Secondary Prevention Trials For Recently Diagnosed T1DM

T1 DM是由免疫介导的对唯一能够分泌胰岛素的细胞，即胰岛β细胞的破坏而引起的。众所周知，大多数新发的T1 DM患者在诊断时仍有β细胞功能残存，并在诊断后持续数周、数月、甚至数年。此外，现在已经认识到，即使保留边缘的β细胞质量，也会对患者将血糖控制在正常范围内的能力产生有益的影响。最后，多年来，人们已经知道，在诊断为T1 DM时实施免疫抑制治疗至少可以暂时保留β细胞团。然而，出于两个很好的原因，在第一次诊断为T1 DM时开始免疫抑制治疗并没有成为一种被接受的做法。首先，β细胞的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的胰岛素替代治疗。第二，现有的免疫抑制剂既对正常的β细胞功能有毒性，也有其他不受欢迎的毒性，包括损害正常的肾功能。后一种影响尤其令人担忧，因为T1 DM具有已知的固有肾毒性。移植和自身免疫科目前正在研究两种保存贝塔细胞的替代方法： 1)注射抗CD3抗体1993年，首次报道了通过注射小鼠抗CD3抗体，最近诊断为糖尿病的非肥胖糖尿病(NOD)小鼠恢复了正常的血糖控制。这种显著效果背后的确切机制仍未完全阐明。我们复制了这些先前报道的研究。此外，我们还研究了在我们建立的大鼠胰岛素启动子-CD80(RIP-CD80)转基因小鼠模型中，抗CD3是否能类似地逆转疾病。与NOD小鼠的经验相反，在RIP-CD80转基因小鼠模型中，抗CD3治疗仅暂时改善了疾病。自从第一份报告称抗CD3治疗可以阻止NOD小鼠正在进行的免疫介导的β细胞破坏，实际上可以恢复正常血糖以来，研究人员一直希望在临床试验中测试类似的抗人CD3抗体。然而，最初的抗人CD3抗体与显著的毒性相关，如显著的淋巴细胞减少和细胞因子释放综合征。因此，对抗体进行了修饰，以限制其毒性。在移植环境中使用改良剂的临床经验有限。1999年，哥伦比亚大学的凯文·赫罗德博士启动了一项对照临床试验，测试改良的OKT3抗体(称为OKT3Gamma，ALA-ALA)是否可以安全地用于新发的T1 DM患者(在6周内确诊)，并测试该试剂是否保留了β细胞团。我们申请了允许三名患者加入该方案，并获得了同情豁免。两名患者在NIH临床中心接受了这种药物治疗，没有出现明显的并发症，另有一名患者作为对照。接受该药物治疗的两名患者都没有经历过任何明显的药物毒性(除了肌痛、暂时性发烧和预期的暂时性T细胞计数下降)，他们正在哥伦比亚大学进行追踪，作为队列的一部分，以测试该药物是否起到了保护β细胞团的作用。2)口服干扰素-α 首次发现摄入干扰素-α可以抑制慢性复发的实验性自身免疫性脑脊髓炎，这代表了多发性硬化症的动物模型。1998年，Brod等人报道，在前面提到的NOD小鼠模型中，口服干扰素-α可以减少胰岛素炎并预防糖尿病的发生。此外，干扰素喂养的供者过继转移未经刺激的脾细胞可以抑制受体动物的自发性糖尿病。与这一发现一致的是，与对照组相比，接受治疗的动物的脾细胞产生了更多的干扰素-Gamman和白介素4和10。随后，11名新发的1型糖尿病患者被纳入休斯顿德克萨斯大学的一项试点研究，在该研究中，仍处于所谓蜜月期(内源性胰岛素持续产生的一段时间)的患者数量超过预期。摄入的干扰素-α的确切作用机制尚不清楚。我们最近启动了一项多中心、对照、双盲临床试验，将病程少于六周的1型糖尿病患者随机分为两组，分别服用两种不同剂量的α-干扰素(每天5,000或30,000单位)或安慰剂。到目前为止，这两个参与中心(NIH、贝塞斯达和德克萨斯大学休斯顿)都有14名年龄在3岁到25岁之间的患者参加了这项试验。我们调查和监测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刺激淋巴细胞中的细胞因子mRNA转录水平。

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.