Combination immunotherapy to preserve beta-cell function in the context of autoimmunity

在自身免疫背景下保护 β 细胞功能的联合免疫疗法

基本信息

批准号：
9035769
负责人：
DANIEL KAUFMAN
金额：
$ 19.25万
依托单位：
UNIVERSITY OF CALIFORNIA LOS ANGELES
依托单位国家：
美国
项目类别：
财政年份：
2016
资助国家：
美国
起止时间：
2016-01-01 至 2017-12-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9035769
关键词：
Adverse effects Amino Acids Animal Model Antigens Apoptotic Autoimmune Responses Autoimmunity Beta Cell Biological Preservation Blood - brain barrier anatomy CD3 Antigens Cell Survival Cell physiology Cells Chronic Clinic Clinical Clinical Research Clinical Trials Combined Modality Therapy Disease Progression Dose Epilepsy Experimental Autoimmune Encephalomyelitis Failure Frequencies Future GABA Receptor Health Human Immune Immune response Immunocompetent Immunotherapy In Vitro Inbred NOD Mice Individual Inflammatory Insulin Insulin-Dependent Diabetes Mellitus Intervention Laboratories Lead Measures Mitogens Monitor Mono-S Mus Natural regeneration Nervous system structure Neurons Newly Diagnosed Non-Insulin-Dependent Diabetes Mellitus Outcome Patients Peripheral Pharmaceutical Preparations Plasma Public Health Regulatory T-Lymphocyte Rheumatoid Arthritis Risk Rodent Seizures T cell response Testing Therapeutic Agents Time Translations abstracting autoreactivity blood glucose regulation diabetic dosage exhaustion gamma-Aminobutyric Acid improved in vivo insulin dependent diabetes mellitus onset neurogenesis neuronal survival novel response

项目摘要

Abstract Due to the failure of monotherapies in T1D clinical trials it is widely thought that combination treatments that can control autoimmune responses and promote ß-cell health and replication will be necessary for T1D intervention. As a poof-of-concept, this proposal will test the immunoregulatory agent anti-CD3 with GABA, the latter of which has both immunoregulatory actions and is a ß-cell mitogen/survival factor. Previous clinical studies with anti-CD3 have failed to maintain normoglycemia in newly diabetic individuals, which may have been due to 1) the chronic exhaustion of the remaining ß-cells, 2) the lack of sufficient ß-cell regeneration and 3) insufficient suppression of autoimmunity. By combining anti-CD3 with GABA, each of these deficiencies can be improved, i.e., GABA promotes mouse and human ß-cell survival, ß-cell replication and mass, and inhibits inflammatory immune cells while enhancing Treg responses. This is unlike any previously tested combination with anti-CD3 (or other immunoregulatory agent) because the second therapeutic agent used in those studies lacked the ability to inhibit autoimmunity/promote Tregs or was not a ß-cell mitogen/survival factor. We hypothesize that the combination of anti-CD3+GABA will sufficiently control autoimmune responses such that GABA's mitogenic and anti-apoptotic actions will be able to better preserve, and perhaps even expand ß-cell mass, in newly diabetic NOD mice. Since no mono- or combined therapy has yet been able to enhance ß-cell replication and mass in diabetic NOD mice, a successful outcome would be novel and have high potential for clinical translation. Additionally, because the actions of anti-CD3 and GABA are expected to synergize, we will test whether lower dosages of each treatment can be effective, which could be useful in the clinic to reduce potential side-effects. Finally, in addition to monitoring the effect of this combination treatment on immune responses and ß-cell replication, mass and function, we will determine the levels of GABA in plasma that are associated with inhibition of autoreactivity and promotion of ß-cell cell replication, which will be informative for GABA dosing in clinical trials. The results have high clinical potential to better preserve and perhaps increase ß-cell mass after T1D onset. Even a small preservation or increase of ß-cell mass will have clinical benefits in those newly diagnosed with T1D by virtue of lowering insulin requirements, improving glucose control and thereby reducing the long-term risk for complications. Our approach is not limited to combining GABA with anti- CD3--in the future, GABA could be combined with other safe immunoregulatory drugs, so that a proof-of- concept is likely to lead to many new possibilities for T1D intervention.

抽象的由于T1D临床试验中的单层疗法失败，因此很广泛地认为组合治疗 T1D需要控制自身免疫反应并促进ß细胞健康和复制干涉。作为概念的概念，该提案将用GABA测试免疫调节剂抗CD3 后者既具有免疫调节作用，又是ß细胞有丝分裂原/生存因子。以前的临床对抗CD3的研究未能维持新的糖尿病患者的正常血糖，这可能具有是由于1）剩余β细胞的慢性疲劳，2）缺乏足够的ß细胞再生和 3）自身免疫的抑制不足。通过将抗CD3与GABA结合，这些缺陷都可以改进，即GABA促进小鼠和人ß细胞存活，ß细胞复制和质量，并抑制炎性免疫细胞，同时增强Treg反应。这与任何先前测试的组合不同使用抗CD3（或其他免疫调节剂），因为这些研究中使用的第二种治疗剂缺乏抑制自身免疫/促进Treg或不是ß细胞有丝分裂原/生存因子的能力。我们假设抗CD3+GABA的组合将充分控制自身免疫反应，以便 GABA的有丝分裂和抗凋亡动作将能够更好地保存，甚至可以扩大ß细胞质量，新糖尿病点头小鼠。由于尚无单一或联合疗法能够增强β细胞糖尿病点头小鼠的复制和质量，成功的结果将是新颖的，并且具有很高的潜力临床翻译。此外，由于预期抗CD3和GABA的动作会协同作用，因此我们将测试每种治疗的较低剂量是否有效，这在诊所中可能很有用潜在的副作用。最后，除了监测这种组合处理对免疫的影响响应和ß细胞复制，质量和功能，我们将确定血浆中GABA的水平与抑制自动反应性和促进β细胞复制相关的相关，这将是有益的 GABA剂量在临床试验中。结果具有更高的临床潜力，可以更好地保存并可能增加 T1D发作后的ß细胞质量。即使是少量保存或增加ß细胞质量也将在那些因降低胰岛素需求，改善葡萄糖控制和从而减少并发症的长期风险。我们的方法不仅限于将GABA与反 - CD3 - 将来，GABA可以与其他安全的免疫调节药物结合使用，以便证明概念可能会导致许多新的T1D干预可能性。