Secondary Prevention Trials For Recently Diagnosed Type 1 Diabetes Mellitus

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，新发T1 DM患者在诊断时具有残留的β细胞功能，并且这些β细胞在诊断后数月甚至数年内仍保持功能。此外，现在认识到，即使保留边缘辟田胞功能也对患者安全控制他/她的血糖的能力具有有益影响。我们还知道，在诊断时进行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首次诊断T1 DM时开始，原因有两个。第一，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，并且它们具有其他不期望的毒性，包括对相当大的少数人的肾毒性。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。 我们测试了两种保存β细胞的替代方法： 1)抗CD 3抗体的给药（试验完成）：1994年，首次报道了通过给药抗小鼠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。虽然显着效果的确切机制尚未完全探索，我们最初复制了报道的研究，然后还研究了抗CD 3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。与非肥胖糖尿病（NOD）小鼠的经验相反，抗CD 3治疗仅延迟RIP-CD 80转基因小鼠模型中的疾病发作。尽管如此，自从首次报道抗CD 3治疗可以恢复患有新近发作的糖尿病的NOD小鼠的免疫功能，并在此过程中阻断正在进行的免疫介导的β细胞破坏以来，研究人员希望在新近发作的T1 DM患者的临床试验中测试抗人CD 3抗体。然后，可用的抗人CD 3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针对小鼠抗人抗体的免疫应答）相关，然而随后对抗体进行修饰以限制毒性。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（在6周内诊断），并测试该药物是否保留了β细胞功能。我们申请了同情豁免许可，以将患者纳入方案。两名患者作为对照组，两名患者在NIH临床中心接受该药物。接受该药物治疗的NIH患者均未出现任何严重的药物毒性（肌痛、暂时性发热和预期的T细胞计数一过性降低除外）。已发表了12个月随访数据（患者和对照组）以及24个月随访数据（对照组的自然史）。 2)口服α-干扰素给药（研究已完成，进一步分析仍在进行中）：1998年，Brod et al报道，非肥胖糖尿病（NOD）小鼠口服α-干扰素可减少胰岛炎并预防糖尿病发作。此外，他们报道过继转移来自干扰素喂养供体的未刺激脾细胞抑制受体动物的自发性糖尿病。与这一发现相一致，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，10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开放标签试点研究，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α干扰素的明显疗效的确切机制仍然未知。我们启动了一项多中心、对照、双盲临床试验，在该试验中，近期发作（诊断时间小于6周）的T1 DM患者随机接受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（NIH，Bethesda;德克萨斯大学，休斯顿和达拉斯;儿童医院，圣保罗，MN，堪萨斯城，堪萨斯）招募了128名年龄在3岁至25岁之间的患者。我们监测β细胞分泌能力、代谢控制、胰岛素需求以及低血糖事件的频率和严重程度。患者对研究药物和随访测试表现出良好的依从性，每3个月返回NIH进行一次所需的混合餐研究，持续1年。报告了4起严重不良事件（均被判定为可能与研究药物无关）。一名儿童被诊断患有恶性脑肿瘤（NIH）。第二个孩子因哮喘住院（休斯顿），另一个孩子患上了败血症（NIH）。第四个孩子因脱水住院。 我们最近在《糖尿病护理》杂志上发表了这项干预的结果。与安慰剂组的个体相比，5000单位hrIFN-α治疗组的患者在入组研究后一年保持了更多的β细胞功能，而在接受30000单位IFN-α的患者中没有观察到这种效果。 目前，正在进一步分析数据和标本（血清/血浆）。

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.