Mechanistic correlates of clinical responses to omalizumab in the setting of oral immunotherapy for milk allergy

JOURNAL OF ALLERGY AND CLINICAL IMMUNOLOGY

卷:140

Article

Frischmeyer-Guerrerio, Pamela A.¹  Masilamani, Madhan²  Gu, Wenjuan³  Brittain, Erica⁴  Wood, Robert⁵  Kim, Jennifer²  Nadeau, Kari^6,7  Jarvinen, Kirsi M.⁸  Grishin, Alexander²  Lindblad, Robert⁹  Sampson, Hugh A.² 

[1] NIAID, Lab Allerg Dis, Food Allergy Res Unit, NIH, 9000 Rockville Pike, Bethesda, MD 20892 USA

[2] Icahn Sch Med Mt Sinai, Dept Pediat, Div Allergy & Immunol, New York, NY 10029 USA

[3] Leidos Biomed Res, Clin Res Directorate, Clin Monitoring Res Program, NCI Campus, Frederick, MD USA

[4] NIH, Biostat Res Branch, Div Clin Res, Bldg 10, Bethesda, MD 20892 USA

[5] Johns Hopkins Univ, Sch Med, Dept Pediat, Div Allergy & Immunol, Baltimore, MD 21205 USA

[6] Stanford Sch Med, Sean N Parker Ctr Allergy & Asthma Res, Dept Med, Stanford, CA USA

[7] Stanford Sch Med, Sean N Parker Ctr Allergy & Asthma Res, Dept Pediat, Stanford, CA USA

[8] Univ Rochester, Med Ctr, Sch Med & Dent, Dept Pediat,Div Allergy & Immunol, Rochester, NY USA

[9] EMMES Corp, Rockville, MD USA

关键词: Oral immunotherapy;    food allergy;    milk allergy;    omalizumab;    desensitization;    sustained unresponsiveness;    basophil activation;    biomarker;    regulatory T cells;   

DOI  :  10.1016/j.jaci.2017.03.028

来源: Elsevier

【 摘 要 】

Background: In our recent clinical trial, the addition of omalizumab to oral immunotherapy (OIT) for milk allergy improved safety, but no significant clinical benefit was detected. Objective: We sought to investigate mechanisms by which omalizumab modulates immunity in the context of OIT and to identify baseline biomarkers that predict subgroups of patients most likely to benefit from omalizumab. Methods: Blood was obtained at baseline and multiple time points during a placebo-controlled trial of OIT for milk allergy in which subjects were randomized to receive omalizumab or placebo. Immunologic outcomes included measurement of basophil CD63 expression and histamine release and casein-specific CD4(+) regulatory T-cell proliferation. Biomarkers were analyzed in relationship to measurements of safety and efficacy. Results: Milk-induced basophil CD63 expression was transiently reduced in whole blood samples from both omalizumab- and placebo-treated subjects. However, IgE-dependent histamine release increased in washed cell preparations from omalizumab-but not placebo-treated subjects. No increase in regulatory T-cell frequency was evident in either group. Subjects with lower rates of adverse reactions, regardless of arm, experienced better clinical outcomes. Pre-OIT basophil reactivity positively associated with occurrence of symptoms during OIT, whereas the baseline milk IgE/total IgE ratio correlated with the likelihood of achieving sustained unresponsiveness. A combination of baseline basophil and serologic biomarkers defined a subset of patients in which adjunctive therapy with omalizumab was associated with attainment of sustained unresponsiveness and a reduction in adverse reactions. Conclusions: Combining omalizumab therapy with milk OIT led to distinct alterations in basophil reactivity but not T-cell responses. Baseline biomarkers can identify subjects most likely to benefit from adjunctive therapy with omalizumab.

【 授权许可】

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