Developmental Clinical Studies- Combined Immunotherapy and Trophic Adrenocortical Stimulation in New Onset Autoimmune Addison's Disease

发育性临床研究 - 联合免疫治疗和营养性肾上腺皮质刺激治疗新发自身免疫性艾迪生病

基本信息

批准号：
MR/J002526/1
负责人：
Simon Pearce
金额：
$ 56.12万
依托单位：
Newcastle University
依托单位国家：
英国
项目类别：
Research Grant
财政年份：
2012
资助国家：
英国
起止时间：
2012 至无数据
项目状态：
已结题

来源：
https://gtr.ukri.org/projects?ref=MR%2FJ002526%2F1
关键词：
Developmental Clinical Studies Combined Immunotherapy

项目摘要

Autoimmune Addison's disease is caused by the immune system attacking and destroying the cortex of the adrenal glands, which gives people a life-threatening problem owing to lack of the adrenal steroid hormones. Symptoms typically include exhaustion, light-headedness, vomiting, weight loss, poor appetite, muscle weakness and cramps. In addition, Addison's people are prone to unpredictable episodes of severe illness, termed adrenal crisis. This means that people with Addison's disease have a life-long dependency on steroid medications, and may become ill within hours of a missed dose. There have been no significant advances in therapy for Addison's disease for sixty years. However, the adrenal cortex is one of the most plastic tissues in the body and this study aims to exploit this innate regenerative capacity to produce a cure for people who have just been diagnosed with Addison's disease.The idea of this study is to combine a hormone therapy that is a synthetic version of the body's natural adrenal stimulating hormone, termed ACTH (adrenocorticotropic hormone), with a treatment to dampen down the immune system's attack on the adrenal cortex. In a previous study, we have found that alternate day injections with synthetic ACTH is effective in stimulating adrenal gland regeneration, but we do not know what sort of treatment will be effective in dampening down the immune response. This will be important to make sure any adrenal regeneration isn't just rapidly destroyed again by the immune attack. The study will take place in 3 stages, each involving 4 people with newly-diagnosed Addison's disease. In each stage of the study, the participants will receive the same dose of alternate day ACTH. However, the first part of the study will use a drug called rituximab, that removes the antibody-producing B lymphocytes from the blood and tissues for about 6 months, to see if this stops the immune attack on the adrenals and allows permanent regeneration. If this doesn't work, we will try a different sort of immunotherapy called abatacept, that affects the function of the T lymphocytes, which act both as the immune system's radar and assassination team. Both these treatments are antibody therapies that are administered for a short period of time (either 2 or 5 doses), but produce long lasting effects on immune system function, for several months. If neither of these immune system treatments work, we will then use a combination of 3 high-dose steroid infusions followed by a daily immunosuppressive tablet called mycophenolate which will be taken for 12 weeks. After each of these treatments adrenal function will be retested in participants at regular intervals for a year to see if the hormonal function of the adrenal gland had been improved. We believe that this therapeutic approach, combining both a drug to quash the immune system attack on the adrenal glands with hormonal stimulation to promote adrenal regeneration, holds genuine promise for cure of this chronic condition.

自身免疫性阿迪森氏病是由免疫系统攻击和破坏肾上腺皮质引起的，由于缺乏肾上腺类固醇激素，这会给人们带来危及生命的问题。症状通常包括精疲力尽、头晕、呕吐、体重减轻、食欲不振、肌肉无力和痉挛。此外，艾迪生氏族人很容易出现不可预测的严重疾病，称为肾上腺危象。这意味着艾迪生氏病患者终生依赖类固醇药物，并且可能在错过剂量后数小时内患病。六十年来，阿狄森氏病的治疗一直没有取得重大进展。然而，肾上腺皮质是体内最具可塑性的组织之一，这项研究旨在利用这种先天的再生能力为刚刚被诊断出患有艾迪生氏病的人提供治疗方法。这项研究的想法是将一种激素结合起来这种疗法是人体天然肾上腺刺激激素的合成版本，称为 ACTH（促肾上腺皮质激素），通过治疗来抑制免疫系统对肾上腺皮质的攻击。在之前的一项研究中，我们发现隔日注射合成 ACTH 可有效刺激肾上腺再生，但我们不知道哪种治疗方法可有效抑制免疫反应。这对于确保肾上腺再生不会再次被免疫攻击迅速破坏非常重要。该研究将分三个阶段进行，每个阶段涉及 4 名新诊断出的阿迪森氏病患者。在研究的每个阶段，参与者将接受相同剂量的隔日 ACTH。然而，该研究的第一部分将使用一种名为利妥昔单抗的药物，该药物可以在大约 6 个月的时间内从血液和组织中去除产生抗体的 B 淋巴细胞，以观察这是否会阻止对肾上腺的免疫攻击并允许永久再生。如果这不起作用，我们将尝试另一种称为阿巴西普的免疫疗法，它会影响 T 淋巴细胞的功能，而 T 淋巴细胞既充当免疫系统的雷达又充当暗杀团队。这两种治疗方法都是抗体疗法，给药时间较短（2 剂或 5 剂），但会对免疫系统功能产生长达数月的持久影响。如果这些免疫系统治疗均无效，我们将联合使用 3 种高剂量类固醇输注，然后每日服用一种名为霉酚酸酯的免疫抑制药片，持续 12 周。每次治疗后，将在一年内定期重新测试参与者的肾上腺功能，以查看肾上腺的激素功能是否得到改善。我们相信，这种治疗方法将消除免疫系统对肾上腺的攻击的药物与促进肾上腺再生的激素刺激相结合，为治愈这种慢性疾病带来了真正的希望。