Secondary Prevention Trials For Recently Diagnosed T1DM

最近诊断的 T1DM 的二级预防试验

• 批准号: 6546668
• 负责人: David Harlan
• 金额: --
• 依托单位: NATIONAL INSTITUTE OF DIABETES AND DIGESTIVE AND KIDNEY DISEASES
• 依托单位国家: 美国
• 资助国家: 美国
• 起止时间: 至
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/6546668
• 关键词: CD3 molecule; NOD mouse; antibody receptor; blood glucose; clinical research; clinical trials; diabetes mellitus therapy; disease /disorder prevention /control; genetically modified animals; human subject; human therapy evaluation; immune tolerance /unresponsiveness; immunomodulators; immunosuppressive; immunotherapy; insulin; insulin dependent diabetes mellitus; insulin sensitivity /resistance; interferon alpha; lymphocyte; messenger RNA; nonhuman therapy evaluation; oral administration; pancreatic islet function; placebos

T1DM is caused by the incompletely understood immune mediated destruction of the only cells capable of secreting insulin, the pancreatic beta cells. It has been known for some time that most individuals with new onset T1DM have residual beta cell function at the time of their diagnosis and lasting for weeks, months, even a few years following diagnosis. Further, it is now recognized that preserving even a marginal beta cell mass has a salutary effect on a patient's ability to control his/her blood sugar within the normal range. Finally, it has been known for a number of years that instituting immunosuppressive therapy at T1DM diagnosis preserves beta cell mass, at least temporarily. However, for two good reasons instituting immunosupressive therapy at the time T1DM is first diagnosed has not become an accepted practice. One, the beta cell protective effect is only temporary in that all treated patients eventually required full insulin replacement therapy. Two, the immunosuppressive agents available are both toxic to normal beta cell function, and have other undesired toxicities including the impairment of normal renal function. The latter effect has been especially worrisome because of T1DM's known intrinsic nephrotoxic effects. Two alternative approaches to beta cell preservation are currently under investigation in the Transplant and Autoimmunity Branch: 1) Administration of anti-CD3 antibodies In 1993, it was first reported that normal blood sugar control was restored in non-obese diabetic (NOD) mice with recently diagnosed diabetes by administering a murine anti-CD3 antibody. The exact mechanism underlying the remarkable effect remains incompletely explored. We have reproduced these previously reported studies. In addition, we have studied whether anti-CD3 could similarly reverse disease in the rat insulin promoter-CD80 (RIP-CD80) transgenic mouse model we developed. Contrary to the experience with the NOD mice, anti-CD3 treatment only temporarily ameliorated disease in the RIP-CD80 transgenic mouse model. Since the first report that anti-CD3 therapy could stop the ongoing immune-mediated beta cell destruction in the NOD mouse, in fact could restore euglycemia, investigators have desired to test the analogous anti-human CD3 antibody in clinical trials. The original anti-human CD3 antibody was associated with significant toxicity, however, such as marked lymphopenia and cytokine release syndrome. Therefore, the antibody has been modified in order to limit the toxicity. Limited clinical experience exits with the modified agent in the transplant setting. In 1999, Dr. Kevan Herold at Columbia University initiated a controlled clinical trial testing whether the modified OKT3 antibody (called OKT3 gamma, ala-ala) could be safely administered to patients with new onset T1DM (diagnosed within 6 weeks), and to test whether the agent preserved beta cell mass. We applied for permission to enter three patients into that protocol under compassionate exemptions. Two patients received the agent in the NIH clinical center without significant complications, and one patient is serving as a control. Neither of the two patients treated with the agent experienced any significant toxicity from the drug (except myalgias, temporary fever, and expected transient decreases in T cell counts), and they are being closed followed as part of the cohort at Columbia University to test whether the agent has acted to preserve beta cell mass. 2) Administration of oral interferon-alpha Ingested interferon-alpha was first found to inhibit chronic relapsing experimental autoimmune encephalomyelitis representing an animal model for multiple sclerosis. In 1998, Brod et al reported that administration of oral interferon-alpha in the previously mentioned NOD mouse model reduced insulitis and prevented the onset of diabetes. Furthermore, adoptive transfer of unstimulated splenocytes from interferon fed donors suppressed spontaneous diabetes in recipient animals. Consistent with this finding, spleen cells from treated animals when compared with controls produced more interferon-gamman and interleukins 4 and 10. Subsequently, eleven patients with new onset type 1 diabetes were included in a pilot study at the University of Texas in Houston, in which more than the expected number of individuals remained in the so called honeymoon phase (period of time with continued endogenous insulin production). The exact mechanisms of action of ingested interferon-alpha remain unknown. We recently initiated a multi-center, controlled, double-blinded clinical trial, in which patients with type 1 diabetes of less than six weeks duration are randomized to two different doses of interferon-alpha (5,000 or 30,000 Units per day) or placebo. So far, fourteen patients between the ages of 3 and 25 years have been included in this trial in both participating centers (NIH, Bethesda and University of Texas, Houston). We investigate and monitor beta cell secretory capacity, metabolic control, insulin requirements, frequency and severity of hypoglycemic events as well as serum cytokine patterns and cytokine mRNA transcript levels in stimulated lymphocytes.

T1 DM是由免疫介导的唯一能够分泌胰岛素的细胞（胰腺β细胞）的破坏引起的。一段时间以来，人们已经知道，大多数新发T1 DM患者在诊断时具有残留的β细胞功能，并在诊断后持续数周、数月甚至数年。此外，现在认识到，即使保留边缘β细胞团也对患者将他/她的血糖控制在正常范围内的能力具有有益的影响。最后，多年来人们已经知道，在T1 DM诊断时采用免疫抑制治疗可以至少暂时保留β细胞群。然而，由于两个很好的原因，在首次诊断T1 DM时进行免疫抑制治疗尚未成为公认的实践。第一，β细胞保护作用只是暂时的，因为所有接受治疗的患者最终都需要完全胰岛素替代治疗。第二，可用的免疫抑制剂对正常β细胞功能都是有毒的，并且具有其他不期望的毒性，包括正常肾功能的损害。由于T1 DM已知的内在肾毒性作用，后一种效应尤其令人担忧。 目前，移植和自身免疫分支正在研究两种保存β细胞的替代方法： 1)1993年，首次报道了通过给予鼠抗CD 3抗体，在最近诊断为糖尿病的非肥胖糖尿病（NOD）小鼠中恢复了正常的血糖控制。这种显著效果背后的确切机制尚未完全探索。我们复制了这些先前报道的研究。此外，我们还研究了抗CD 3抗体是否可以类似地逆转我们开发的大鼠胰岛素启动子-CD 80（RIP-CD 80）转基因小鼠模型中的疾病。与NOD小鼠的经验相反，抗CD 3治疗仅暂时改善RIP-CD 80转基因小鼠模型中的疾病。自从第一次报道抗CD 3治疗可以阻止NOD小鼠中正在进行的免疫介导的β细胞破坏，实际上可以恢复正常，研究人员希望在临床试验中测试类似的抗人CD 3抗体。然而，最初的抗人CD 3抗体与显著的毒性相关，例如显著的淋巴细胞减少症和细胞因子释放综合征。因此，已对抗体进行修饰以限制毒性。在移植环境中使用改良药物的临床经验有限。 1999年，哥伦比亚大学的Kevan赫罗尔德博士发起了一项对照临床试验，测试修饰的OKT 3抗体（称为OKT 3 gamma，ala-ala）是否可以安全地用于新发T1 DM患者（6周内诊断），并测试该试剂是否保留了β细胞群。我们申请了三个病人的豁免权。两名患者在NIH临床中心接受了该药物，没有出现明显的并发症，一名患者作为对照。接受该药物治疗的两名患者均未出现药物的任何显著毒性（除了肌痛、暂时性发热和预期的T细胞计数一过性降低），他们作为哥伦比亚大学队列的一部分被关闭，以测试该药物是否起到了保护β细胞群的作用。 2)口服α干扰素的给药 首次发现摄入的干扰素-α可以抑制慢性复发性实验性自身免疫性脑脊髓炎（代表多发性硬化症的动物模型）。1998年，Brod等报道在上述NOD小鼠模型中口服α-干扰素可减少胰岛炎并预防糖尿病的发生。此外，过继转移未刺激的脾细胞从干扰素喂养的捐助者抑制自发性糖尿病受体动物。与这一发现相一致的是，与对照组相比，治疗组动物的脾细胞产生更多的干扰素-γ和白细胞介素4和10。随后，11名新发1型糖尿病患者被纳入德克萨斯大学休斯顿分校的一项试点研究，其中超过预期数量的个体仍处于所谓的蜜月期（持续内源性胰岛素产生的时间段）。摄入干扰素-α的确切作用机制仍不清楚。我们最近启动了一项多中心、对照、双盲临床试验，在该试验中，病程少于6周的1型糖尿病患者随机接受两种不同剂量的干扰素-α（每天5，000或30，000单位）或安慰剂。到目前为止，两个参与中心（NIH，Bethesda和德克萨斯大学休斯顿分校）的14名年龄在3至25岁之间的患者已被纳入本试验。我们研究和监测β细胞分泌能力，代谢控制，胰岛素需求，低血糖事件的频率和严重程度，以及血清细胞因子模式和细胞因子mRNA转录水平在刺激的淋巴细胞。