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: 8770696
• 负责人: Mei X Wu
• 金额: $ 25.22万
• 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 2016-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8770696
• 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 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; Peanuts - dietary; 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; public health relevance; seal; subcutaneous; treatment duration; vaccine delivery; 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 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; Peanuts - dietary; 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; public health relevance; 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（由应用程序提供）：该提案的总体目标是开发一种基于激光的技术，用于微递送的粉末状过敏原，以使其更安全，更快的表皮免疫疗法，名为«epit。迄今为止，过敏原特异性免疫疗法仍然是对IgE介导的过敏的持久临床益处的唯一治疗方法，但由于过敏反应和不便，患者选择治疗量不到5％。 epit可能会缩短治疗的持续时间并降低过敏性风险，因为表皮不仅富含抗原呈递细胞（APC），而且还富含非血管化组织。不幸的是，由于皮肤对大分子的不渗透是不渗透的，因此，过敏原的表皮递送面临许多挑战，而破裂的皮肤屏障通常会触发不需要的TH2免疫调查。我们与其他人一起使用了烧蚀的微分类激光器（A¿FL）来在皮肤中生成一系列可自我再生微通道（MC）进行疫苗输送，并引起强烈的TH1免疫呼吸。这些MC为Epit提供了独特的优势，因为它们不仅可以作为粉末状过敏原进入表皮的“免费”路径，而且还可以在表皮中维持过敏原，不断刺激有利于免疫耐受性的免疫系统。此外，由于过敏原在MCS过敏反应内受到很大的限制，因此可以很好地预防。我们创建了一种简单的方法来制造基于粉末的微阵列贴片（PMP），当将其应用于激光处理的皮肤上时，它会产生有效的表皮递送。我们假设激光辅助表皮»粉末性过敏原/辅助剂的递送可以极大地提高epit效率，而不会引起过敏反应的风险。我们将使用花生蛋白提取物（PPE）以及TH1或免疫抑制剂调节剂制造PMP。 PPE/佐剂通过激光服用皮肤的表皮递送将在幼稚和敏感的C3H/HEJ小鼠以及敏感的新生猪中进行优化（AIM 1.1）。局部先天免疫组织化学将在接种部位进行测量，并将针对花生过敏原的体液免疫调查员分配在血液样本中。我们还将研究Th1，Th2和T调节性（TREG）细胞，以证实针对过敏原的TH1/Treg-抗促主体免疫学（AIM 1.2）。最后，我们将在鼠生的花生过敏模型中寻求三剂epit是否优于常规18剂量的皮下免疫疗法来治疗花生过敏（AIM 2）。 IgE介导的过敏发生在工业化国家的速度越来越高。如果成功的话，这将导致对花生过敏的更安全和更快的治疗方法，并且很容易扩展到其他IgE介导的过敏，这将对公共卫生系统产生深远的影响。