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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.

摘要