Abstract
Food allergy is a growing public health problem with ~15 million people affected in the United States. In allergic food disease, IgE on mast cells bind to ingested antigens leading to the activation and degranulation of mast cells. Stem cell factor (SCF) is mast cell growth and activation factor that is required for peripheral tissue mast cells. We targeted a specific isoform of SCF, the larger 248 amino acid form, that drives peripheral tissue mast cell differentiation using a specific monoclonal antibody in a model of food allergy. Ovalbumin sensitized and intragastrically challenged mice were monitored for symptoms of anaphylaxis including respiratory distress, diarrhea, and a reduction in body temperature. During the second week of challenges, allergic mice were injected with an antibody to block SCF248 or given IgG control. Mice treated with α-SCF248 had a decreased incidence of diarrhea and no reduction in body temperature suggesting a reduction in anaphylaxis compared to IgG control treated animals. Re-stimulated mesenteric lymph nodes indicated that α-SCF248 treated mice had decreased OVA-specific Th2 cytokine production compared to IgG control treated allergic animals. The reduction of food induced anaphylaxis was accompanied by a significant reduction in gut leak. The mesenteric lymph node cells were analyzed by flow cytometry and showed a decrease in the number of type 2 innate lymphoid cells in mice injected with α-SCF248. Morphometric enumeration of esterase+ mast cells demonstrated a significant reduction throughout the small intestine. Using a more chronic model of persistent food-induced anaphylaxis, short term therapeutic treatment with α-SCF248 during established disease effectively blocked food induced anaphylaxis. Together, these data suggest that therapeutically blocking SCF248 in food allergic animals can reduce the severity of food allergy by reducing mast cell mediated disease activation.
Highlights
The incidence and severity of food allergy early in life has been growing considerably over the past two decades
After the 7th challenge mice were assessed by temperature and anaphylactic scores for the severity of their responses. Those mice treated with α-SCF248 displayed a minimal loss of temperature and a minimal anaphylactic score overall, while those treated with control IgG showed a significant decrease in body temperature and a substantial anaphylactic response (Figure 1C)
We found that mice treated with OVA had increased FITC-Dextran in the plasma, but this was inhibited in mice treated with αSCF248 (Figure 4B), indicating that the decreased number and activation of mast cells protects barrier function
Summary
The incidence and severity of food allergy early in life has been growing considerably over the past two decades. Diagnostic assessment of children with potential food anaphylaxis include elevated food specific serum IgE and severe skin challenge reactivity [3] These latter parameters are not predictive of whether a child will fail a food challenge in the clinic [4]. A key molecule that has a central role in mast cell development, survival and activation is stem cell factor (SCF knowns as kit ligand) [15, 16] In both humans and mice, endogenous SCF occurs in two isoforms, “membrane” (220 amino acids) and “soluble” (248 amino acids) forms [17, 18]. Our studies highlight that blocking a specific isoform of SCF (SCF248) associated with development and activation of mast cells diminished the anaphylactic phenotype in food allergic mice that may be developed for future therapeutic application in food-induced anaphylaxis
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