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进行的同种异体移植手术——近 40,000 例 每年在美国和全球执行超过 200,000 例病例。作为手术技术，眼 银行程序和针对移植物排斥反应的预防措施有所改善，该领域也 对供体组织的质量变得更加敏感，包括可能影响长期的供体因素 移植物存活。在这方面，在糖尿病全球“流行”的背景下，糖尿病影响了超过 10% 的人 在美国人口（超过 3000 万人）中，越来越多的报道表明捐赠者的糖尿病状况 会对角膜移植物的存活产生不利影响。而移植受者的糖尿病状态与 延迟愈合和长期炎症长期以来一直被认为是移植寿命的危险因素， 组织捐献者的糖尿病史也会影响移植物的存活这一概念既新颖又有效。 从眼库和组织选择的角度来看，可能具有很大的影响力。这意味着 角膜移植风险分层将在组织决策算法中包括捐赠者的糖尿病状态 分配。为了研究供体糖尿病状态对移植物免疫的潜在作用，我们开始进行初步研究 在糖尿病小鼠模型中进行研究，以评估它将如何影响角膜的常驻免疫细胞， 这可能会影响宿主致敏和同种免疫。我们的初步数据显示：（1） 糖尿病小鼠中成熟的角膜驻留抗原呈递细胞 (APC)，(2) 穿透细胞和层状细胞 (DSEK) 从糖尿病供体小鼠获得的同种异体移植物的存活率明显低于从糖尿病供体小鼠获得的同种异体移植物 来自非糖尿病供体的宿主，(3) 接受糖尿病组织的宿主表现出增强的 T 辅助细胞 1 (Th1) 免疫力 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 降低 MHC-II 表达。因此，我们假设糖尿病状态会诱发 改变角膜微环境，改变角膜的免疫稳态，诱导 APC 成熟和调节性 T 细胞功能障碍，导致宿主敏感性和移植物增强 拒绝。为了检验这一假设，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 功能表型的变化并评估宿主的同种免疫反应 接受糖尿病供体组织（PK 和 DSEK）。然后我们将研究移植的机制 来自糖尿病供体的衍生 APC 影响宿主异体敏化（目标 2）和调节性 T 细胞 (Treg) 功能障碍 （目标 3）。这笔资助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， 研究角膜移植免疫已超过 25 年。从这笔赠款中获得的知识仍然有效 影响眼库和组织分配以及开辟新的转化场所的潜力，例如 离体操纵供体组织 APC 成熟/激活，改善移植结果并减少 由于排除所有糖尿病组织而导致供体组织短缺的风险。