Secondary Prevention Trials For Recently Diagnosed Type 1 Diabetes Mellitus

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，新发的T1 DM患者在诊断时仍有残留的β细胞功能，这些β细胞在诊断后几个月甚至几年内仍保持功能。此外，现在已经认识到，即使保留边缘的β细胞功能也会对患者安全控制血糖的能力产生有益的影响。我们还知道，在确诊时实施免疫抑制治疗可以保护β细胞功能，至少是暂时的。然而，免疫抑制治疗通常不会在第一次诊断为T1 DM时开始，有两个很好的原因。首先，β细胞的保护作用似乎只是暂时的，因为接受治疗的患者最终需要胰岛素替代疗法。第二，现有的免疫抑制剂是有毒的：它们损害正常的β细胞功能，还有其他不受欢迎的毒性，包括对相当大一部分人的肾脏毒性。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。 我们测试了两种保存贝塔细胞的替代方法： 1)注射抗CD3抗体(试验完成)：1994年，首次报道通过注射抗小鼠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。虽然这种显著作用的确切机制仍不完全清楚，但我们最初复制了已报道的研究，然后还研究了抗CD3是否可以类似地逆转我们建立的大鼠胰岛素启动子-CD80(RIP-CD80)转基因小鼠模型的疾病。与非肥胖糖尿病(NOD)小鼠的经验相反，在RIP-CD80转基因小鼠模型中，抗CD3治疗仅推迟了疾病的发病。然而，自从首次报道抗CD3治疗可以恢复新发糖尿病NOD小鼠的正常血糖并通过这样做来阻止正在进行的免疫介导的β细胞破坏以来，研究人员希望在一项针对新发T1糖尿病患者的临床试验中测试抗人CD3抗体。然后，可用的抗人CD3抗体与显著的毒性(例如，显著的淋巴细胞减少症、细胞因子释放综合征和对鼠抗人抗体的免疫反应)有关，但随后对抗体进行了修饰以限制毒性。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细胞功能。我们申请了体恤豁免许可，允许患者进入协议。两名患者作为对照组，两名患者在NIH临床中心接受药物治疗。接受该药物治疗的NIH患者均未出现任何严重的药物毒性(除了肌痛、一过性发热和预期的一过性T细胞计数下降)。已经公布了12个月的随访数据(患者和对照)以及24个月的随访数据(对照的自然病史)。 2)口服α-干扰素(研究已经完成，进一步的分析仍在进行中)：1998年，Brod等人报告说，口服α-干扰素给非肥胖糖尿病(NOD)小鼠减少了胰岛素炎症并预防了糖尿病的发生。此外，他们报告说，过继转移干扰素喂养的供者未受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-伽马和白细胞介素4和白介素10。随后，10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开放标签试点研究，在该研究中，仍处于所谓的“蜜月期”(内源性胰岛素持续产生的时间段)的个体数量超过预期数量。摄入的阿尔法干扰素的明显疗效背后的确切机制仍不清楚。我们启动了一项多中心、对照、双盲临床试验，将新近发病(确诊不到6周)的T1 DM患者随机分为两组，分别服用两种不同剂量的口服干扰素-α(每天5,000或30,000单位)或安慰剂。我们在所有5个参与中心(美国国立卫生研究院、贝塞斯达；德克萨斯大学、休斯顿和达拉斯；明尼苏达州圣保罗儿童医院、堪萨斯州堪萨斯城)招募了128名年龄在3到25岁之间的患者。我们监测了β细胞分泌能力、代谢控制、胰岛素需求量以及低血糖事件的频率和严重程度。患者表现出对研究用药和后续测试的良好依从性，他们回到NIH进行所需的每3个月进行一次的混合膳食研究，为期一年。已经报告了四种严重的不良事件(所有事件都被判断为与研究药物无关)。一名儿童被诊断出患有恶性脑瘤(NIH)。第二个孩子因哮喘住院(休斯顿)，另一个孩子患上葡萄球菌败血症(NIH)。第四个孩子因脱水入院治疗。 我们最近在《糖尿病护理》杂志上发表了这项干预的结果。与安慰剂组相比，5000单位干扰素治疗组的患者在登记参加研究一年后保持了更多的β细胞功能，而在接受30000单位干扰素治疗的患者中没有观察到这种影响。 目前，正在对数据和标本(血清/血浆)进行进一步分析。

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 individuals with new onset T1DM have residual beta cell function at the time of their diagnosis, and that those beta cells remain functional for months, even years following diagnosis. Further, it is now recognized that preserving even marginal beta cell function has a beneficial effect on a patient's ability to safely control his/her blood sugar. We also know that instituting immunosuppressive therapy at diagnosis preserves beta cell function, at least temporarily. Nevertheless, immunosupressive therapy is typically not instituted when T1DM is first diagnosed, and for two good reasons. One, the beta cell protective effect appears to be only temporary in that treated patients eventually require insulin replacement therapy. Two, the available immunosuppressive agents are toxic: they impair normal beta cell function, and they have other undesired toxicities including renal toxicity for a sizeable minority. The latter effect has been especially worrisome because of T1DM's known intrinsic nephrotoxic effects. We have tested two alternative approaches to beta cell preservation: 1) Administration of anti-CD3 antibodies (trial completed): In 1994, it was first reported that normal blood sugar control was restored in non-obese diabetic (NOD) mice with recently diagnosed diabetes by administering an anti-mouse CD3 antibody. While the exact mechanism underlying the remarkable effect remains incompletely explored, we initially reproduced the reported studies, then also studied whether the anti-CD3 could similarly reverse disease in a rat insulin promoter-CD80 (RIP-CD80) transgenic mouse model we developed. Contrary to the experience with non-obese diabetic (NOD) mice, anti-CD3 treatment only delayed disease onset in the RIP-CD80 transgenic mouse model. Nevertheless, since the first report that anti-CD3 therapy could restore euglycemia to NOD mice with recent onset diabetes and in so doing, block ongoing immune-mediated beta cell destruction, investigators have wished to test anti-human CD3 antibody in a clinical trial of patients with recent onset T1DM. Then available anti-human CD3 antibody was associated with significant toxicity (e.g. marked lymphopenia, a cytokine release syndrome, and immune responses against the mouse anti-human antibody) however the antibody was subsequently modified to limit toxicity. 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 function. We applied for compassionate exemption permission to enter patients into the protocol. Two patients served as controls and two patients received the agent at the NIH clinical center. Neither NIH patient treated with the agent experienced any serious toxicity from the drug (except myalgias, temporary fever, and expected transient decreases in T cell counts). Twelve month follow-up data (patients and controls) as well as 24 month follow-up data (natural history of controls) have been published. 2) Administration of oral interferon-alpha (study completed, further analyses are still being performed): In 1998, Brod et al reported that oral interferon-alpha administered to non-obese diabetic (NOD) mice reduced insulitis and prevented the onset of diabetes. Further, they reported that adoptively transfering 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-gamma and interleukins 4 and 10. Subsequently, ten patients with new onset type 1 diabetes were included in an open label 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 underlying the apparent efficacy of the ingested alpha interferon remains unknown. We initiated a multi-center, controlled, double-blinded clinical trial in which patients with recent onset (diagnosed less than 6 weeks) T1DM are randomized to two different doses of oral interferon-alpha (5,000 or 30,000 Units per day) or placebo. We enrolled 128 patients between the ages of 3 and 25 years in all 5 participating centers (NIH, Bethesda; University of Texas, Houston and Dallas; Children's Hospital St. Paul, MN, Kansas City, Kansas). We monitored beta cell secretory capacity, metabolic control, insulin requirements, and frequency and severity of hypoglycemic events. Patients showed excellent compliance with the study medication and follow-up testing, returning to the NIH for the required mixed meal studies performed every 3 months for 1 year. Four serious adverse events (all judged to be likly unrelated to study drug) have been reported. One child was diagnosed with a malignant brain tumor (NIH). The second child was hospitalized with asthma (Houston) and another youngster developed staphylococcus septicemia (NIH). The fourth child was hospitalized with dehydration. We recently published the results of this intervention in Diabetes Care. Patients in the 5000 unit hrIFN-alpha treatment group maintained more beta-cell function one year after enrollment into the study compared to individuals in the placebo group, while this effect was not observed in patients who received 30000 units IFN-alpha. Currently, data and specimens (serum/plasma) are being further analyzed.