Short Course G-CSF as Immunomodulatory Therapy for Type 1 Diabetes ? A Pilot Stud

短期 G-CSF 作为 1 型糖尿病的免疫调节疗法？

• 批准号: 8000947
• 负责人: MICHAEL JAMES HALLER
• 金额: $ 8.55万
• 依托单位: UNIVERSITY OF FLORIDA
• 依托单位国家: 美国
• 财政年份: 2010
• 资助国家: 美国
• 起止时间: 2010-01-15 至 2011-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8000947
• 关键词: Activities of Daily Living; Address; Affect; Affinity; Animals; Antigen-Presenting Cells; Antigens; Apoptosis; Ascaridil; Attention; Autoantibodies; Autoimmune Diabetes; Autoimmune Diseases; Autoimmune Process; Autoimmune Responses; Autoimmunity; B-Lymphocytes; Blood Glucose; Bone Marrow; C-Peptide; CD4 Positive T Lymphocytes; Candida; Cell physiology; Cells; Child; Clinical; Clinical Trials; Colony-Stimulating Factor Therapy; Colony-Stimulating Factors; Conflict (Psychology); Data; Defect; Dendritic Cells; Development; Diabetes Mellitus; Diet; Disease; Disease Progression; Disease susceptibility; Double-Blind Method; Effector Cell; Elements; Enrollment; Equilibrium; Equipoise; Eragrostis; Event; Eye; Failure; Foundations; Frequencies; Genetic; Genetic Risk; Glutamate Decarboxylase; Glycosylated hemoglobin A; Goals; Granulocyte Colony-Stimulating Factor; Heart; Helper-Inducer T-Lymphocyte; Human; Hypersensitivity; IA-2-autoantibody; IL2RA gene; Immune; Immune response; Immune system; Immunity; Immunization; Immunologic Factors; Immunologics; Immunomodulators; Immunotherapy; Inbred NOD Mice; Individual; Injection of therapeutic agent; Insulin; Insulin-Dependent Diabetes Mellitus; Investigation; Islet Cell; Islets of Langerhans Transplantation; Kidney; Lead; Life; Literature; Longevity; Measurement; Mediating; Methods; Modeling; Monitor; Morbidity - disease rate; Movement; Natural History; Nerve; Non obese; Pancreas; Pathogenesis; Patients; Peptides; Pharmaceutical Preparations; Pilot Projects; Placebo Control; Placebos; Play; Population; Premature Mortality; Procedures; Process; Production; Protocols documentation; Randomized; Regulation; Regulatory T-Lymphocyte; Reporting; Research; Risk; Role; Safety; Self Tolerance; Self-control as a personality trait; Severities; Signal Transduction; Study Subject; Susceptibility Gene; T cell response; T-Cell Antigen Receptor Specificity; T-Lymphocyte; Tetanus; Therapeutic; Therapeutic Agents; Therapeutic Intervention; Therapeutic immunosuppression; Thymus Gland; Transplantation; Treatment Efficacy; United States; Up-Regulation; Work; autoreactive T cell; base; cell type; design; diabetes control; diabetic; disorder risk; early childhood; granulocyte; immunoregulation; improved; innovation; insight; interest; mouse model; novel; oncology; peripheral blood; prevent; response; subcutaneous; tool

DESCRIPTION (provided by applicant): Type 1 diabetes (T1D) is associated with tremendous morbidity and premature mortality. Patients require multiple daily insulin injections throughout their lives as well as close monitoring of their diet and blood sugar levels to prevent disease associated complications. Unfortunately, there is presently no permanent cure for T1D. Whole pancreas or islet cell transplantation is available only to a very limited number of patients and necessitates potential lifelong immunosuppressive therapy. Granulocyte colony stimulating factor (G-CSF) has recently been shown to prevent T1D in the Non Obese Diabetic (NOD) mouse model of the disease. Those studies demonstrated that the benefits of G-CSF therapy are likely due to mobilization of T regulatory cells (Treg) from the bone marrow. Since Treg function is known to be diminished in patients with T1D, G- CSF may have the potential to dampen the autoimmune response by acting as a potent immunomodulator involving Treg stimulation. [Prior to the initiation of appropriately powered clinical trials of G-CSF, we must obtain a better understanding of the potential mechanisms associated with G-CSF stimulated mobilization of Treg in the T1D population. As such, we will perform a randomized, double-blinded, placebo controlled pilot study to document G-CSF's augmentation of Treg number and function in subjects with T1D. Twenty-one patients with persistent stimulated c-peptide 0.2 pmol/ml, will be randomized 2:1 (drug:placebo) to receive a 5 day course of daily subcutaneous G-CSF (10 mcg/kg/d) versus placebo]. Our primary goals will be to document the safety of G-CSF therapy and [characterize the mechanisms by which G-CSF augments] Treg number and function in the T1D population. Type 1 diabetes affects 1 in 300 people in the United States, requires lifelong administration of multiple daily insulin injections, frequently results in nerve, eye, kidney, and heart damage, and often results in a shortened lifespan. Type 1 diabetes is caused by an abnormal activation of the immune system that results in the destruction of the patients own insulin producing cells. This protocol will explore the potential of the drug Granulocyte Colony Stimulation Factor (GCSF) to stimulate immune cells that can potentially change the immune system and protect insulin producing cells from further damage.

描述（由申请人提供）：1 型糖尿病 (T1D) 与巨大的发病率和过早死亡率相关。患者一生中需要每天多次注射胰岛素，并密切监测饮食和血糖水平，以预防疾病相关的并发症。不幸的是，目前没有永久治愈 T1D 的方法。全胰腺或胰岛细胞移植仅适用于非常有限的患者，并且需要潜在的终生免疫抑制治疗。最近，粒细胞集落刺激因子 (G-CSF) 在非肥胖糖尿病 (NOD) 小鼠模型中被证明可以预防 T1D。这些研究表明，G-CSF 疗法的益处可能是由于动员了骨髓中的 T 调节细胞 (Treg)。由于已知 T1D 患者的 Treg 功能会减弱，因此 G-CSF 可能通过充当涉及 Treg 刺激的有效免疫调节剂来抑制自身免疫反应。 [在启动适当动力的 G-CSF 临床试验之前，我们必须更好地了解与 G-CSF 刺激 T1D 人群中 Treg 动员相关的潜在机制。因此，我们将进行一项随机、双盲、安慰剂对照的试点研究，以记录 G-CSF 对 T1D 受试者 Treg 数量和功能的增强作用。 21 名持续刺激 c 肽 0.2 pmol/ml 的患者将按 2:1（药物：安慰剂）随机分配，接受为期 5 天的每日皮下 G-CSF 疗程（10 mcg/kg/d）与安慰剂比较]。我们的主要目标是记录 G-CSF 治疗的安全性，并[描述 G-CSF 增强] T1D 人群中 Treg 数量和功能的机制。在美国，每 300 人中就有 1 人患有 1 型糖尿病，需要终生每天注射多次胰岛素，经常导致神经、眼睛、肾脏和心脏损伤，并常常导致寿命缩短。 1 型糖尿病是由免疫系统异常激活引起的，导致患者自身的胰岛素产生细胞遭到破坏。该协议将探索药物粒细胞集落刺激因子 (GCSF) 刺激免疫细胞的潜力，从而可能改变免疫系统并保护胰岛素产生细胞免受进一步损害。