Pig to Non-Human Primate Islet Xenografts

猪到非人类灵长类动物胰岛异种移植

基本信息

批准号：
7687594
负责人：
Bernhard Josef Hering
金额：
--
依托单位：
UNIVERSITY OF MINNESOTA
依托单位国家：
美国
项目类别：
财政年份：
2005
资助国家：
美国
起止时间：
2005-07-12 至 2011-06-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/7687594
关键词：
Adult Adverse effects Alabama Allogenic Anatomic Sites Antibodies Cells Chronic Clinical Collaborations Core Facility Data Development Diabetes Mellitus Disease Endothelial Cells Engineering Family suidae Farming environment Galactose Gene Transfer Goals Human Immune Immune response Immunobiology Immunologic Tests Immunosuppression Immunosuppressive Agents Immunotherapeutic agent Immunotoxins Infiltration Insulin Insulin-Dependent Diabetes Mellitus Islets of Langerhans Transplantation Kindling (Neurology)Liver Minnesota Modeling Outcome Pancreas Patients Pharmaceutical Preparations Proteins Protocols documentation Public Health Reporting Research Research Personnel Research Project Grants Risk Safety Site Source Supplementation Survivors T-Lymphocyte Technology Therapeutic Therapeutic immunosuppression Translations Transplantation Universities base comparative efficacy data sharing design diabetes mellitus therapy diabetic experience functional loss innovation interest intrahepatic islet islet allograft islet xenograft macrophage multidisciplinary nonhuman primate novel novel strategies optimism pre-clinical prevent programs research study success

项目摘要

DESCRIPTION: Recent clinical reports of allogeneic human islet transplantation provide proof of principle that cell-based diabetes therapy can reverse the course of diabetes mellitus. As demand for islet transplantation increases the human islet donor shortage precludes widespread application. Xenogeneic porcine islets could provide a limitless source of donor cells, if safe and effective protocols are crafted to promote long term islet xenograft survival. The rational design and development of such protocols requires greater understanding of the immunobiology of anti-pig islet immune responses in a preclinical nonhuman primate (NHP) model close to humans. The proposed research program brings together a group of collaborating investigators, combining diverse scientific interests and backgrounds in an endeavor to develop innovative therapeutic approaches for promoting long term pig-to-NHP islet xenograft (XPITx) acceptance without lifelong immunosuppressive therapy. Furthermore, the projects and supporting core facilities are unified in a multidisciplinary effort to elucidate underlying mechanisms related to long term XPITx acceptance and acquired tolerance in diabetic NHP. The program will be centered at the University of Alabama at Birmingham with 2 research projects and 1 administrative core, while the University of Minnesota is the consortium partner with 1 research project and 2 scientific cores. Project 1 will examine the efficacy of tolerance induction to XPITx in diabetic NHP without chronic therapy. The approach will apply a brief (2 wk) tolerance induction protocol that has induced long term allogeneic islet tolerance in NHP. Local and systemic immune adaptations and XPITx outcome will be examined in two anatomic sites, the liver and omental pouch (OP), wherein supplemental immunomodulatory molecules will be delivered. Project 2 will endeavor to engineer the NHP OP to enhance revascularization of the pig islets and to optimize local delivery of immunoregulatory proteins into the islet milieu, including gene transfer using transposon technology in collaboration with Core C. Project 3 will develop low-risk immunotherapeutic strategies to prevent XPITx rejection in liver and OP sites in diabetic NHP, by examining a novel protocol with triple costimulatory blockade. Project 3 will also compare the efficacy and safety of systemic vs. local immunosuppression in the OP XPITx site. Close interactions and data sharing among the projects will accelerate advances in basic understanding and success of NHP XPITx. PROJECT 1: A New Approach to Tolerance in Islet Xenografts (Thomas, J.) DESCRIPTION (provided by applicant) Diabetes mellitus (DM) is a leading public health concern, with over 1 million Type 1 DM patients in the USA. The Edmonton Study showed that intrahepatic pancreas islet transplantation can reverse DM, restoring euglycemia. At present, gradual loss of functional islet mass and a requirement for multiple transplants limit widespread application. With the critical shortage of human donors, there is a need for xenogeneic islets. Porcine islets are appealing, since pig insulin is well tolerated in humans, and pigs are adapted to large scale domestic farming. Unlike normal pig endothelial cells that express the galactose a(1,3) galactose (aGal), to which humans and old world nonhuman primates (NHP) have natural antibodies, adult pig islets express exceptionally low levels of aGal and are not subject to hyperacute rejection. Recent findings from Dr. Hering, showing long term survival of pig-to-NHP islet transplant (XPITx) under chronic immunosuppressive therapy, kindle optimism for clinical translation. The importance of tolerance induction to eliminate lifelong immunosuppressive therapy cannot be over-emphasized, since side effects of this therapy can generate problems as deleterious as the original disease. The goal of the proposed experiments is to develop new approaches that facilitate safe and effective immunosuppression to induce tolerance of pig-to-NHP XPITx, without need for chronic immunosuppressive therapy. The studies will build on our previous experience gained in NHP tolerance, using a strategy of brief anti-CD3 immunotoxin and 15-deoxyspegualin treatment that has yielded NHP islet allograft survivors, drug-free and euglycemic for >5 years post-transplant. This will involve intense immunological testing of the mechanisms involved in the; outcome of pig-to-NHP XPITx: The tolerance induction protocol will be modified to counter the rigorous immune response to discordant XPITx, and examined in both intrahepatic (IH) and omental pouch (OP) sites. Since there is no precedent for NHP xenotolerance, the data will guide the design and implementation of strategic refinements to achieve XPITx acceptance. Accordingly, the aims of the proposed experiments are to: (1) Compare the outcome of pig-to-NHP XPITx in IH vs. OP sites using brief systemic immunosuppression that targets T cells and DC, shown to promote stable tolerance to islet allografts in diabetic NHP; (2) Examine a hypothesis that long term acceptance of XPITx in the OP can be achieved following supplementation of the above tolerance protocol with local immunosuppression. We will examine supplemental local vs. systemic immunosuppression with IL- 10 and anti-LFA-1 to minimize macrophage infiltration; (3) Define the immune mechanisms governing XPITx acceptance or rejection in NHP recipients treated under the immunosuppressive conditions described in the previous aims. These studies are unique and will generate new data on pig-to-NHP XPITx immunobiology and the immune mechanisms influencing development of pig XPITx tolerance.

描述：同种异体胰岛移植的最新临床报道提供了原理证明，基于细胞的糖尿病治疗可以逆转糖尿病的进程。随着对胰岛移植的需求，人类胰岛供体短缺无法广泛应用。如果制定安全有效的方案以促进长期的胰岛异种移植物存活，则异种猪胰岛可以提供无限的供体细胞来源。此类方案的理性设计和开发需要对临床前非人类灵长类动物（NHP）模型中抗猪胰岛免疫反应的免疫生物学有更深入的了解。拟议的研究计划汇集了一群合作的研究人员，将多样化的科学利益和背景结合在一起，以开发创新的治疗方法，用于促进长期猪至NHP Islet iSlet Xenograft（XPITX）接受（XPITX）接受，而无需终身免疫抑制治疗。此外，在多学科的努力中统一了项目和支持核心设施，以阐明与长期XPITX接受性相关的基本机制，并在糖尿病NHP中获得了耐受性。该计划将以2个研究项目和1个行政核心为以阿拉巴马大学为中心，而明尼苏达大学是1个研究项目和2个科学核心的财团合作伙伴。项目1将检查XPITX耐受性在没有慢性治疗的情况下诱导XPITX的疗效。该方法将采用简短的（2周）公差诱导方案，该方案已诱导NHP中的长期同种异体胰岛耐受性。将在两个解剖部位（肝脏和膜袋（OP））中检查局部和全身免疫适应和XPITX结果，其中将传递补充免疫调节分子。项目2将努力设计NHP OP来增强猪胰岛的血运重建，并优化将免疫调节蛋白的本地输送到胰岛环境中，包括使用Transposon技术与COREC合作进行基因转移。项目3将与Project 3合作，将开发低风险的免疫疗法策略，以防止Xpitx在Liver和Op aption in live and liver and apoction a liver and apoction a live and apotion n a-live sere n ap nep nep nep nep nep nep nep nhne nh nh nh nh nh nh nh nh nh nh nh nh nh nhe co虫封锁。项目3还将比较OP XPITX站点中系统性与局部免疫抑制的功效和安全性。项目之间的紧密互动和数据共享将加速NHP XPITX的基本理解和成功的进步。项目1：胰岛异种移植物中一种新的容忍方法（Thomas，J。）描述（由申请人提供）糖尿病（DM）是领先的公共卫生问题，在美国有超过100万型DM患者。埃德蒙顿（Edmonton）的研究表明，肝内胰腺胰岛移植可以逆转DM，恢复尤格血糖。目前，功能性胰岛质量的逐渐损失和多次移植的要求限制了广泛的应用。由于人类捐助者的严重短缺，需要异构胰岛。猪胰岛具有吸引力，因为猪胰岛素在人类中的耐受性很好，并且猪适应了大规模的家庭农业。与表达半乳糖A（1,3）半乳糖（AGAL）的正常猪内皮细胞不同，人类和旧世界非人类灵长类动物（NHP）具有天然抗体，成年猪胰岛表达了异常低的AGAL水平，并且不受超急性排斥的抑制。 Hering博士的最新发现显示，在慢性免疫抑制疗法下，猪至NHP胰岛移植（XPITX）的长期存活，对临床翻译的Kindle乐观。耐受性诱导消除终身免疫抑制疗法的重要性不能过分强调，因为这种疗法的副作用会产生像原始疾病一样有害的问题。拟议的实验的目的是开发新方法，以促进安全有效的免疫抑制，以诱导猪至NHP XPITX的耐受性，而无需慢性免疫抑制治疗。这项研究将基于我们以前在NHP公差中获得的经验，使用短暂的抗CD3免疫毒素和15-脱氧蛋白治疗的策略，该策略在转移后替代了5年的NHP胰岛同种异体移植幸存者，无药物和euglecemic> 5年。这将涉及对涉及的机制进行激烈的免疫测试；猪至NHP XPITX的结果：将修改耐受性诱导方案，以应对对不一致XpITX的严格免疫反应，并在肝内（IH）和Omental Pouch（OP）位点进行检查。由于没有NHP Xenotolerance的先例，因此数据将指导战略改进以实现XPITX接受的设计和实施。因此，提出的实验的目的是：（1）使用靶向T细胞和DC的简短系统性免疫抑制在IH与OP位点的PIG-to-NHP XPITX的结果进行比较，该结果靶向T细胞和DC，显示出可促进糖尿病NHP中胰岛同种异体移植物的稳定耐受性；（2）检查一个假设，即在补充上述耐受性方案并用局部免疫抑制补充上述耐受方案后，可以长期接受XPITX。我们将使用IL-10和抗LFA-1检查补充局部与全身免疫抑制，以最大程度地减少巨噬细胞的渗透；（3）定义在先前目标中描述的免疫抑制条件下治疗的NHP接受者中管理XPITX接受或排斥反应的免疫机制。这些研究是独一无二的，将生成有关猪至NHP XPITX免疫生物学的新数据以及影响PIG XPITX耐受性发展的免疫机制。

项目成果

期刊论文数量（6）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

Rapid quantitative assessment of the pig pancreas biopsy predicts islet yield.

对猪胰腺活检的快速定量评估可预测胰岛产量。

DOI：
10.1016/j.transproceed.2010.05.113
发表时间：
2010
期刊：
Transplantation proceedings
影响因子：
0.9
作者：
Anazawa,T;Balamurugan,AN;Matsumoto,S;Lafreniere,SA;O'Brien,TD;Sutherland,DER;Hering,BJ
通讯作者：
Hering,BJ

What strain of pig should be used?

DOI：
10.1111/j.1399-3089.2008.00456.x
发表时间：
2008-04-01
期刊：
XENOTRANSPLANTATION
影响因子：
3.9
作者：
Prabhakaran, Sangeetha;Hering, Bernhard J.
通讯作者：
Hering, Bernhard J.

Serum cytokine profiles in healthy nonhuman primates are blunted by sedation and demonstrate sexual dimorphism as detected by a validated multiplex immunoassay.

DOI：
10.1038/s41598-021-81953-7
发表时间：
2021-01-27
期刊：
Scientific reports
影响因子：
4.6
作者：
Hocum Stone L;Oppler SH;Nugent JL;Gresch S;Hering BJ;Murtaugh MP;Hegstad-Davies RL;Ramachandran S;Graham ML
通讯作者：
Graham ML

Clinically available immunosuppression averts rejection but not systemic inflammation after porcine islet xenotransplant in cynomolgus macaques.