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

基本信息

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
项目类别：
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

项目摘要

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（由适用提供）：胰岛移植是1型糖尿病的潜在治疗疗法，这是一种影响数百万的自身免疫性疾病。胰岛移植的成功受到T细胞介导的排斥反应和毒性的阻碍，这是基于钙调神经酶抑制剂（CNI）免疫抑制的不良影响。 CNIS是用于移植的小分子磷酸酶抑制剂，用于其潜在的T细胞抑制，但通过许多副作用来完成。 T细胞介导的组织破坏导致1型糖尿病和移植排斥。 T细胞需要三个信号进行激活：T细胞受体（TCR）参与，CD28-B7结合提供的共刺激以及通过共享的IL-2/IL-15受体信号传导。为了提供T细胞特异性免疫抑制，但减少与CNI治疗相关的发病率，开发了T细胞特异性的COLTIMATION BLEBATACEPT。与接受CNIS治疗的患者相比，肾脏移植后接受BELATACEPT治疗的患者具有改善的谷物存活，肾功能，心血管健康和胰岛功能。然而，接受Belatacept治疗的患者的速率更高，急性T细胞介导的排斥反应的率更高。最近，当我们结合了共刺激性阻滞和抗CD122处理时，我们的实验室表现出同种异体移植存活率的显着改善。这不仅延长了小鼠的谷物存活，而且在临床前非人类私人肾脏移植模型中也有效。在某种程度上，这种处理是有效的，因为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信号已被证明是1型糖尿病中自动反应性的特异性T细胞发展中的必不可少的途径。这是我们建议使用联合CD122阻断和共刺激阻滞作为防止同层和自动反应性T细胞介导的移植胰岛破坏的策略。我们将首先评估合并治疗在完全同种异体幼稚和自身免疫模型中的有效性，而与仅共刺激封锁相比。然后，我们将使用鼠OVA TCR转基因系统，该系统已在我们的实验室中广泛用于表征长期耐受性诱导的细胞机制，这种抗CD122的新型组合和Costimimulation Blockade的这种新型组合。拟议的工作将作为申请人培训计划的框架，通过将基础科学研究与临床重点整合到移植中，成为身体科学家。这些研究将使用免疫调节疗法来解决末期肾脏疾病和内分泌疾病。