Tolerance In Organ Transplantation And Autoimmune Disease By T Cell Immunotoxin

T 细胞免疫毒素对器官移植和自身免疫性疾病的耐受性

基本信息

项目摘要

The general aim of this project is to study the effects of immunotoxin induced transient T-cell depletion on the modulation of T cells from immunization responses towards tolerizing responses, and to use this knowledge for the experimental and clinical treatment of T cell driven autoimmune diseases, graft-versus-host disease, and the induction of tolerance to mismatched organ and cell transplants. We previously showed that a 2-3 day course of anti-rhesus CD3 immunotoxin constructed with CRM9, a binding site mutant of diphtheria toxin, depletes lymph node and blood T cells by 99% after a 48 hour lag period. This process was associated with a marked prolongation of survival of mismatched functioning rhesus kidney transplants, 50% over 9 months without further immunosuppressive therapy. Rejections, were preceded by the appearance of anti-graft antibodies (done with S. Knechtle and J. Thomas). To circumvent this adverse T cell mediated B cell response that is apparently initiated during the delay in immunotoxin induced T cell killing, we have added a short course of agents that are believed to block antigen presentation such as deoxyspergualin (DSG). Out of 5 bilaterally rephrectomized recipients long term tolerance was achieved in 3 without further immunosuppresion as judged by a graft survival of 4 years or longer. Congeneic pancreatic islet cell transplants in monkeys suffering from spontaneous insulin dependent diabetes have been shown to reverse diabetes as judged by returning non-fasting blood glucose and glycosylated hemoglobin values to normal in the absence of exogenous insulin. A short course of immunotoxin, methyl prednisolone and cyclosporine provide induction of stable operational tolerance to islets that has lasted over one year in one case. This is the first reported reversal of diabetes using a tolerizing protocol that does not depend on chronic immunosuppression, a process previously shown to compromise transplanted islet function (done with J. Thomas). Streptozotocin induced diabetes in monkeys has been successfully reversed by using anti-T cell immunotoxin in combination with 14 days of DSG and allografted pancreatic islets (done with J. Thomas). Three out of seven are long term tolerant survivors (6-7 years). A recombinant divalent anti-human anti-T cell immunotoxin has been developed that has 20-fold the potency of the previous chemical conjugates. This is expressed in Pichia pastoris. This material has now been produced for a phase I clinical trial in T cell leukemia and an INDA has been filed. In order to aid the production of immunotoxin and other bioactive proteins in Pichia pastoris, new strains have been constructed that exhibit toxin resistance and increased heterologous protein production in the presence of an active unfolded-protein response. Recently, a recombinant anti-CD3 immunotoxin active against monkey T cells has been developed. This was done in order to facilitate pre-clinical studies in organ transplantation and autoimmune diseases. A side benefit of this study was that it required explorations of different recombinant antibody geometries for optimal activity. A fold-back diabody structure was found to be most optimal toward monkey CD3. Model building studies predicted that this structure should have very high binding activity towards targets that contain homodimeric epitopes rotated by 180 degrees. This prediction was found to be true in the case of a human solid tumor epitope and clinical studies at another institution are planned.
该项目的总体目标是研究免疫毒素诱导的短暂 T 细胞耗竭对 T 细胞从免疫反应到耐受反应的调节的影响,并将这些知识用于 T 细胞驱动的自身免疫性疾病、移植物抗宿主病以及诱导对不匹配的器官和细胞移植的耐受性的实验和临床治疗。我们之前表明,用 CRM9(白喉毒素的结合位点突变体)构建的抗恒河猴 CD3 免疫毒素的 2-3 天疗程,在 48 小时滞后期后可将淋巴结和血液 T 细胞消耗 99%。这一过程与功能不匹配的恒河猴肾移植的存活率显着延长有关,在不进行进一步免疫抑制治疗的情况下,9个月内存活率提高了50%。在拒绝之前,出现了抗移植物抗体(由 S. Knechtle 和 J. Thomas 完成)。为了避免这种不利的 T 细胞介导的 B 细胞反应(这种反应显然是在免疫毒素诱导的 T 细胞杀伤延迟期间启动的),我们添加了短期的药物,据信可以阻断抗原呈递,例如脱氧精胍菌素 (DSG)。根据移植物存活 4 年或更长时间来判断,5 名双侧肾切除受者中有 3 名在没有进一步免疫抑制的情况下实现了长期耐受。患有自发性胰岛素依赖型糖尿病的猴子的同种胰岛细胞移植已被证明可以逆转糖尿病,这是通过在不存在外源胰岛素的情况下将非空腹血糖和糖化血红蛋白值恢复到正常来判断的。短期疗程的免疫毒素、甲基泼尼松龙和环孢菌素可诱导对胰岛的稳定操作耐受,在一个病例中这种耐受持续了一年多。这是首次报道使用不依赖于慢性免疫抑制的耐受方案逆转糖尿病,此前已证明慢性免疫抑制会损害移植的胰岛功能(由 J. Thomas 完成)。通过使用抗 T 细胞免疫毒素并结合 14 天的 DSG 和同种异体移植胰岛(由 J. Thomas 完成),链脲佐菌素诱导的猴子糖尿病已成功逆转。 七分之三是长期耐受的幸存者(6-7 年)。一种重组二价抗人抗 T 细胞免疫毒素已被开发出来,其效力是之前化学缀合物的 20 倍。这在毕赤酵母中得到表达。该材料现已生产用于 T 细胞白血病的 I 期临床试验,并已提交 INDA。为了帮助巴斯德毕赤酵母产生免疫毒素和其他生物活性蛋白,我们构建了新菌株,在存在活性未折叠蛋白反应的情况下表现出毒素抗性并增加异源蛋白产量。 最近,开发出了一种对猴 T 细胞具有活性的重组抗 CD3 免疫毒素。 这样做是为了促进器官移植和自身免疫性疾病的临床前研究。 这项研究的一个附带好处是,它需要探索不同的重组抗体几何形状以获得最佳活性。 发现折回双抗体结构对于猴 CD3 是最优化的。 模型构建研究预测,该结构对包含旋转 180 度的同二聚体表位的靶标应具有非常高的结合活性。 这一预测在人类实体瘤表位的情况下被发现是正确的,并且计划在另一个机构进行临床研究。

项目成果

期刊论文数量(20)
专著数量(0)
科研奖励数量(0)
会议论文数量(0)
专利数量(0)
T-cell depletion and graft survival induced by anti-human CD3 immunotoxins in human CD3epsilon transgenic mice.
人 CD3ε 转基因小鼠中抗人 CD3 免疫毒素诱导 T 细胞耗竭和移植物存活。
  • DOI:
    10.1097/00007890-200205270-00023
  • 发表时间:
    2002
  • 期刊:
  • 影响因子:
    6.2
  • 作者:
    Weetall,Marla;Digan,MaryEllen;Hugo,Ronald;Mathew,Sheba;Hopf,Christine;Tart-Risher,Nicole;Zhang,Jin;Shi,Victor;Fu,Fumin;Hammond-McKibben,Denise;West,Susan;Brack,Richard;Brinkmann,Volker;Bergman,Reinhard;NevilleJr,David;Lake,
  • 通讯作者:
    Lake,
Chimeric fusion proteins--diphtheria toxin-based.
嵌合融合蛋白——基于白喉毒素。
Effects of xenogeneic thymic transplantation in baboons.
异种胸腺移植对狒狒的影响。
  • DOI:
    10.1016/s0041-1345(00)02244-2
  • 发表时间:
    2001
  • 期刊:
  • 影响因子:
    0.9
  • 作者:
    Wu,A;Yamada,K;Awwad,M;Kitamura,H;Wain,J;Neville,DM;Cooper,DK;Sykes,M;Sachs,DH
  • 通讯作者:
    Sachs,DH
Xenogeneic thymus transplantation in a pig-to-baboon model.
猪狒狒模型中的异种胸腺移植。
  • DOI:
    10.1097/01.tp.0000044137.97841.99
  • 发表时间:
    2003
  • 期刊:
  • 影响因子:
    6.2
  • 作者:
    Wu,Anette;Yamada,Kazuhiko;Neville,DavidM;Awwad,Michel;Wain,JohnC;Shimizu,Akira;Gojo,Satoshi;Kitamura,Hiroshi;Colvin,RobertB;Cooper,DavidKC;Sykes,Megan;Sachs,DavidH
  • 通讯作者:
    Sachs,DavidH
Minimization of aggregation of secreted bivalent anti-human T cell immunotoxin in Pichia pastoris bioreactor culture by optimizing culture conditions for protein secretion.
通过优化蛋白质分泌的培养条件,最大限度地减少毕赤酵母生物反应器培养中分泌的二价抗人 T 细胞免疫毒素的聚集。
  • DOI:
    10.1016/j.jbiotec.2005.07.004
  • 发表时间:
    2006
  • 期刊:
  • 影响因子:
    4.1
  • 作者:
    Woo,JungHee;Liu,YuanYi;NevilleJr,DavidM
  • 通讯作者:
    NevilleJr,DavidM
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David M. Neville其他文献

Proteines de fusion d'immunotoxines et leurs moyens d'expression
免疫毒素融合蛋白和表达途径
  • DOI:
  • 发表时间:
    2001
  • 期刊:
  • 影响因子:
    0
  • 作者:
    David M. Neville;Jerry T. Thompson;Huaizhong Hu;Jung;Shenglin Ma;J. M. Hexham;Mary Ellen Digan
  • 通讯作者:
    Mary Ellen Digan
Insulin Action in Isolated Rat Thymocytes: I. BINDING OF <sup>125</sup>I-INSULIN AND STIMULATION OF α-AMINOISOBUTYRIC ACID TRANSPORT
  • DOI:
    10.1016/s0021-9258(19)44673-5
  • 发表时间:
    1972-11-01
  • 期刊:
  • 影响因子:
  • 作者:
    Ira D. Goldfine;Jerry D. Gardner;David M. Neville
  • 通讯作者:
    David M. Neville
Receptors for polypeptide hormones: Direct studies of insulin binding to purified liver plasma membranes
Tolerance to composite tissue allografts across a major histocompatibility barrier in miniature swine1
小型猪对跨主要组织相容性障碍的复合组织同种异体移植物的耐受性1
  • DOI:
  • 发表时间:
    2004
  • 期刊:
  • 影响因子:
    6.2
  • 作者:
    S. Hettiaratchy;E. Melendy;Mark A. Randolph;Rebecca C. Coburn;David M. Neville;D. H. Sachs;Christene A. Huang;W. P. A. Lee
  • 通讯作者:
    W. P. A. Lee
γ‐Glutamyltransferase in kidney brush border membranes
肾刷状缘膜中的γ-谷氨酰转移酶
  • DOI:
  • 发表时间:
    1972
  • 期刊:
  • 影响因子:
    0
  • 作者:
    Hartmut Glossmann;David M. Neville
  • 通讯作者:
    David M. Neville

David M. Neville的其他文献

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{{ truncateString('David M. Neville', 18)}}的其他基金

Tolerance In Organ Transplantation And Autoimmune Diseas
器官移植和自身免疫性疾病的耐受性
  • 批准号:
    6823951
  • 财政年份:
  • 资助金额:
    $ 113.17万
  • 项目类别:
Tolerance In Organ Transplantation And Autoimmune Diseas
器官移植和自身免疫性疾病的耐受性
  • 批准号:
    7312867
  • 财政年份:
  • 资助金额:
    $ 113.17万
  • 项目类别:
Tolerance In Organ Transplantation And Autoimmune Diseas
器官移植和自身免疫性疾病的耐受性
  • 批准号:
    6671607
  • 财政年份:
  • 资助金额:
    $ 113.17万
  • 项目类别:
TOLERANCE IN ORGAN TRANSPLANTATION AND AUTOIMMUNE DISEASE BY T CELL IMMUNOTOXIN
T 细胞免疫毒素对器官移植和自身免疫性疾病的耐受性
  • 批准号:
    6432850
  • 财政年份:
  • 资助金额:
    $ 113.17万
  • 项目类别:
Treatment of childhood regresive autism with minocycline.
用米诺环素治疗儿童回归自闭症。
  • 批准号:
    7594593
  • 财政年份:
  • 资助金额:
    $ 113.17万
  • 项目类别:
Tolerance In Organ Transplantation & Autoimmune Disease
器官移植的耐受性
  • 批准号:
    7136268
  • 财政年份:
  • 资助金额:
    $ 113.17万
  • 项目类别:
Treatment of childhood regresive autism with minocycline
米诺环素治疗儿童回归自闭症
  • 批准号:
    7312936
  • 财政年份:
  • 资助金额:
    $ 113.17万
  • 项目类别:
TOLERANCE IN ORGAN TRANSPLANTATION AND AUTOIMMUNE DISEASE BY T CELL IMMUNOTOXIN
T 细胞免疫毒素对器官移植和自身免疫性疾病的耐受性
  • 批准号:
    6111217
  • 财政年份:
  • 资助金额:
    $ 113.17万
  • 项目类别:
TOLERANCE IN ORGAN TRANSPLANTATION AND AUTOIMMUNE DISEASE BY T CELL IMMUNOTOXIN
T 细胞免疫毒素对器官移植和自身免疫性疾病的耐受性
  • 批准号:
    6290587
  • 财政年份:
  • 资助金额:
    $ 113.17万
  • 项目类别:
Tolerance In Organ Transplantation And Autoimmune Diseas
器官移植和自身免疫性疾病的耐受性
  • 批准号:
    6541860
  • 财政年份:
  • 资助金额:
    $ 113.17万
  • 项目类别:

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Establishment of novel osteochondral allografting combined with growth factor- collagen-binding domain fusion technology
新型同种异体骨软骨移植联合生长因子-胶原蛋白结合域融合技术的建立
  • 批准号:
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将 PTH 疗法转化为结构性同种异体移植的佐剂
  • 批准号:
    8344380
  • 财政年份:
    2012
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    $ 113.17万
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Allografting for Lukemia
白血病同种异体移植
  • 批准号:
    8260361
  • 财政年份:
    2011
  • 资助金额:
    $ 113.17万
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Composite Allografting for Promoting Survival of Corneal Transplants
复合同种异体移植促进角膜移植的存活
  • 批准号:
    7878675
  • 财政年份:
    2009
  • 资助金额:
    $ 113.17万
  • 项目类别:
Composite Allografting for Promoting Survival of Corneal Transplants
复合同种异体移植促进角膜移植的存活
  • 批准号:
    7677758
  • 财政年份:
    2009
  • 资助金额:
    $ 113.17万
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Augmenting Antitumor Immunity after Allografting
增强同种异体移植后的抗肿瘤免疫力
  • 批准号:
    7466112
  • 财政年份:
    2008
  • 资助金额:
    $ 113.17万
  • 项目类别:
Augmenting Antitumor Immunity after Allografting
增强同种异体移植后的抗肿瘤免疫力
  • 批准号:
    8010394
  • 财政年份:
    2008
  • 资助金额:
    $ 113.17万
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Augmenting Antitumor Immunity after Allografting
增强同种异体移植后的抗肿瘤免疫力
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    8208131
  • 财政年份:
    2008
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    $ 113.17万
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增强同种异体移植后的抗肿瘤免疫力
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    7575273
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    2008
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    $ 113.17万
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Augmenting Antitumor Immunity after Allografting
增强同种异体移植后的抗肿瘤免疫力
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    7765518
  • 财政年份:
    2008
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    $ 113.17万
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