Laser-facilitated powder-allergen delivery for epicutaneous immunotherapy

用于表皮免疫治疗的激光促进粉末过敏原递送

• 批准号: 8892996
• 负责人: Mei X Wu
• 金额: $ 21.27万
• 依托单位: MASSACHUSETTS GENERAL HOSPITAL
• 依托单位国家: 美国
• 财政年份: 2014
• 资助国家: 美国
• 起止时间: 2014-08-01 至 2017-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8892996
• 关键词: Accounting; Adjuvant; Allergens; Allergic Disease; Allergy to peanuts; Anaphylaxis; Antigen-Presenting Cells; Antigens; Area; Biological Assay; Blood; Blood Circulation; Blood specimen; C3H/HeJ Mouse; Caliber; Clinical; Cone; Confocal Microscopy; Cosmetics; Dermis; Developed Countries; Development; Dose; Ensure; Epidermis; Epithelial Cells; Family suidae; Figs - dietary; Food Hypersensitivity; Health; Health system; Hypersensitivity; IgE; Immune; Immune Tolerance; Immune response; Immune system; Immunity; Immunologist; Immunosuppressive Agents; Immunotherapeutic agent; Immunotherapy; Industry; Intestines; Investigation; Lasers; Lighting; Lymph; Lymphatic; Measures; Mediating; Medicine; Modeling; Morbidity - disease rate; Mus; Names; Natural Immunity; Nerve; Newborn Infant; Patients; Pattern; Penetration; Powder dose form; Proteins; Public Health; Qualifying; Regulatory T-Lymphocyte; Resources; Risk; Safety; Shapes; Site; Skin; Structure of parenchyma of lung; Technology; Time; Tissues; Treatment Efficacy; base; compliance behavior; face skin; improved; intradermal injection; macromolecule; new technology; novel strategies; pre-clinical; prevent; seal; subcutaneous; treatment duration; vaccine delivery

DESCRIPTION (provided by applicant): The overall objective of this proposal is to develop a laser-based technology for micro-delivering powdered allergens for safer and faster epicutaneous immunotherapy, named �EPIT. To date, allergen specific immunotherapy remains the only treatment for long-lasting clinical benefit to IgE-mediated allergies, but fewer than 5% o patients choose the treatment because of a risk of anaphylaxis and inconvenience. EPIT can potentially shorten the duration of the treatment and reduce anaphylactic risk because the epidermis is not only rich in antigen-presenting cells (APCs), but also a non-vascularized tissue. Unfortunately, epidermic delivery of allergen via intact skin faces numerous challenges as the skin is impermeable for macromolecules, whereas breaking skin barrier often triggers unwanted Th2 immune responses. We, along with others, have used ablative micro-fractional laser (A�FL) to generate an array of self-renewable microchannels (MCs) in the skin for vaccine delivery and to elicit strong Th1 immune responses. These MCs offer unique advantages for EPIT as they not only serve as "free" paths for powdered allergens to enter the epidermis but also sustain the allergen in the epidermis constantly stimulating immune system that favors immune tolerance. Moreover, because the allergen is largely restricted inside the MCs anaphylaxis can be well prevented. We have created a simple way to fabricate a powder-based microarray patch (PMP), which gave rise to efficient epidermic delivery when applied onto laser-treated skin. We hypothesize that the laser-facilitated epidermic �-delivery of powdered allergens/adjuvants can greatly augment efficacy of EPIT without incurring a risk of anaphylaxis. We will fabricate PMP with peanut protein extract (PPE), along with Th1 or immunosuppressant adjuvants. Epidermic delivery of PPE/adjuvants via laser-perforated skin will be optimized in naive and sensitized C3H/HeJ mice as well as in sensitized newborn pigs (Aim 1.1). Local innate immunity will be measured at the inoculation site and humoral immune responses against peanut allergens will be assayed in blood samples. We will also investigate Th1, Th2 and T regulatory (Treg) cells to corroborate Th1/Treg-predominant immunity against the allergen (Aim 1.2). Finally, we will seek in a murine peanut allergy model whether three doses of �EPIT are superior to conventional 18 doses of subcutaneous immunotherapy in treatment of peanut allergy (Aim 2). IgE-mediated allergy occurs at an increasing rate in industrialized countries. This �EPIT, if successful, would result in safer and faster treatments of peanut allergy and can be readily extended to other IgE-mediated allergies, which will have profound impact on public health systems.

描述（由申请人提供）：该提案的总体目标是开发一种基于激光的微量粉末状过敏原技术，以实现更安全、更快速的表皮免疫治疗，称为“EPIT”。迄今为止，过敏原特异性免疫疗法仍然是长期的唯一治疗方法。 - IgE 介导的过敏具有持久的临床益处，但只有不到 5% 的患者选择这种治疗，因为存在过敏反应的风险，并且 EPIT 可能会缩短治疗的持续时间。治疗并降低过敏风险，因为表皮不仅富含抗原呈递细胞（APC），而且还是非血管化组织，不幸的是，由于皮肤对大分子是不可渗透的，通过完整皮肤的表皮递送过敏原面临着许多挑战。破坏皮肤屏障通常会引发不必要的 Th2 免疫反应 我们和其他人一起使用烧蚀微点阵激光 (A�FL) 来产生一系列自我更新的微通道。这些 MC 为 EPIT 提供了独特的优势，因为它们不仅可以作为粉状过敏原进入表皮的“自由”路径，而且可以持续维持表皮中的过敏原。刺激免疫系统，有利于免疫耐受。此外，由于过敏原主要限制在 MC 内，因此可以很好地预防过敏反应。 (PMP)，当应用于激光治疗的皮肤时，会产生表皮递送，我们追求的是，​​激光促进粉末状过敏原/佐剂的表皮递送可以大大提高 EPIT 的功效，而不会产生过敏反应的风险。使用花生蛋白提取物 (PPE) 以及 Th1 或免疫抑制剂佐剂通过 PPE/佐剂的表皮递送来制备 PMP。将在幼稚和致敏的 C3H/HeJ 小鼠以及致敏的新生猪中优化激光穿孔皮肤（目标 1.1），将在接种部位测量局部先天免疫，并在血液样本中测定针对花生过敏原的体液免疫反应。我们还将研究 Th1、Th2 和 T 调节 (Treg) 细胞，以证实 Th1/Treg 对过敏原的免疫作用（Aim）。 1.2). 最后，我们将在小鼠花生过敏模型中探讨 3 剂 EPIT 是否优于 18 剂传统皮下免疫疗法治疗花生过敏（目标 2），工业化中 IgE 介导的过敏发生率不断增加。该“EPIT”如果成功，将带来更安全、更快速的花生过敏治疗方法，并可轻松推广到其他 IgE 介导的过敏症，这将对公共卫生系统产生深远影响。

项目成果

Physical activation of innate immunity by spiky particles.

尖刺粒子物理激活先天免疫

• DOI: 10.1038/s41565-018-0274-0
• 发表时间: 2018-11
• 期刊: Nature nanotechnology
• 影响因子: 38.3
• 作者: Wang J;Chen HJ;Hang T;Yu Y;Liu G;He G;Xiao S;Yang BR;Yang C;Liu F;Tao J;Wu MX;Xie X
• 通讯作者: Xie X

Delivery of Allergen Powder for Safe and Effective Epicutaneous Immunotherapy.

• DOI: 10.1016/j.jaci.2019.11.022
• 发表时间: 2019-11
• 期刊: The Journal of allergy and clinical immunology
• 作者: Yang Yu;Mudnakudu Nagaraju Kiran Kumar;Mei X. Wu

BCG vaccine powder-laden and dissolvable microneedle arrays for lesion-free vaccination.

• DOI: 10.1016/j.jconrel.2017.03.397
• 发表时间: 2017-06-10
• 期刊: Journal of controlled release : official journal of the Controlled Release Society
• 作者: Chen F;Yan Q;Yu Y;Wu MX
• 通讯作者: Wu MX

Laser-facilitated epicutaneous immunotherapy to IgE-mediated allergy.

• DOI: 10.1016/j.jconrel.2016.05.057
• 发表时间: 2016-08-10
• 期刊: Journal of controlled release : official journal of the Controlled Release Society
• 作者: Kumar MNK;Zhou C;Wu MX
• 通讯作者: Wu MX