Suppression of IgE-Mediated Disease by Polyclonal Rapid Desensitization

描述(由申请人提供)：这项翻译建议使用快速脱敏方法来开发一种安全、有效和快速的方法来抑制人类IgE介导的疾病。我们已经可以安全、快速地使小鼠对所有抗原(Ag)脱敏，方法是每小时给它们注射双倍剂量的抗FcϵRIα单抗(MAb)，从太小的剂量开始，不能引起临床反应。使用该方案治疗仅与FcϵRI不被α占据的FcϵRI结合的小鼠：(1)快速诱导对Ig E/FϵRI信号的短暂抑制；(2)缓慢地去除所有肥大细胞膜FcϵRI和Ig E，即使在具有高血清Ig E水平的小鼠中也是如此。在小鼠中，我们的方法比用Ag快速脱敏更安全，并且可以通过反复注射抗FcϵRIα单抗来安全地无限期维持。我们现在将使这种方法适用于人类，使其更快，并使其更安全。目的1使用一种具有与我们的抗鼠FcϵRIα单抗相似特性的抗人(Hu)FcϵRIα单抗来脱敏：(1)经回热处理的表达HuFcϵRIα的转基因小鼠，而不是小鼠FcϵRIα；(2)缺乏细胞因子受体的免疫缺陷NOD/SCID小鼠 普通吗？链，表达转基因huSCF、huIL-3和huGM-CSF，并与 人脐血细胞(这些小鼠分泌人IgE并产生人肥大细胞和嗜碱性粒细胞)。我们还修改了我们的脱敏方案，通过皮下注射抗huFcϵRIα单抗而不是腹膜内注射使其更适合潜在的人类使用。目的2通过使用一种可去除所有肥大细胞的单抗来加速抗huFcϵRIα单抗的脱敏，而不考虑其ϵ的占有率。我们还制备了自己的具有这一特性的单抗，以便在Aim 3中对其结构进行修饰。Aim 3增加了抗huFcϵRIα单抗快速脱敏的安全性。我们通过以下方法进一步抑制快速脱敏过程中可能发生的任何临床反应：(1)抑制H1和H2受体；(2)抑制酪氨酸激酶；(3)设计抗FcϵRIα单抗，使其更能与抑制性受体FcγRIIb结合。成功完成这些目标可以提供一种安全和快速地预防所有FcϵRI介导的疾病的方法。

DESCRIPTION (provided by applicant): This translational proposal uses a rapid desensitization approach to develop a safe, effective and rapid way to suppress human IgE-mediated disease. We can already safely, rapidly desensitize mice to all antigens (Ags) by injecting them hourly with doubling doses of an anti-FcϵRIα monoclonal antibody (mAb), starting with a dose too small to elicit a clinical reaction. Using this protocol to treat mice with an anti-FcϵRIα mAb that only binds FcϵRI that is not occupied by IgE: (1) rapidly induces short-lived suppression of IgE/FϵRI signaling; and (2) slowly removes all mast cell membrane FcϵRI and IgE, even in mice that have high serum IgE levels. In mice, our approach is safer than rapid desensitization with Ag and can safely be maintained indefinitely by repeated injection of anti-FcϵRIα mAb. We will now adapt this approach to humans, make it more rapid, and make it even safer. Aim 1 uses an anti-human (hu) FcϵRIα mAb that has characteristics similar to our anti-mouse FcϵRIα mAb to desensitize: (1) huIgE-treated transgenic mice that express huFcϵRIα instead of mouse FcϵRIα; and (2) immunodeficient NOD/SCID mice that lack the cytokine receptor common ? chain, express transgenic huSCF, huIL-3, and huGM-CSF and have been reconstituted with human cord blood cells (these mice secrete human IgE and generate human mast cells and basophils). We also modify our desensitization protocol to make it more compatible with potential human use by injecting anti-huFcϵRIα mAb subcutaneously instead of intraperitoneally. Aim 2 accelerates desensitization with antihuFcϵRIα mAb by using a commercially available mAb that removes all mast cell huFcϵRI, regardless of its IgE occupancy. We also generate our own mAb that has this property so that we can modify its structure in Aim 3. Aim 3 increases the safety of rapid desensitization with anti-huFcϵRIα mAb. We further suppress any clinical reactions that might occur during rapid desensitization by: (1) inhibiting H1 and H2 receptors; (2) inhibiting the tyrosine kinase syk; and (3) engineering anti-FcϵRIα mAb to bind more avidly to the inhibitory receptor, FcγRIIb. Successful completion of these aims could provide a way to safely and rapidly protect against all FcϵRI-mediated disease.