Tolerance to Composite Islet-Kidney Transplants in Non-Human Primates

非人类灵长类动物对复合胰岛肾移植的耐受性

基本信息

  • 批准号:
    8725786
  • 负责人:
  • 金额:
    $ 35.2万
  • 依托单位:
  • 依托单位国家:
    美国
  • 项目类别:
  • 财政年份:
    2012
  • 资助国家:
    美国
  • 起止时间:
    2012-08-01 至 2017-07-31
  • 项目状态:
    已结题

项目摘要

Although many diabetic patients in renal failure, especially children, have potential donors willing to provide both a kidney and islets, the quantity of islets necessary to achieve insulin independence hampers successful islet Tx by partial pancreatectomy from living donors. Project 2 is designed toward developing a tolerance-inducing strategy for curative treatment of end-stage diabetic nephropathy using living donor composite Islet-Kidney (IK) transplantation (Tx). We have previously demonstrated that the strategy of transplanting pre-vascularized islets as part of IKs in large animal models is successful, using far fewer islets than are required for Tx of free, non-vascularized islets. Both renal and islet function were restored by IK Tx across fully allogeneic barriers in nephrectomized diabetic baboons using a clinically relevant immunosuppression protocol. More recently, our preliminary data have shown the successful induction of tolerance of IKs in rhesus monkeys treated with hematopoietic cell Tx in a "mother-to-son" combination. In order to transition the IK strategy to clinical applicability, and thus justify the additional donor risk required for IK preparation, the present studies are directed toward achieving consistent tolerance induction to IKs with our historical bone marrow (BM) chimerism regimen, as well as determining the minimal degree of pancreatectomy required for successful IK creation. These studies will be carried out using cynomologous monkeys and our BM Tx conditioning regimen that has already been introduced into human protocols and continues to be refined for more widespread clinical application (see Project 1 of this U19). We will first determine whether tolerance and long-term islet function can be induced reproducibly across both one-haplotype and fully mismatched barriers, in order to determine whether this strategy will be applicable for both living related and unrelated donor combinations (Aim 1). We will then assess the optimal timing of IK Tx in relation to BM Tx for tolerance induction, as well as assess the minimal donor pancreatectomy required for IK preparation (Aim 2). Finally, we will examine the effects of recipient age, memory T-cells (Tmem), and innate immune reactivity on the induction of tolerance, utilizing appropriate strategies, including thymic rejuvenation, T-mem depletion (in conjunction with Project 1) and inhibition of inflammation (Core B), respectively, to overcome these anticipated barriers (Aim 3). We will study the effects of adaptive and innate immune factors on tolerance induction in collaboration with Project 3 for all three aims. Among the advantages of this approach in the treatment of end-stage diabetic nephropathy, in contrast to current clinical management, are that it would obviate the need for chronic immunosuppresion, avoid the morbidity associated with whole organ pancreas Tx, and circumvent the long wait list times currently required for deceased donor Tx by providing euglycemia with limited islet volume safely obtained from living donors.
尽管许多肾衰竭的糖尿病患者,特别是儿童,有潜在的捐赠者愿意提供肾脏和胰岛,但实现胰岛素非依赖性所需的胰岛数量阻碍了通过活体供体的部分胰腺切除术成功进行胰岛Tx。项目2旨在开发一种耐受诱导策略,用于使用活体供体复合胰岛-肾(IK)移植(Tx)治愈性治疗终末期糖尿病肾病。我们之前已经证明,在大型动物模型中移植预血管化胰岛作为IKs的一部分的策略是成功的,使用的胰岛比游离非血管化胰岛的Tx所需的胰岛少得多。肾和胰岛功能恢复IK Tx在肾切除糖尿病狒狒使用临床相关的免疫抑制协议完全同种异体屏障。最近,我们的初步数据表明,成功诱导耐受性的IKs在恒河猴与造血细胞Tx治疗的“母子”组合。为了将IK策略过渡到临床适用性,从而证明IK制备所需的额外供体风险,本研究旨在用我们的历史骨髓(BM)嵌合体方案实现对IK的一致耐受诱导,以及确定成功创建IK所需的最小程度的胰腺切除术。这些研究将使用食蟹猴和我们的BM Tx预处理方案进行,该方案已经引入人体方案,并继续进行改进以获得更广泛的临床应用(参见本U19的项目1)。我们将首先确定耐受性和长期胰岛功能是否可以在单倍型和完全错配障碍中重复诱导,以确定该策略是否适用于活体相关和无关供体组合(目标1)。然后,我们将评估IK Tx相对于BM Tx诱导耐受的最佳时机,以及评估IK准备所需的最小供体胰腺切除术(目标2)。最后,我们将研究受体年龄、记忆T细胞(T-cell)和先天免疫反应性对诱导耐受的影响,分别利用适当的策略,包括胸腺再生、T-cell耗竭(与项目1结合)和炎症抑制(核心B),以克服这些预期的障碍(目标3)。我们将与项目3合作研究适应性和先天免疫因素对耐受诱导的影响。与目前的临床管理相比,这种方法在治疗终末期糖尿病肾病中的优点在于,它将减少对慢性免疫抑制的需要,避免与全器官胰腺Tx相关的发病率,并通过提供具有从活体供体安全获得的有限胰岛体积的真核细胞来避免目前死亡供体Tx所需的长等待时间。

项目成果

期刊论文数量(0)
专著数量(0)
科研奖励数量(0)
会议论文数量(0)
专利数量(0)

数据更新时间:{{ journalArticles.updateTime }}

{{ item.title }}
{{ item.translation_title }}
  • DOI:
    {{ item.doi }}
  • 发表时间:
    {{ item.publish_year }}
  • 期刊:
  • 影响因子:
    {{ item.factor }}
  • 作者:
    {{ item.authors }}
  • 通讯作者:
    {{ item.author }}

数据更新时间:{{ journalArticles.updateTime }}

{{ item.title }}
  • 作者:
    {{ item.author }}

数据更新时间:{{ monograph.updateTime }}

{{ item.title }}
  • 作者:
    {{ item.author }}

数据更新时间:{{ sciAawards.updateTime }}

{{ item.title }}
  • 作者:
    {{ item.author }}

数据更新时间:{{ conferencePapers.updateTime }}

{{ item.title }}
  • 作者:
    {{ item.author }}

数据更新时间:{{ patent.updateTime }}

KAZUHIKO YAMADA其他文献

KAZUHIKO YAMADA的其他文献

{{ item.title }}
{{ item.translation_title }}
  • DOI:
    {{ item.doi }}
  • 发表时间:
    {{ item.publish_year }}
  • 期刊:
  • 影响因子:
    {{ item.factor }}
  • 作者:
    {{ item.authors }}
  • 通讯作者:
    {{ item.author }}

{{ truncateString('KAZUHIKO YAMADA', 18)}}的其他基金

Preclinical Studies of Living Donor Islet-Kidney Allograft Tolerance
活体胰岛肾同种异体移植物耐受性的临床前研究
  • 批准号:
    10216979
  • 财政年份:
    2017
  • 资助金额:
    $ 35.2万
  • 项目类别:
Tolerance to Composite Islet-Kidney Transplants in Non-Human Primates
非人类灵长类动物对复合胰岛肾移植的耐受性
  • 批准号:
    8432086
  • 财政年份:
    2012
  • 资助金额:
    $ 35.2万
  • 项目类别:
GalT-KO Vascularized Thymic Transplantation for Xenograft Tolerance
GalT-KO 血管化胸腺移植以提高异种移植耐受性
  • 批准号:
    8190111
  • 财政年份:
    2011
  • 资助金额:
    $ 35.2万
  • 项目类别:
Use of GAIT-KO Vascularized Thymic Transplantation for the Induction of..........
使用 GAIT-KO 血管化胸腺移植来诱导…………
  • 批准号:
    7007095
  • 财政年份:
    2005
  • 资助金额:
    $ 35.2万
  • 项目类别:
Achieving Xenograft Tolerance through Thymic Programming in Primates
通过灵长类动物的胸腺编程实现异种移植耐受
  • 批准号:
    9073458
  • 财政年份:
    2001
  • 资助金额:
    $ 35.2万
  • 项目类别:
Use of GAIT-KO Vascularized Thymic Transplantation for the Induction of..........
使用 GAIT-KO 血管化胸腺移植来诱导…………
  • 批准号:
    7609171
  • 财政年份:
    2000
  • 资助金额:
    $ 35.2万
  • 项目类别:
Use of GAIT-KO Vascularized Thymic Transplantation for the Induction of..........
使用 GAIT-KO 血管化胸腺移植来诱导…………
  • 批准号:
    7790538
  • 财政年份:
    2000
  • 资助金额:
    $ 35.2万
  • 项目类别:
Achieving Xenograft Tolerance through Thymic Programming in Primates
通过灵长类动物的胸腺编程实现异种移植耐受
  • 批准号:
    10328001
  • 财政年份:
    2000
  • 资助金额:
    $ 35.2万
  • 项目类别:
Achieving Xenograft Tolerance through Thymic Programming in Primates
通过灵长类动物的胸腺编程实现异种移植耐受
  • 批准号:
    10553284
  • 财政年份:
    2000
  • 资助金额:
    $ 35.2万
  • 项目类别:
GalT-KO Vascularized Thymic Transplantation for Xenograft Tolerance
GalT-KO 血管化胸腺移植以提高异种移植耐受性
  • 批准号:
    8377256
  • 财政年份:
  • 资助金额:
    $ 35.2万
  • 项目类别:

相似海外基金

Hormone therapy, age of menopause, previous parity, and APOE genotype affect cognition in aging humans.
激素治疗、绝经年龄、既往产次和 APOE 基因型会影响老年人的认知。
  • 批准号:
    495182
  • 财政年份:
    2023
  • 资助金额:
    $ 35.2万
  • 项目类别:
Investigating how alternative splicing processes affect cartilage biology from development to old age
研究选择性剪接过程如何影响从发育到老年的软骨生物学
  • 批准号:
    2601817
  • 财政年份:
    2021
  • 资助金额:
    $ 35.2万
  • 项目类别:
    Studentship
RAPID: Coronavirus Risk Communication: How Age and Communication Format Affect Risk Perception and Behaviors
RAPID:冠状病毒风险沟通:年龄和沟通方式如何影响风险认知和行为
  • 批准号:
    2029039
  • 财政年份:
    2020
  • 资助金额:
    $ 35.2万
  • 项目类别:
    Standard Grant
Neighborhood and Parent Variables Affect Low-Income Preschool Age Child Physical Activity
社区和家长变量影响低收入学龄前儿童的身体活动
  • 批准号:
    9888417
  • 财政年份:
    2019
  • 资助金额:
    $ 35.2万
  • 项目类别:
The affect of Age related hearing loss for cognitive function
年龄相关性听力损失对认知功能的影响
  • 批准号:
    17K11318
  • 财政年份:
    2017
  • 资助金额:
    $ 35.2万
  • 项目类别:
    Grant-in-Aid for Scientific Research (C)
Affect regulation and Beta Amyloid: Maturational Factors in Aging and Age-Related Pathology
影响调节和 β 淀粉样蛋白:衰老和年龄相关病理学中的成熟因素
  • 批准号:
    9320090
  • 财政年份:
    2017
  • 资助金额:
    $ 35.2万
  • 项目类别:
Affect regulation and Beta Amyloid: Maturational Factors in Aging and Age-Related Pathology
影响调节和 β 淀粉样蛋白:衰老和年龄相关病理学中的成熟因素
  • 批准号:
    10166936
  • 财政年份:
    2017
  • 资助金额:
    $ 35.2万
  • 项目类别:
Affect regulation and Beta Amyloid: Maturational Factors in Aging and Age-Related Pathology
影响调节和 β 淀粉样蛋白:衰老和年龄相关病理学中的成熟因素
  • 批准号:
    9761593
  • 财政年份:
    2017
  • 资助金额:
    $ 35.2万
  • 项目类别:
How age dependent molecular changes in T follicular helper cells affect their function
滤泡辅助 T 细胞的年龄依赖性分子变化如何影响其功能
  • 批准号:
    BB/M50306X/1
  • 财政年份:
    2014
  • 资助金额:
    $ 35.2万
  • 项目类别:
    Training Grant
Inflamm-aging: What do we know about the effect of inflammation on HIV treatment and disease as we age, and how does this affect our search for a Cure?
炎症衰老:随着年龄的增长,我们对炎症对艾滋病毒治疗和疾病的影响了解多少?这对我们寻找治愈方法有何影响?
  • 批准号:
    288272
  • 财政年份:
    2013
  • 资助金额:
    $ 35.2万
  • 项目类别:
    Miscellaneous Programs
{{ showInfoDetail.title }}

作者:{{ showInfoDetail.author }}

知道了