ApoFasL: a Novel Immunotherapeutic for T1D

ApoFasL:一种新型 T1D 免疫疗法

基本信息

  • 批准号:
    7325628
  • 负责人:
  • 金额:
    $ 42.17万
  • 依托单位:
  • 依托单位国家:
    美国
  • 项目类别:
  • 财政年份:
    2007
  • 资助国家:
    美国
  • 起止时间:
    2007-08-06 至 2009-01-31
  • 项目状态:
    已结题

项目摘要

DESCRIPTION (provided by applicant): Type 1 Diabetes (T1D) is an autoimmune disease that targets insulin secreting pancreatic beta cells for destruction and remains a major cause of morbidity and mortality in over 1% of the population worldwide. Although insulin therapy and islet transplantation are currently the most effective treatments, both of these approaches suffer from major limitations including the inability of insulin therapy to totally prevent diabetes- associated complications, the limited availability of human islets for transplantation, and the rejection of islet allografts irrespective of the use of immunosuppressive drugs. Therefore, the use of islets from a different species, such as pigs, and induction of tolerance without the chronic use of immunosuppressive drugs will be important therapeutic advancements required for the efficient treatment of T1D in the clinic. The main objective of this proposal is to establish proof-of-principle for a novel, safe, and practical approach designated as ApoFasL to induce transplantation tolerance to xenogeneic pancreatic islets as a therapeutic intervention for the treatment of Type 1 diabetes Given the important role played by Fas/FasL system in immune tolerance to self antigens, immune privilege, and lymphocyte homeostasis, and the extensive use of FasL to induce allograft tolerance in various settings, the Principle Investigator of this grant, Dr. Haval Shirwan, developed a novel form of FasL with potent apoptotic activity using ApoImmune's ProtEx(tm) technology. ProtEx(tm) involves the generation of chimeric immunological ligands with a modified form of core streptavidin, modification of a cell membrane with biotin, and decoration of biotinylated membrane with chimeric proteins. Preliminary data have demonstrated that the display of FasL on pancreatic islets (ApoFasL therapy) using ProtEx(tm) resulted in the prevention of graft rejection and treatment of chemically-induced diabetes in an allogeneic transplant model. Expanding on these data, the focus of this proposal is to develop proof-of-principle for an effective, clinically applicable approach to induce immune tolerance to xenogeneic islet grafts in a rat-to-mouse model for the treatment of diabetes. FasL will be displayed on rat donor islets for transplantation into both chemically-induced diabetic mice and spontaneously diabetic non-obese diabetic (NOD) mice, which exhibit destructive autoimmune pancreatic insulitis. Transplants will be done in the presence of rapamycin a pharmaceutical agent used in the clinic for the prevention of graft rejection. We hypothesize that islets decorated with FasL will induce tolerance by eliminating xenoreactive lymphocytes via apoptosis and expanding T regulatory cells. Rapamycin is expected to further augment this response by eliminating T effector cells and/or expanding T regulatory cells, thereby creating donor specific immune tolerance, leading to the survival of transplanted islets. Proof-of-principle will be followed by a Phase II STTR application to further develop ApoFasL into a lead product by testing its efficacy in a pig-to-nonhuman primate xenograft model. Tolerance to xenogeneic islets will serve as the first step towards the translation of this novel approach to the clinic for the treatment of T1D. If proven effective, ApoFasL may improve the quality of life of millions of individuals worldwide with an economic impact in billions of dollars. Xenograft islet transplantation represents an alternative therapeutic approach for Type 1 diabetes over classic allogeneic islet transplantation and insulin treatment therapies, and promises to yield a more definitive solution. The ApoFasL approach, when successful, will ensure a pathway to the treatment of Type 1 diabetes.
描述(由申请人提供):1型糖尿病(T1 D)是一种自身免疫性疾病,其靶向胰岛素分泌胰腺β细胞进行破坏,并且仍然是全球超过1%人口发病和死亡的主要原因。尽管胰岛素治疗和胰岛移植是目前最有效的治疗方法,但这两种方法都存在主要的局限性,包括胰岛素治疗不能完全预防糖尿病相关并发症,用于移植的人胰岛的可用性有限,以及与使用免疫抑制药物无关的胰岛同种异体移植物的排斥.因此,使用来自不同物种(如猪)的胰岛以及诱导耐受性而不长期使用免疫抑制药物将是临床有效治疗T1 D所需的重要治疗进展。本提案的主要目的是建立一种新的、安全的、实用的方法的原理验证,该方法被命名为ApoFasL,以诱导异种胰岛移植耐受,作为治疗1型糖尿病的治疗干预。鉴于Fas/FasL系统在对自身抗原的免疫耐受、免疫豁免和淋巴细胞稳态中发挥的重要作用,以及FasL在各种情况下诱导同种异体移植耐受的广泛应用,该基金的主要研究者Haval Shirwan博士使用ApoImmune的ProtEx(tm)技术开发了一种具有强效凋亡活性的新型FasL。ProtEx(tm)涉及产生具有修饰形式的核心链霉亲和素的嵌合免疫配体、用生物素修饰细胞膜以及用嵌合蛋白修饰生物素化的膜。初步数据已经证明,在同种异体移植模型中,使用ProtEx(tm)在胰岛上展示FasL(ApoFasL疗法)导致移植物排斥的预防和化学诱导的糖尿病的治疗。在这些数据的基础上,本提案的重点是开发一种有效的、临床适用的方法的原理验证,以在大鼠-小鼠模型中诱导对异种胰岛移植物的免疫耐受,用于治疗糖尿病。FasL将在大鼠供体胰岛上展示,用于移植到化学诱导的糖尿病小鼠和自发性糖尿病非肥胖糖尿病(NOD)小鼠中,其表现出破坏性自身免疫性胰岛炎。移植将在雷帕霉素的存在下进行,雷帕霉素是一种临床上用于预防移植排斥反应的药剂。我们推测,FasL修饰的胰岛将通过凋亡和扩增T调节细胞消除异种反应性淋巴细胞来诱导耐受。预期雷帕霉素通过消除T效应细胞和/或扩增T调节细胞来进一步增强这种应答,从而产生供体特异性免疫耐受,导致移植的胰岛存活。在原理证明之后将进行II期STTR申请,通过在猪与非人灵长类动物异种移植模型中测试其功效,进一步将ApoFasL开发为主导产品。对异种胰岛的耐受性将作为将这种新方法转化为临床治疗T1 D的第一步。如果证明有效,ApoFasL可能会改善全球数百万人的生活质量,产生数十亿美元的经济影响。异种胰岛移植代表了1型糖尿病相对于经典同种异体胰岛移植和胰岛素治疗疗法的替代治疗方法,并有望产生更明确的解决方案。ApoFasL方法如果成功,将确保1型糖尿病的治疗途径。

项目成果

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ROLF M HUSEBY其他文献

ROLF M HUSEBY的其他文献

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{{ truncateString('ROLF M HUSEBY', 18)}}的其他基金

Chimeric CD80-SA as a Novel Cancer Vaccine
嵌合 CD80-SA 作为新型癌症疫苗
  • 批准号:
    6992408
  • 财政年份:
    2005
  • 资助金额:
    $ 42.17万
  • 项目类别:
Chimeric CD80-SA as a Novel Cancer Vaccine
嵌合 CD80-SA 作为新型癌症疫苗
  • 批准号:
    7126430
  • 财政年份:
    2005
  • 资助金额:
    $ 42.17万
  • 项目类别:

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