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分配程序，几乎是40,000 每年在美国和全球超过200,000个案件。作为手术技术，眼睛 银行程序和针对移植拒绝的预防措施有所改善，该领域也已有 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 移植生存。在这方面，以及在全球糖尿病的“流行病”的背景下，影响了超过10％的糖尿病 美国人口（超过3000万人），有越来越多的报道说捐助者的糖尿病状况 会对角膜移植物的生存产生不利影响。而嫁接接受者中的糖尿病状态，这与 长期以来，延迟的愈合和长时间感染已被确定为移植寿命的危险因素， 组织供体中糖尿病病史也可能影响移植物存活的概念既是新颖，又是 从眼睛堤防和组织选择的角度来看，潜在的影响力很大。这意味着 角膜移植风险分层将在组织的决策算法中包括供体糖尿病状态 分配。为了研究供体糖尿病状态在移植免疫的潜在作用，我们开始初步 在糖尿病的小鼠模型中的研究，以评估其如何影响角膜的居民免疫细胞， 这可能会影响宿主灵敏度和同种免疫力。我们的初步数据表明（1）还有更多 糖尿病小鼠中成熟的角膜居民抗原呈递细胞（APC），（2）穿透和层状 （DSEK）从糖尿病供体小鼠中采购的同类物的生存率明显比购买 （3）接受糖尿病组织的宿主在非糖尿病供体中显示出Thelper-1（Th1）免疫史的增强 供体衍生的抗原。此外，我们的初步数据表明（4）糖尿病患者血糖控制 通过角膜APC降低MHC-II表达。根据，我们假设糖尿病状态会影响 改变角膜的免疫稳态的改变角膜微环境诱导了APC 成熟和调节性T细胞功能障碍，导致宿主敏感性和移植 拒绝。为了检验这一假设，我们将追求三个具体目标。在AIM 1中，我们将定义 糖尿病小鼠中角膜APC功能表型的变化，并评估宿主的同种异体反应 接受糖尿病供体组织（PK和DSEK）。然后，我们将研究移植的机制 从糖尿病供体派生的APC影响宿主的敏感性（AIM 2）和调节性T细胞（Treg）功能障碍 （目标3）。代表一个新的投资领域的这笔赠款，基于我们实验室的核心专业知识， 它具有研究二25年以上的角膜移植免疫。从这笔赠款中获得的知识 影响眼睛银行和组织分配以及开放新的翻译场所的潜力 操纵供体组织APC的成熟/激活，从而改善移植预后并减少 由于排除了所有糖尿病组织，供体组织短缺的风险。