INGESTED IFN-ALPHA IN NEWLY DIAGNOSED TYPE I DIABETES

这个子项目是利用由NIH/NCRR资助的中心拨款提供的资源的许多研究子项目之一。子项目和调查员(PI)可能从另一个NIH来源获得了主要资金，因此可能会出现在其他CRISE条目中。列出的机构是针对中心的，而不一定是针对调查员的机构。1型糖尿病是一种慢性疾病，由产生胰岛素的胰腺b细胞的自身免疫破坏引起。在美国，20岁时1型糖尿病的患病率为0.26%，终生患病率接近0.40%；因此，大约有100万美国人患有IDDM。组织学研究表明，诱发症状性IDDM需要将b细胞体积减少80%。1型糖尿病的自然病史在通常被称为“蜜月期”的阶段是独一无二的，在这一阶段，胰岛素需求变得最少，血糖控制得到改善。感觉到b细胞已经恢复了。然而，就像所有的蜜月一样，蜜月结束后，患者就会完全缺乏胰岛素。国际糖尿病界的普遍共识是在新诊断的患者中测试1型糖尿病的潜在预防疗法。延长“蜜月期”的干预措施被认为是积极的，预示着疾病的逆转。本研究的目的是：1-确定摄入5000和30,000个单位的重组人干扰素-α(hrIFN-a)在延长1型糖尿病患者的“蜜月期”和保护b细胞功能方面的有效性。我们将在为期一年的第二阶段每日摄入试验中，确定在120名新诊断的1型糖尿病患者中摄入5000和30,000单位hrIFN-a的安全性和有效性。主要的结果指标将是在入选后3、6、9和12个月时，经刺激后C-肽水平增加30%。升高的C-肽水平将与对照组的C-肽水平进行比较，并且必须明显更高。2-确定摄入5000或30,000个单位的hr干扰素-a是否会改变疾病的替代标志。我们的实验室证明，摄入干扰素-α能增加NOD小鼠脾细胞和供体细胞的抗炎IL-4和IL-10，对NOD受体的自发性1型糖尿病具有保护作用。我们I期开放标签临床试验的初步数据显示，在7名残留b细胞功能的1型糖尿病患者(蜜月患者)中，有4名患者的抗GAD抗体效价比研究开始时和研究结束时的水平有所下降。对比研究开始和结束时的血清细胞因子数据的检查显示，七名蜜月者中有六名的IL-4或IL-10水平升高。因此，我们将确定摄入hrIFN-a是否会增加血清IL-4或IL-10细胞因子、IL-4或IL-10细胞因子mRNA体外转录水平，或降低新发1型糖尿病患者的抗GAD和抗IA-2抗体效价，这些患者在积极治疗组治疗12个月后仍保留b细胞功能。我们将比较5000和3万单位剂量的结果，看看两者是否同样有效。针对胰腺b细胞及其抗原的体液和细胞免疫反应。每隔3个月获取PMNC的体外细胞因子mRNA，特别是IL-1、IL-4、IL-6、IL-10、肿瘤坏死因子-a、肿瘤坏死因子-b、干扰素-a和干扰素-g。将在0、1、2、3、6、9和12个月时采集血清，用于测定GAD和IA-2抗体水平(M.Atkinson Ph.D.)血清IL-4、IL-10水平。所有患者将在1、2、3、6、9和12个月进行后续血液检查，以监测干扰素-α的毒性。

This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. The subproject and investigator (PI) may have received primary funding from another NIH source, and thus could be represented in other CRISP entries. The institution listed is for the Center, which is not necessarily the institution for the investigator. Type 1 diabetes is a chronic disorder that results from autoimmune destruction of the insulin-producing pancreatic b-cell. In the United States, the prevalence of type 1 diabetes by age 20 years is 0.26% and lifetime prevalence approaches 0.40%; thus approximately 1 million Americans have IDDM. Histologic studies suggest that an 80% reduction in the volume of b-cells is required to induce symptomatic IDDM. The natural history of type 1 diabetes is unique for a phase frequently referred to as the "honeymoon", a period in which the insulin need becomes minimal and glycemic control improves. It is felt that the b-cell recovers. However, as with all honeymoons, they end and the patient becomes completely insulin deficient. The general consensus of the international diabetes community is to test potential preventive therapies for type 1 diabetes in newly diagnosed patients. Interventions prolonging the "honeymoon", indicative of the reversal of the disease, are considered positive. This study is designed to: 1- Determine the efficacy of 5000 and 30,000 IU ingested human recombinant interferon-alpha (hrIFN-a) in prolonging the 'honeymoon'-like period and preserving b-cell function in type 1 diabetes. We will determine the safety and efficacy of 5000 and 30,000 units ingested hrIFN-a in 120 patients with newly diagnosed type 1 diabetes in a phase II trial of daily ingestion for one year. Primary outcome measures will be a 30% increase in C-peptide levels released after Sustacal stimulation at 3, 6, 9, and 12 months after entry. The increased C-peptide level will be compared to C-peptide levels from the control group and must be significantly higher. 2- Determine if 5000 or 30,000 units ingested hrIFN-a alters surrogate markers of disease. Our laboratory demonstrated that ingested IFN-a increased anti-inflammatory IL-4 and IL-10 in NOD spleen cells and donor cells from IFN-fed mice protected against spontaneous type 1 diabetes in NOD recipients. Preliminary data from our phase I open label clinical trial showed that in four out of the seven type 1 diabetes patients with residual b-cell function ('honeymooners'), anti-GAD antibody titers decreased comparing entry to end of study levels. Examinations of serum cytokine data comparing entry to end of study levels show increased IL-4 or IL-10 levels in six of seven 'honeymooners'. Therefore, we will determine if ingested hrIFN-a increases serum IL-4 or IL-10 cytokines, IL-4 or IL-10 cytokine mRNA transcripts ex vivo in peripheral blood mononuclear cells (PMNC), or decreases titers of anti-GAD and anti-IA-2 antibodies from patients with recent onset type 1 diabetes that retain residual b-cell function after 12 months on the active treatment arm. We will compare the results from the 5000 and 30,000 units dose to see if both are equally effective. Humoral and cyto- immune responses directed at pancreatic b-cells and their antigens. PMNC will be obtained at three monthly interval for ex vivo cytokine mRNA, in particular IL-1, IL-4, IL-6, IL-10, TNF-a, TNF-b, IFN-a and IFN-g. Sera will be obtained at 0, 1, 2, 3, 6, 9, and 12 months for measurement of GAD and IA-2 antibody levels (M. Atkinson Ph.D.) and serum IL-4 and IL-10 levels. Follow-up blood studies to monitor for IFN-a toxicity will be performed on all patients at 1, 2, 3, 6, 9, and 12 months.