RESUMO
Mechanisms driving acute food allergic reactions have not been fully characterized. We profile the dynamic transcriptome of acute peanut allergic reactions using serial peripheral blood samples obtained from 19 children before, during, and after randomized, double-blind, placebo-controlled oral challenges to peanut. We identify genes with changes in expression triggered by peanut, but not placebo, during acute peanut allergic reactions. Network analysis reveals that these genes comprise coexpression networks for acute-phase response and pro-inflammatory processes. Key driver analysis identifies six genes (LTB4R, PADI4, IL1R2, PPP1R3D, KLHL2, and ECHDC3) predicted to causally modulate the state of coregulated networks in response to peanut. Leukocyte deconvolution analysis identifies changes in neutrophil, naive CD4+ T cell, and macrophage populations during peanut challenge. Analyses in 21 additional peanut allergic subjects replicate major findings. These results highlight key genes, biological processes, and cell types that can be targeted for mechanistic study and therapeutic targeting of peanut allergy.
Assuntos
Reação de Fase Aguda/genética , Hipersensibilidade a Amendoim/genética , RNA Mensageiro/metabolismo , Reação de Fase Aguda/imunologia , Adolescente , Linfócitos T CD4-Positivos/imunologia , Criança , Método Duplo-Cego , Enoil-CoA Hidratase/genética , Feminino , Perfilação da Expressão Gênica , Redes Reguladoras de Genes , Humanos , Inflamação/genética , Inflamação/imunologia , Macrófagos/imunologia , Masculino , Proteínas dos Microfilamentos/genética , Proteínas do Tecido Nervoso/genética , Neutrófilos/imunologia , Hipersensibilidade a Amendoim/imunologia , Proteína Fosfatase 1/genética , Proteína-Arginina Desiminase do Tipo 4 , Desiminases de Arginina em Proteínas/genética , Distribuição Aleatória , Receptores Tipo II de Interleucina-1/genética , Receptores do Leucotrieno B4/genética , Reprodutibilidade dos TestesRESUMO
BACKGROUND: Initial doses of OKT3 are associated with a cytokine-induced acute clinical syndrome (ACS). This study assessed the safety of a recombinant human tumor necrosis factor receptor fusion protein (TNFR:Fc) given to minimize OKT3-ACS symptoms in renal allograft recipients undergoing induction therapy. METHODS: Sixteen patients were randomized into treatment or control groups. Treated patients received TNFR:Fc 1 hr before OKT3 on days 0 and 3. Patients were monitored after transplant for OKT3-ACS symptoms. Levels of cytokines, serum creatinine, and C-reactive protein were followed. RESULTS: Patients receiving TNFR:Fc had lower OKT3-ACS symptoms as measured by a scoring system. There was a higher incidence of infection in treated patients (10/12) compared to controls (1/4) in the 3 months after transplant, but the etiology of this difference was unclear. There were no significant differences in cytokine profiles. CONCLUSIONS: TNFR:Fc is well tolerated by renal transplant patients receiving OKT3 induction therapy and modestly decreases the symptoms associated with OKT3-ACS.