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
项目成果
期刊论文数量(0)
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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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