The Impact of Donor Diabetes on Corneal Immune Cells and Graft Survival

供体糖尿病对角膜免疫细胞和移植物存活的影响

• 批准号: 10707166
• 负责人: Reza Dana
• 金额: $ 49.25万
• 依托单位: SCHEPENS EYE RESEARCH INSTITUTE
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-09-30 至 2027-08-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10707166
• 关键词: Accounting; Adult; Affect; Algorithms; Allografting; American; Antigen-Presenting Cells; Antigens; Area; Cell Maturation; Cell Survival; Cells; Coculture Techniques; Cohort Studies; Cornea; Data; Diabetes Mellitus; Diabetic mouse; Endothelium; Epidemic; Exclusion; Exhibits; Eye Banks; Eye Surgeon; Failure; Functional disorder; Graft Rejection; Graft Survival; Grant; Homeostasis; Immune; Immunity; Impaired healing; Impairment; Inflammation; Inflammatory; Insulin; Investigation; Keratoplasty; Kinetics; Knowledge; Letters; Link; Longevity; Lymphoid Tissue; Measures; Mediating; Mus; Operative Surgical Procedures; Organ Transplantation; Outcome; Panthera leo; Penetrating Keratoplasty; Penetration; Persons; Phenotype; Population; Prevalence; Procedures; Recording of previous events; Registries; Regulatory T-Lymphocyte; Reporting; Risk; Risk Factors; Risk Reduction; Role; Survival Rate; Techniques; Testing; Tissue Donors; Tissue Grafts; Tissues; Transplantation; United States; cell motility; corneal allograft; cytokine; diabetic; experience; glycemic control; improved; insight; isoimmunity; non-diabetic; novel; prophylactic; response; risk stratification; success

Corneal transplantation is the most commonly performed allografting procedure in the world—nearly 40,000 cases in the United States and over 200,000 globally are performed each year. As surgical techniques, eye banking procedures and prophylactic measures against graft rejection have improved, the field has also become more sensitized to the quality of the donor tissue, including donor factors that can impact long-term graft survival. In this regard, and in the context of the global `epidemic' of diabetes which affects over 10% of the American population (over 30 million people), there are increasing reports that the diabetic status of donors can adversely impact corneal graft survival. While the diabetic state in graft recipients, which is associated with delayed healing and prolonged inflammation, has long been identified as a risk factor for transplant longevity, the concept that a history of diabetes in the tissue donor can also impact graft survival is both novel and potentially highly impactful from an eye banking and tissue selection standpoint. This would mean that corneal transplant risk stratification would include the donor diabetic state in the decision algorithm for tissue allocation. To investigate the potential role of the donor diabetic state on graft immunity, we began preliminary studies in a mouse model of diabetes to assess how it would affect the resident immune cells of the cornea, which could impact host sensitization and alloimmunity. Our preliminary data show that (1) there are more matured corneal resident antigen-presenting cells (APC) in diabetic mice, (2) both penetrating and lamellar (DSEK) allografts procured from diabetic donor mice have significantly worse survival than those procured from non-diabetic donors, (3) hosts receiving diabetic tissue show heightened T helper-1 (Th1) immunity to donor-derived antigens. Moreover, our preliminary data suggest that (4) glycemic control in diabetics decreases MHC-II expression by corneal APC. Accordingly, we hypothesize that the diabetic state induces an altered corneal microenvironment that alters the immune homeostasis of the cornea, inducing APC maturation and regulatory T cell dysfyunction, that lead to heightened host sensitization and graft rejection. To test this hypothesis, we will pursue three specific aims. In Aim 1, we will define the degree of change in corneal APC functional phenotype in diabetic mice and assess the alloimmune response in hosts receiving diabetic donor tissue (PK and DSEK). We will then investigate the mechanisms by which graft- derived APC from diabetic donors impact host allosensitization (Aim 2) and regulatory T cell (Treg) dysfunction (Aim 3). This grant, which represents a new area of investigation, is anchored in the core expertise of our lab, which has studied corneal transplant immunity for more than 25 years. Knowledge gained from this grant holds the potential to impact eye banking and tissue allocation as well as open new translational venues such as manipulating donor tissue APC maturation/activation ex vivo, improving transplant outcomes and reducing the risk of donor tissue shortages as a result of excluding all diabetic tissues.

角膜移植是世界上最常见的同种异体移植手术--近4万例 美国和全球每年处理的案件超过20万起。作为外科技术，眼睛 银行程序和预防移植物排斥的措施得到了改善，该领域也 对供体组织的质量更加敏感，包括可能影响长期的供体因素 移植物存活率。在这方面，并在全球糖尿病“流行”的背景下，影响10%以上的人 在美国人口(超过3000万人)中，有越来越多的报道称献血者的糖尿病状况 会对角膜移植物的存活率产生不利影响。而移植受者的糖尿病状态与 长期以来，愈合延迟和长期炎症一直被认为是移植手术寿命的风险因素。 组织捐赠者的糖尿病病史也会影响移植物存活这一概念是新颖的，也是 从眼库和组织选择的角度来看，这可能是非常有影响力的。这将意味着 角膜移植风险分层将在组织决策算法中包括供者糖尿病状态。 分配。为了研究供者糖尿病状态对移植物免疫的潜在作用，我们开始了初步的研究。 在糖尿病小鼠模型上进行的研究，以评估它将如何影响角膜的常驻免疫细胞， 这可能会影响宿主的致敏性和同种免疫。我们的初步数据显示：(1)有更多 糖尿病小鼠成熟的角膜常驻抗原提呈细胞(APC)，(2)穿透性和板层性 从糖尿病供体小鼠获取的(DSEK)同种异体移植物的存活率明显低于获得的移植物 来自非糖尿病捐献者，(3)接受糖尿病组织的宿主表现出对Th-1(Th1)免疫增强 供体来源的抗原。此外，我们的初步数据表明(4)糖尿病患者的血糖控制 通过角膜APC减少MHC-II的表达。因此，我们假设糖尿病状态导致 一种改变的角膜微环境，改变了角膜的免疫动态平衡，引发了APC 成熟和调节性T细胞功能障碍，导致宿主高度敏感化和移植物 拒绝。为了验证这一假设，我们将追求三个具体目标。在目标1中，我们将定义 糖尿病小鼠角膜APC功能表型的变化及宿主同种免疫反应的评估 接受糖尿病供体组织(PK和DSEK)。然后我们将调查嫁接的机制- 糖尿病供者来源的APC影响宿主同种异体致敏(AIM 2)和调节性T细胞(Treg)功能障碍 (目标3)。这笔拨款代表了一个新的研究领域，以我们实验室的核心专业知识为基础， 它已经研究角膜移植免疫超过25年了。从这笔赠款中获得的知识 可能会影响眼库和组织分配，以及开设新的翻译场所，如 体外操纵供体组织APC成熟/激活，改善移植结果并减少 排除所有糖尿病组织导致供体组织短缺的风险。