Preclinical in vivo assessment of a combination of protein and cell therapies to prevent human islet transplant rejection as a cure for Type 1 diabete

蛋白质和细胞疗法组合预防人类胰岛移植排斥反应作为 1 型糖尿病治疗方法的临床前体内评估

• 批准号: MR/K013165/1
• 负责人: Giovanna Lombardi
• 金额: $ 47.16万
• 依托单位: King's College London
• 依托单位国家: 英国
• 项目类别: Research Grant
• 财政年份: 2013
• 资助国家: 英国
• 起止时间: 2013 至 无数据
• 项目状态: 已结题
• 来源: https://gtr.ukri.org/projects?ref=MR%2FK013165%2F1
• 关键词: Preclinical; vivo; assessment; combination; protein

Type 1 diabetes (T1DM) is an autoimmune disease in which the beta-cells of the pancreas are destroyed by autoreactive lymphocytes and insulin is no longer produced. The only clinically acceptable treatment for T1DM is insulin replacement by daily injection of the hormone. This treatment makes T1DM very difficult to control, with the result that patients are exposed to high blood glucose and risk of diabetic complications and/or intermittent low blood glucose that can cause unconsciousness, fits and even, albeit rarely, death. Transplantation of pancreatic islets became an alternative strategy to whole pancreas transplantation due to the advantage of a relatively non invasive technique and to the low risk of surgical complications. However, transplanted islets are subjected to progressive loss, with most of the patients requiring exogenous insulin within 2 years post-transplant. Therefore, there is an urgent need for improvements in islet transplantation. This project, by establishing a new preclinical animal model, will provide novel insights into the mechanisms of human islet graft rejection in vivo and will offer a perfect platform for the development of new therapies in the prevention of islet graft rejection. We have already demonstrated that: 1. A recombinant cytoprotective protein (APT070) can protect kidney grafts from complement-mediated post-ischaemic damage; 2. In vitro expanded human regulatory T cells (Tregs) can prolong human skin allograft survival in immunodeficient mice reconstituted with PBMC. 3. In a similar model to the one proposed in this project, ex-vivo expanded human Tregs can delay human islet rejection. 4. Complement influences human T cell responses to antigenic stimulation. Indeed APT070 is already in Phase 1 clinical trial in kidney transplantation and adoptive transfer of Tregs has been already applied successfully in bone marrow transplantation to prevent Graft versus Host Disease. We hypothesize that combining Treg injection with pre-treatment of islets with cytoprotective proteins targeting complement activation will successfully induce indefinite survival of transplanted allogeneic islets. To test this hypothesis, we will 1) further refine the humanised mouse model by using immunodeficient mice transgenic for human MHC molecules; 2) study the immune responses (innate and adaptive) to allogeneic islets in vivo; 3) investigate the therapeutic use of Tregs in combination with the cytoprotective therapeutic protein in preventing rejection of human islets.The results from the proposed study will provide new insights into establishing the optimal therapy to achieve indefinite survival of islet cells in the cure of Type I diabetes.

1型糖尿病（T1DM）是一种自身免疫性疾病，其中胰腺的β细胞被自身反应性淋巴细胞破坏，胰岛素不再产生。临床唯一可接受的治疗T1DM是每日注射胰岛素替代激素。这种治疗使得T1DM非常难以控制，其结果是患者暴露于高血糖和糖尿病并发症和/或间歇性低血糖的风险中，这可能导致昏迷，痉挛甚至死亡，尽管很少。胰岛移植由于其相对无创技术和手术并发症风险低的优势而成为替代全胰腺移植的一种策略。然而，移植的胰岛会发生进行性损失，大多数患者在移植后2年内需要外源性胰岛素。因此，胰岛移植技术亟待改进。本项目通过建立一种新的临床前动物模型，将为人类胰岛移植排斥反应的体内机制提供新的见解，并为开发预防胰岛移植排斥反应的新疗法提供完美的平台。我们已经证明了：1。重组细胞保护蛋白（APT070）可以保护肾移植物免受补体介导的缺血后损伤；2. 体外扩增的人调节性T细胞（Tregs）可延长PBMC重组免疫缺陷小鼠同种异体皮肤移植存活时间。3. 在这个项目中提出的一个类似的模型中，体外扩增的人类treg可以延缓人类胰岛排斥反应。4. 补体影响人T细胞对抗原刺激的反应。事实上，APT070已经在肾移植的1期临床试验中，Tregs的过继性转移已经成功应用于骨髓移植，以预防移植物抗宿主病。我们假设Treg注射与靶向补体激活的细胞保护蛋白相结合的胰岛预处理将成功诱导移植的异体胰岛无限期存活。为了验证这一假设，我们将1)通过使用转人MHC分子的免疫缺陷小鼠进一步完善人源化小鼠模型；2)在体内研究同种异体胰岛的免疫反应（先天和适应性）；3)探讨Tregs联合细胞保护治疗蛋白在预防胰岛排斥反应中的治疗作用。该研究的结果将为建立最佳治疗方法提供新的见解，以实现胰岛细胞在1型糖尿病治疗中的无限期存活。

项目成果

APT070 (mirococept), a membrane-localizing C3 convertase inhibitor, attenuates early human islet allograft damage in vitro and in vivo in a humanized mouse model.

• DOI: 10.1111/bph.13388
• 发表时间: 2016-02
• 期刊: British journal of pharmacology
• 影响因子: 7.3
• 作者: Xiao F;Ma L;Zhao M;Smith RA;Huang G;Jones PM;Persaud S;Pingitore A;Dorling A;Lechler R;Lombardi G
• 通讯作者: Lombardi G