BACKGROUND In previous clinical trials involving children with X-linked severe combined immunodeficiency (SCID-X1), a Moloney murine leukemia virus–based γ-retrovirus vector expressing interleukin-2 receptor γ-chain (γc) complementary DNA successfully restored immunity in most patients but resulted in vector-induced leukemia through enhancer-mediated mutagenesis in 25% of patients. We assessed the efficacy and safety of a self-inactivating retrovirus for the treatment of SCID-X1. METHODS We enrolled nine boys with SCID-X1 in parallel trials in Europe and the United States to evaluate treatment with a self-inactivating (SIN) γ-retrovirus vector containing deletions in viral enhancer sequences expressing γc (SIN-γc). RESULTS All patients received bone marrow–derived CD34+ cells transduced with the SIN-γc vector, without preparative conditioning. After 12.1 to 38.7 months of follow-up, eight of the nine children were still alive. One patient died from an overwhelming adenoviral infection before reconstitution with genetically modified T cells. Of the remaining eight patients, seven had recovery of peripheral-blood T cells that were functional and led to resolution of infections. The patients remained healthy thereafter. The kinetics of CD3+ T-cell recovery was not significantly different from that observed in previous trials. Assessment of insertion sites in peripheral blood from patients in the current trial as compared with those in previous trials revealed significantly less clustering of insertion sites within LMO2 , MECOM, and other lymphoid proto-oncogenes in our patients. CONCLUSIONS This modified γ-retrovirus vector was found to retain efficacy in the treatment of SCID-X1. The long-term effect of this therapy on leukemogenesis remains unknown. (Funded by the National Institutes of Health and others; ClinicalTrials.gov numbers, NCT01410019, NCT01175239, and NCT01129544.)

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Histamine (0.004–2 μM) induced a concentration‐dependent shape change of human eosinophils, but not of neutrophils or basophils, detected as an increase in forward scatter (FSC) in the gated autofluorescence/forward scatter (GAFS) assay. The histamine‐induced eosinophil shape change was completely abolished by thioperamide (10 μM), an H3/H4 receptor antagonist, but was not inhibited by pyrilamine or cimetidine (10 μM), H1 and H2 receptor antagonists, respectively. The H4 receptor agonists, clobenpropit and clozapine (0.004–2 μM), which are also H3 receptor antagonists, both induced eosinophil shape change, which was inhibited by thioperamide (10 μM). The H3/H4 receptor agonists, imetit, R‐α‐methyl histamine and N‐α‐methyl histamine (0.004–2 μM) also induced eosinophil shape change. Histamine induced actin polymerisation (0.015–10 μM), intracellular calcium mobilisation (10–100 μM) and a significant upregulation of expression of the cell adhesion molecule CD11b (0.004–10 μM) in eosinophils, all of which were inhibited by thioperamide (10–100 μM). In addition, the H4 receptor agonist/H3 receptor antagonist clozapine (20 μM) stimulated a rise in intracellular calcium in eosinophils. Activation of H4 receptors by histamine (1 μM) primed eosinophils for increased chemotactic responses to eotaxin, but histamine (0.1–10 μM) did not directly induce chemotaxis of eosinophils. Pertussis toxin (1 μg ml−1) inhibited shape change and actin polymerisation responses induced by histamine showing that these effects are mediated by coupling to a Gαi/o G‐protein. This study demonstrates that human eosinophils express functional H4 receptors and may provide a novel target for allergic disease therapy. British Journal of Pharmacology (2003) 140, 1117–1127. doi:

We have used blockade of Th2 function and strain differences to show for the first time that resolution of allergic inflammation and AHR may be dependent on the T1/ST2-IL-33 pathway and the presence of Th2 cells, suggesting they are necessary not only for the development of an allergic response but also for its maintenance.