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:
- 金额:$ 19.25万
- 依托单位:
- 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:
- 关键词:Adverse effectsAmino AcidsAnimal ModelAntigensApoptoticAutoimmune ResponsesAutoimmunityBeta CellBiological PreservationBlood - brain barrier anatomyCD3 AntigensCell SurvivalCell physiologyCellsChronicClinicClinicalClinical ResearchClinical TrialsCombined Modality TherapyDisease ProgressionDoseEpilepsyExperimental Autoimmune EncephalomyelitisFailureFrequenciesFutureGABA ReceptorHealthHumanImmuneImmune responseImmunocompetentImmunotherapyIn VitroInbred NOD MiceIndividualInflammatoryInsulinInsulin-Dependent Diabetes MellitusInterventionLaboratoriesLeadMeasuresMitogensMonitorMono-SMusNatural regenerationNervous system structureNeuronsNewly DiagnosedNon-Insulin-Dependent Diabetes MellitusOutcomePatientsPeripheralPharmaceutical PreparationsPlasmaPublic HealthRegulatory T-LymphocyteRheumatoid ArthritisRiskRodentSeizuresT cell responseTestingTherapeutic AgentsTimeTranslationsabstractingautoreactivityblood glucose regulationdiabeticdosageexhaustiongamma-Aminobutyric Acidimprovedin vivoinsulin dependent diabetes mellitus onsetneurogenesisneuronal survivalnovelresponse
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
由于T1 D临床试验中单药治疗的失败,人们普遍认为联合治疗
能够控制自身免疫反应并促进T细胞健康和复制的药物将是T1 D所必需的
干预作为一个概念,这项建议将测试免疫调节剂抗CD 3与GABA,
后者具有免疫调节作用并且是一种β-细胞有丝分裂原/存活因子。既往临床
抗CD 3的研究未能在新发糖尿病患者中维持正常血糖,这可能
这是由于1)剩余的胰岛细胞的慢性衰竭,2)缺乏足够的胰岛细胞再生,
3)自身免疫抑制不足。通过将抗CD 3与GABA结合,这些缺陷中的每一种都可以
改善,即,GABA促进小鼠和人的β细胞存活、β细胞复制和质量,并抑制
炎性免疫细胞,同时增强Treg反应。这与以前测试的任何组合都不同
与抗CD 3(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T细胞增殖的能力或不是T细胞有丝分裂原/存活因子。我们
假设抗CD 3 +GABA的组合将充分控制自身免疫应答,
GABA的促有丝分裂和抗凋亡作用将能够更好地保存,甚至可能扩大细胞增殖。
在新糖尿病NOD小鼠中。由于没有单一或联合疗法能够提高胰岛细胞增殖,
复制和质量,成功的结果将是新颖的,并具有很高的潜力,
临床翻译此外,由于抗CD 3和GABA的作用预期会协同作用,我们将
测试每种治疗的较低剂量是否有效,这在临床上可能有助于减少
潜在的副作用最后,除了监测这种联合治疗对免疫功能的影响外,
反应和γ-细胞复制,质量和功能,我们将确定血浆中的GABA水平,
与自身反应性的抑制和β细胞复制的促进有关,这将为
临床试验中的GABA剂量。这些结果具有很高的临床潜力,可以更好地保存,
T1 D发作后的β-细胞团块。即使是少量的保留或增加的胰岛细胞群也会有临床益处,
那些新诊断为T1 D的患者,由于降低胰岛素需求,改善血糖控制,
从而降低并发症的长期风险。我们的方法不仅限于将GABA与抗-
CD 3--将来,GABA可以与其他安全的免疫调节药物联合使用,
这一概念很可能为T1 D干预带来许多新的可能性。
项目成果
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DANIEL KAUFMAN其他文献
DANIEL KAUFMAN的其他文献
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{{ truncateString('DANIEL KAUFMAN', 18)}}的其他基金
Oral GABA treatment as a novel and safe therapy to ameliorate Sjögren’s syndrome
口服 GABA 治疗是改善干燥综合征的一种新颖且安全的疗法
- 批准号:
9808690 - 财政年份:2019
- 资助金额:
$ 19.25万 - 项目类别:
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
- 批准号:
9198975 - 财政年份:2016
- 资助金额:
$ 19.25万 - 项目类别:
Reversal of T1D in NOD mice using a safe combination therapy
使用安全的联合疗法逆转 NOD 小鼠的 T1D
- 批准号:
8292993 - 财政年份:2012
- 资助金额:
$ 19.25万 - 项目类别:
Reversal of T1D in NOD mice using a safe combination therapy
使用安全的联合疗法逆转 NOD 小鼠的 T1D
- 批准号:
8464092 - 财政年份:2012
- 资助金额:
$ 19.25万 - 项目类别:
Reversal of T1D in NOD mice using a safe combination therapy
使用安全的联合疗法逆转 NOD 小鼠的 T1D
- 批准号:
8665415 - 财政年份:2012
- 资助金额:
$ 19.25万 - 项目类别:
Multimodality imaging of beta-cell in anaimal models of T1DM and T2DM
T1DM 和 T2DM 动物模型中 β 细胞的多模态成像
- 批准号:
7690828 - 财政年份:2008
- 资助金额:
$ 19.25万 - 项目类别:
Multimodality imaging of beta-cell in anaimal models of T1DM and T2DM
T1DM 和 T2DM 动物模型中 β 细胞的多模态成像
- 批准号:
7588447 - 财政年份:2008
- 资助金额:
$ 19.25万 - 项目类别:
Characterizing autoimmunity NOD mouse islets, PLN/spleen
表征自身免疫性 NOD 小鼠胰岛、PLN/脾
- 批准号:
7210042 - 财政年份:2006
- 资助金额:
$ 19.25万 - 项目类别:
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