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

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

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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 MHCI's neuroactivity
描述 MHCI 的神经活动
  • 批准号:
    7018998
  • 财政年份:
    2006
  • 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:
Characterizing MHCI's neuroactivity
描述 MHCI 的神经活动
  • 批准号:
    7345643
  • 财政年份:
    2006
  • 资助金额:
    $ 19.25万
  • 项目类别:

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