stromal lymphopoietin (TSLP) have both been implicated in epicutaneous sensitization and food allergy, albeit in different murine models. OBJECTIVE: We assessed the respective contributions of TSLP and IL-33 to the development of atopic dermatitis (AD) and subsequent food allergy in TSLP and IL-33 receptor (ST2)-deficient mice using an AD model that does not require tape stripping. METHOD: TSLP receptor (TSLPR)-/-, ST2-/-, and BALB/cJ control mice were exposed to 3 weekly epicutaneous skin patches of one of saline, ovalbumin (OVA), or a combination of OVA and Aspergillus fumigatus (ASP), followed by repeated intragastric OVA challenges and development of food allergy. RESULTS: ASP and/or OVA patched, but not OVA-alone patched, BALB/cJ mice developed an AD-like skin phenotype. However, epicutaneous OVA sensitization occurred in OVA patched mice and was decreased in ST2-/- mice, resulting in lower intestinal mast cell degranulation and accumulation, as well as OVA-induced diarrhea occurrences on intragastric OVA challenges. In TSLPR-/- mice, intestinal mast cell accumulation was abrogated, and no diarrhea was observed. AD was significantly milder in OVA + ASP patched TSLPR-/- mice compared to wild type and ST2-/- mice. Accordingly, intestinal mast cell accumulation and degranulation were impaired in OVA + ASP patched TSLPR-/- mice compared to wild type and ST2-/- mice, protecting TSLPR-/- mice from developing allergic diarrhea. CONCLUSION: Epicutaneous sensitization to food allergen and development of food allergy can occur without skin inflammation and is partly mediated by TSLP, suggesting that prophylactic targeting of TSLP may be useful in mitigating the development of AD and food allergy early in life in at-risk infants.

Fetal lung development via quantitative biomarkers from diffusion MRI and histological validation in rhesus macaques.

OBJECTIVE: To demonstrate sensitivity of diffusion-weighted MRI (DW-MRI) to pulmonary cellular-space changes during normal in utero development using fetal rhesus macaques, compared to histological biomarkers. STUDY DESIGN: In vivo/ex vivo DW-MRI was acquired in 26 fetal rhesus lungs (early-canalicular through saccular stages). Apparent diffusion coefficients (ADC) from MRI and tissue area density (H&E), alveolar type-II cells (ABCA3), and epithelial cells (TTF1) from histology were compared between gestational stages. RESULTS: In vivo/ex vivo ADC correlated with each other (Spearman ρ = 0.47, P = 0.038; Bland-Altman bias = 0.0835) and with area-density (in vivo ρ = -0.56, P = 0.011; ex vivo ρ = -0.83, P < 0.0001). In vivo/ex vivo ADC increased exponentially toward saturation with gestational stage (R2 = 0.49/0.49), while area-density decreased exponentially (R2 = 0.53). ABCA3 and TTF1 stains demonstrated expected fetal cellular development. CONCLUSIONS: Fetal DW-MRI provides a non-invasive biomarker for pulmonary structural maturation, with a strong correlation to histological markers during tissue development in rhesus macaques. This method has strong potential for assessing human fetal development, particularly in patients with pulmonary hypoplasia.

Alveolar injury and regeneration following deletion of ABCA3.

Adaptation to air breathing after birth is dependent upon the synthesis and secretion of pulmonary surfactant by alveolar type 2 (AT2) cells. Surfactant, a complex mixture of phospholipids and proteins, is secreted into the alveolus, where it reduces collapsing forces at the air-liquid interface to maintain lung volumes during the ventilatory cycle. ABCA3, an ATP-dependent Walker domain containing transport protein, is required for surfactant synthesis and lung function at birth. Mutations in ABCA3 cause severe surfactant deficiency and respiratory failure in newborn infants. We conditionally deleted the Abca3 gene in AT2 cells in the mature mouse lung. Loss of ABCA3 caused alveolar cell injury and respiratory failure. ABCA3-related lung dysfunction was associated with surfactant deficiency, inflammation, and alveolar-capillary leak. Extensive but incomplete deletion of ABCA3 caused alveolar injury and inflammation, and it initiated proliferation of progenitor cells, restoring ABCA3 expression, lung structure, and function. M2-like macrophages were recruited to sites of AT2 cell proliferation during the regenerative process and were present in lung tissue from patients with severe lung disease caused by mutations in ABCA3. The remarkable and selective regeneration of ABCA3-sufficient AT2 progenitor cells provides plausible approaches for future correction of ABCA3 and other genetic disorders associated with surfactant deficiency and acute interstitial lung disease.