Local immunomodulation using a microneedle patch for the management of skin transplant

使用微针贴片进行局部免疫调节来管理皮肤移植

• 批准号: 10743084
• 负责人: Natalie Artzi
• 金额: $ 38.76万
• 依托单位: BRIGHAM AND WOMEN'S HOSPITAL
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-12-19 至 2023-11-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10743084
• 关键词: Alloantigen; Allogenic; Allografting; Autologous Transplantation; Automobile Driving; Biocompatible Materials; Biological Markers; Biological Process; Biopsy; CCL22 gene; Cells; Chemicals; Clinical; Data; Diagnostic; Dose; Engineering; Enhancement Technology; FOXP3 gene; Family; Flow Cytometry; Formulation; Foundations; Future; Genetic; Homeostasis; Homing; Hyaluronic Acid; Hydrogels; IL2RA gene; IL7 gene; Immune; Immune Tolerance; Immune system; Immunocompetent; Immunologic Surveillance; Immunomodulators; Immunosuppression; Immunosuppressive Agents; In Situ; In Vitro; Infection; Infiltration; Inflammation; Intercellular Fluid; Interleukin 7 Receptor; Interleukin-2; Islets of Langerhans; Kinetics; Libraries; Life; Maintenance; Microscopy; Modeling; Monitor; Morbidity - disease rate; Mus; Needles; Organ Transplantation; Patients; Peripheral; Phenotype; Polymers; Process; Proliferating; Property; Regulatory T-Lymphocyte; Research; Retrieval; Role; Sampling; Severities; Site; Skin; Skin Transplantation; Specificity; T-Cell Proliferation; Therapeutic; Therapeutic Studies; Thick; Transgenic Mice; Translational Research; Transplantation; Treatment Efficacy; Vascularization; Vertebral column; Wild Type Mouse; allograft rejection; arm; chemokine; cohort; cytokine; design; diagnostic value; drug release kinetics; enzyme linked immunospot assay; high risk; humanized mouse; immune function; immunoregulation; infection risk; insight; islet allograft; isoimmunity; migration; minimally invasive; mortality; mouse model; novel; patient population; pre-clinical; preservation; recruit; severe burns; skin allograft; therapeutic evaluation; therapeutic patch; translational medicine; translational potential; transplant model; treatment response; wound

ABSTRACT Skin allograft transplantation is a lifesaving approach for the management of severe burn patients when skin autografts or artificial substitutes are not available due to the severity of the wound. However, their ultimate rejection increases patient morbidity and mortality and requires regrafting. Clinically-used systemic immunosuppression, while useful in other organ transplants, cannot be prescribed for this patient cohort as they present a high risk of life-threatening infections. Therefore, new strategies that can generate donor-specific tolerance, while preserving other protective immune functions through local immunoregulation, are needed. We recently demonstrated that hydrogel-based microneedle (MN) patches can be used to promote proliferation of regulatory T cells (Tregs) in skin allografts, by locally delivering immunomodulators (CCL22 and IL-2) at the transplant site. The MNs also facilitate the monitoring of the Treg homing process via skin interstitial fluid (ISF) sampling (Artzi, azzi, et al, Advanced Materials, 2021). Here, we will develop a novel family of hydrogel-based MNs that will be chemically functionalized to tailor the release kinetic profile of the immunomodulators to identify the optimal Treg recruitment to the allograft to sustain a local, immunosuppressive effect and to restore allo- tolerance. We will study the immunomodulatory role of the top CCL22/IL-2-doped MN platform in prolonging long-term skin allograft while providing mechanistic insight into the biological processes driving local immune regulation and Treg homeostasis in the allograft via ISF sampling in both an immunocompetent- and a humanized-skin transplant murine model. Specifically, we aim to define the optimal dose of CCL22 and IL-2 needed to maximize Treg recruitment and Treg proliferation respectively, and to assess the role of supplementary cytokines such as IL-7 in supporting Treg homeostasis (based on our previous data, Azzi et al, Science Translational Medicine, 2020) when co-delivered with our MN platform. Moreover, we will gain mechanistic insight into Treg stability, function and alloantigen specificity following MN-based therapy using a transgenic mouse model, which allows tracing the genetic lineage of Tregs. Also, we will validate the diagnostic ability of the MN-platform for in situ monitoring of the response to therapy. Finally, we will test the therapeutic and diagnostic merit of the MN platform in a humanized mouse model when delivering the optimal therapeutic combination of cytokines/chemokines and its capacity to induce long-term allograft survival. Our study will provide the foundation to develop safer technologies for enhancing skin transplant survival in a local, minimally-invasive way without compromising the regulatory arm of the immune system of burn patients while offering an opportunity to continuously monitor the response to the therapy.

抽象的 同种异体皮肤移植是治疗严重烧伤患者的一种救生方法 由于伤口严重，无法使用自体移植物或人工替代物。然而，他们的最终 排斥反应会增加患者的发病率和死亡率，并需要重新移植。临床上使用的全身 免疫抑制虽然可用于其他器官移植，但不能用于该患者群体，因为它们 存在危及生命的感染的高风险。因此，可以产生捐助者特定的新策略 需要耐受性，同时通过局部免疫调节保留其他保护性免疫功能。我们 最近证明，基于水凝胶的微针（MN）贴片可用于促进细胞增殖 通过在皮肤同种异体移植物中局部递送免疫调节剂（CCL22 和 IL-2），调节性 T 细胞 (Treg) 移植部位。 MN 还有助于通过皮肤间质液 (ISF) 监测 Treg 归巢过程 采样（Artzi、azzi 等人，Advanced Materials，2021）。在这里，我们将开发一个新型的基于水凝胶的家族 MN 将被化学功能化，以定制免疫调节剂的释放动力学曲线，以识别 最佳 Treg 募集到同种异体移植物以维持局部免疫抑制作用并恢复同种异体 宽容。我们将研究顶级 CCL22/IL-2 掺杂 MN 平台在 延长同种异体皮肤移植的长期时间，同时提供对生物过程的机制洞察 通过 ISF 采样驱动同种异体移植物中的局部免疫调节和 Treg 稳态 免疫活性和人源化皮肤移植小鼠模型。具体来说，我们的目标是定义 CCL22 和 IL-2 分别最大化 Treg 募集和 Treg 增殖所需的最佳剂量，并 评估补充细胞因子（例如 IL-7）在支持 Treg 稳态中的作用（基于我们之前的研究） 数据，Azzi 等人，科学转化医学，2020）与我们的 MN 平台共同交付。此外，我们 在基于 MN 的治疗后，将获得对 Treg 稳定性、功能和同种异体抗原特异性的机制洞察 使用转基因小鼠模型，可以追踪 Tregs 的遗传谱系。此外，我们将验证 MN 平台的诊断能力，用于原位监测治疗反应。最后，我们将测试 MN 平台在人源化小鼠模型中的治疗和诊断优点 细胞因子/趋化因子的治疗组合及其诱导长期同种异体移植物存活的能力。我们的 研究将为开发更安全的技术奠定基础，以提高当地皮肤移植的存活率， 微创方式，不损害烧伤患者免疫系统的调节臂，同时 提供持续监测治疗反应的机会。