Rapid IgE desensitization provides temporary tolerization for patients who have presented severe hypersensitivity reactions to food and drugs, protecting them from anaphylaxis, but the underlying mechanisms are still incompletely understood. Thus, here we develop an effective and reproducible in vitro model of rapid IgE desensitization for mouse BM-derived mast cells (BMMCs) under physiologic calcium conditions, and we characterize its antigen specificity and primary events. BMMCs were challenged with DNP-human serum albumin conjugated (DNP-HSA) and/or OVA antigens, delivered either as a single dose (activation) or as increasing sequential doses (desensitization). Compared to activated cells, desensitized BMMCs had impaired degranulation, calcium flux, secretion of arachidonic acid products, early and late TNF-a production, IL-6 production, and phosphorylation of STAT6 and p38 mitogen-activated protein kinase (p38 MAPK). OVA-desensitized cells responded to DNP and DNPdesensitized cells responded to OVA, proving specificity. Internalization of specific antigen, IgE and high-affinity receptor for IgE (FceRI) were impaired in desensitized BMMCs. Our results demonstrate that rapid IgE desensitization is antigen specific and inhibits early and late mast cell activation responses and internalization of the antigen/IgE/FceRI complexes.

Adverse reactions to drugs are increasingly being recognized as important contributions to disease in their own right as well as impediments to the best treatment of various conditions, including infectious, autoimmune, and neoplastic maladies. Rapid drug desensitization (RDD) is an effective mechanism for safely administering important medications while minimizing or entirely circumventing such adverse reactions in sensitized patients. We reviewed the literature on RDD in the last 10 years, including our experience from the Brigham and Women's Hospital Desensitization Program with hundreds of patients desensitized to a broad variety of drugs. RDD in our programme has been uniformly successful in patients with hypersensitivity reactions to antibiotics, chemotherapeutics, and monoclonal antibodies. Any reactions that occur during desensitization are generally much less severe than the initial hypersensitivity reaction to the drug, and patients have received the full dose of the desired medication 99.9% of the time out of (796) desensitizations. To date, there have been no fatalities. RDD is a safe and highly effective method for treating sensitized patients with the optimal pharmacologic agents. Its use should be expanded, but because patient safety is paramount, protocols must be created, reviewed, and overseen by allergist-immunologists with special training and experience in modern techniques of desensitization.

Surveillance of Barrett's oesophagus allows us to study the evolutionary dynamics of a human neoplasm over time. Here we use multicolour fluorescence in situ hybridization on brush cytology specimens, from two time points with a median interval of 37 months in 195 non-dysplastic Barrett's patients, and a third time point in a subset of 90 patients at a median interval of 36 months, to study clonal evolution at single-cell resolution. Baseline genetic diversity predicts progression and remains in a stable dynamic equilibrium over time. Clonal expansions are rare, being detected once every 36.8 patient years, and growing at an average rate of 1.58 cm2 (95% CI: 0.09–4.06) per year, often involving the p16 locus. This suggests a lack of strong clonal selection in Barrett's and that the malignant potential of ‘benign' Barrett's lesions is predetermined, with important implications for surveillance programs.