Novel Combined Costimulation and CD122 Blockade in Islet Transplantation

胰岛移植中的新型联合共刺激和 CD122 阻断

• 批准号: 9124430
• 负责人: David Mathews
• 金额: $ 4.86万
• 依托单位: EMORY UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2016
• 资助国家: 美国
• 起止时间: 2016-05-01 至 2019-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9124430
• 关键词: Acute; Address; Adoption; Adoptive Transfer; Adverse effects; Affect; Affinity; Allogenic; Allografting; Animals; Antigens; Autoimmune Diseases; Autoimmune Process; Basic Science; Binding; CD28 gene; CD8B1 gene; CTLA4-Ig; Calcineurin inhibitor; Cell Death; Cells; Clinical; Dependence; Development; Diabetes Mellitus; End stage renal failure; Endocrine System Diseases; Engraftment; Frequencies; Graft Rejection; Graft Survival; Homeostasis; IL2 gene; IL2RB gene; Immunization; Immunosuppression; Immunosuppressive Agents; Incidence; Insulin; Insulin-Dependent Diabetes Mellitus; Interleukin 2 Receptor; Interleukin-15; Interleukin-2; Islet Cell; Islets of Langerhans Transplantation; Kidney Failure; Kidney Transplantation; Lead; Mediating; Memory; Mission; Modeling; Morbidity - disease rate; Mus; Myocardial Infarction; Natural Killer Cells; Pathway interactions; Patients; Phenotype; Physicians; Public Health; Reagent; Renal function; Replacement Therapy; Research; Resistance; Role; Scientist; Seizures; Signal Transduction; Stroke; System; T cell differentiation; T cell response; T cell therapy; T memory cell; T-Cell Receptor; T-Lymphocyte; Therapeutic Agents; Tissues; Toxic effect; Training; Transgenic Organisms; Transplant Recipients; Transplantation; Work; autoreactive T cell; base; cardiovascular health; curative treatments; cytokine; experience; improved; improved outcome; islet; nonhuman primate; novel; phosphatase inhibitor; pre-clinical; prevent; public health relevance; receptor; response; safety testing; small molecule; success

 DESCRIPTION (provided by applicant): Islet transplantation is a potentially curative therapy for Type 1 Diabetes, an autoimmune disease that affects millions. The success of islet transplantation is hampered by T cell mediated rejection and toxicities from the untoward effects of calcineurin inhibitor (CNI) based immunosuppression. CNIs are small molecule phosphatase inhibitors used in transplantation for their potent T cell suppression but they are accompanied by many side effects. Type 1 diabetes and transplant rejection result from a T cell mediated destruction of tissue. T cells require three signals for activation: T cell receptor (TCR) engagement, costimulation provided by CD28-B7 binding, and signaling through the shared IL-2/IL-15 receptor. In order to provide T cell specific immunosuppression, but reduce morbidity related to CNI therapy, the T cell specific costimulation blocker Belatacept was developed. Patients treated with Belatacept after kidney transplant enjoy improved graft survival, kidney function, cardiovascular health and islet function compared to those treated with CNIs. However, patients treated with Belatacept experience higher rates and more severe grades of acute T cell mediated rejection. Recently, our lab has demonstrated a dramatic improvement in allograft survival when we combine costimulatory blockade and anti-CD122 treatments. This not only prolongs graft survival in mice but is also effective in a pre-clinical non-human primate kidney transplant model. In part this treatment was effective because it reduced the number of antigen-specific T cells available for rejection. Importantly IL15 signaling has been shown to be an essential pathway in the development of autoreactive, islet specific T cells in Type 1 Diabetes. Thus, we propose using combined CD122 blockade and costimulation blockade as a strategy to prevent both allo- and autoreactive T cell mediated destruction of transplanted islets. We will first evaluate the efficacy of combined therapy in fully allogeneic naïve and autoimmune models of islet transplantation in comparison with costimulation blockade alone. Then we will use the murine OVA TCR transgenic system that has been used extensively in our lab to characterize cellular mechanisms of long-term tolerance induction with this novel combination of anti-CD122 and costimulation blockade. The proposed work will serve as a framework for the applicant's training plan to become a physician-scientist by integrating basic science research with a clinical focus in transplantation. These studies will address end stage kidney disease and endocrine disorders using immunomodulatory therapies.

 描述（由申请人提供）：胰岛移植是治疗 1 型糖尿病的一种潜在疗法，1 型糖尿病是一种影响数百万人的自身免疫性疾病。胰岛移植的成功受到 T 细胞介导的排斥反应和基于钙调神经磷酸酶抑制剂 (CNI) 的免疫抑制的不良影响的毒性的阻碍。 CNI 是用于移植的小分子磷酸酶抑制剂，具有有效的 T 细胞抑制作用，但伴随着许多副作用。 1 型糖尿病和移植排斥是由 T 细胞介导的组织破坏引起的。 T 细胞需要三种信号才能激活：T 细胞受体 (TCR) 接合、CD28-B7 结合提供的共刺激以及通过共享 IL-2/IL-15 受体发出的信号。为了提供 T 细胞特异性免疫抑制，同时降低与 CNI 治疗相关的发病率，开发了 T 细胞特异性共刺激阻断剂 Belatacept。与接受 CNI 治疗的患者相比，肾移植后接受 Belatacept 治疗的患者移植物存活率、肾功能、心血管健康和胰岛功能得到改善。然而，接受 Belatacept 治疗的患者出现急性 T 细胞介导的排斥反应的发生率更高且等级更严重。最近，我们的实验室证明，当我们结合共刺激阻断和抗 CD122 治疗时，同种异体移植物的存活率得到显着改善。这不仅延长了小鼠移植物的存活时间，而且在临床前非人灵长类肾移植模型中也有效。这种治疗之所以有效，部分原因在于它减少了可用于排斥的抗原特异性 T 细胞的数量。重要的是，IL15 信号传导已被证明是 1 型糖尿病自身反应性胰岛特异性 T 细胞发育的重要途径。因此，我们建议联合使用 CD122 阻断和共刺激阻断作为防止同种异体和自身反应性 T 细胞介导的移植胰岛破坏的策略。 我们将首先评估联合治疗在完全同种异体胰岛移植和自身免疫模型中与单独共刺激阻断相比的疗效。然后，我们将使用我们实验室广泛使用的小鼠 OVA TCR 转基因系统来表征抗 CD122 和共刺激阻断的这种新型组合诱导长期耐受性的细胞机制。拟议的工作将通过将基础科学研究与移植临床重点相结合，作为申请人成为医师科学家的培训计划的框架。这些研究将使用免疫调节疗法解决终末期肾病和内分泌失调问题。