Consequences of Aging on Immune Response and Transplant Outcome

衰老对免疫反应和移植结果的影响

• 批准号: 8723030
• 负责人: Stefan Gunther Tullius
• 金额: $ 30.6万
• 依托单位: BRIGHAM AND WOMEN'S HOSPITAL
• 依托单位国家: 美国
• 财政年份: 2012
• 资助国家: 美国
• 起止时间: 2012-09-30 至 2017-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8723030
• 关键词: Activities of Daily Living; Acute; Address; Affect; Age; Aging; Alloantigen; Allogenic; Allografting; Antigen-Presenting Cells; Antigens; Beds; C57BL/6 Mouse; CD8B1 gene; CTLA4 gene; CTLA4-Ig; Cell surface; Cells; Cessation of life; Clinical Research; Data; Dendritic Cells; Disease; Down-Regulation; Effector Cell; Elderly; Engraftment; Frequencies; Generations; Graft Rejection; Graft Survival; Heart; Heart Transplantation; IL2RA gene; IL2RB gene; ITGAX gene; Immune; Immune response; Immune system; Immunosuppression; Immunosuppressive Agents; In Vitro; Individual; Inflammatory Response; Interleukin-2; Kidney Transplantation; Link; Modeling; Modification; Molecular; Mus; Nature; Organ; Organ Donor; Organ Transplantation; Outcome; Population; Process; Production; Protocols documentation; Public Health; Publishing; Regulatory T-Lymphocyte; Reporter; Reporting; Research; Role; Signal Pathway; Signal Transduction; Sirolimus; Societies; Solid; Splenocyte; T cell response; T-Cell Proliferation; T-Lymphocyte; TCR Activation; Testing; Therapeutic; Time; Transgenic Mice; Transplant Recipients; Transplantation; Viral Tumor Antigens; age related; aging population; allograft rejection; clinically relevant; cytokine; graft function; heart allograft; immunogenic; in vivo; mTOR Signaling Pathway; novel; novel therapeutic intervention; older patient; prevent; public health relevance; receptor; research study; response; treatment effect

DESCRIPTION (provided by applicant): Older individuals show the highest proportional increase of those being waitlisted or receiving an organ transplant. The increasing need has been compensated, at least in part, by utilizing older donor organs. Aging is associated with significant changes of the immune system, but little is known about underlying mechanisms and the potential impact on immune responses in organ transplantation. Moreover, little is known on how organ age may impact immune responses. We have shown in a large scale clinical study that older renal transplant recipients had less acute rejections and a better (death censored) graft survival. In contrast, engraftment of older organs had been linked with significantly more acute rejections. In a bed-to-bench approach, we have recently reported experimental data showing that advanced donor age was associated with significantly higher frequencies of activated T cells, an intensified T-cell proliferation and alloreactive IFNg production. We have now also established an experimental transplant model that shows a significantly shorter survival of old allografts. Recipient age, in our experimental studies delayed graft rejection and was associated with impaired T cell responses, reduced T-cell proliferation and limited IFNg production. At the same time, we observed a well preserved suppressor function of old alloantigen-specific CD4+CD25+FoxP3+ T cells. Our preliminary experimental data in old recipients have also shown an alteration of the CD8+ TCR signaling machinery that was associated with a down-regulation of CD122. We were also able to show experimentally that immunouppressants have age-specific effects: treatment of old and young recipient mice with rapamycin or CTLA4-Ig, two clinically relevant immunosuppressants that have different mechanisms of action showed age-dependent effects on allograft survival. Rapamycin promoted long-term graft function in old recipients while cardiac allografts in young recipients showed a significantly reduced survival. In contrast, treatment with CTLA4-Ig promoted graft survival in young but not old recipients. In this application, we will dissect mechanisms of age-specific alloimmune responses. In specific aim 1, we will identify whether aging augments the immunogenic capacity of donor dendritic cells (DCs). Moreover, we will define the role of old DCs in allograft rejection that is associated with aging using DTR transgenic mice and identify activating signaling pathway(s). In specific aim 2, we will assess functional changes of CD4+ and CD8+ T cells in old and young mice. Moreover, we will test in-vivo proliferation and conversion of effector T cells into Tregs using Foxp3-GFP reporter transgenic mice. In specific aim 3, we will define age-specific responses to rapamycin and CTLA4-Ig. As our society is embracing an expanding aging population our studies will be of considerable significance and will allow creating effective therapeutic protocols with relevance in and beyond organ transplantation.

描述（由申请人提供）：老年人表明，等待列表或接受器官移植的人比例最高。至少部分通过使用较老的捐赠者器官来补偿增加的需求。衰老与免疫系统的显着变化有关，但是关于潜在机制以及对器官移植中免疫反应的潜在影响知之甚少。此外，关于器官年龄如何影响免疫反应的知之甚少。我们在一项大规模的临床研究中表明，较老的肾移植受者的急性拒绝和更好（死亡）的移植物存活率较低。相比之下，较旧器官的植入与更大的急性拒绝有关。在床到基础的方法中，我们最近报道了实验数据，表明高级供体年龄与激活的T细胞的频率显着较高，T细胞增强和同种异体IFNG产生。现在，我们还建立了一个实验性移植模型，该模型显示出旧同种异体移植物的生存率明显较短。在我们的实验研究中，受体年龄延迟了移植物排斥，并且与T细胞反应受损，T细胞增殖减少和IFNG产生有限有关。同时，我们观察到了旧的同种抗原特异性CD4+CD25+FOXP3+T细胞的保存完好的抑制功能。我们在旧接收者中的初步实验数据还显示了与CD122下调有关的CD8+ TCR信号机械的改变。我们还能够在实验上证明免疫抑制剂具有特异性影响：用雷帕霉素或CTLA4-IG治疗老年人和年轻受体小鼠，两种临床相关的免疫抑制剂具有不同的作用机理，表明作用机制不同，表明年龄依赖于同种异体移植物。雷帕霉素促进了旧接受者的长期移植功能，而年轻接受者的心脏同种异体移植物显示出显着降低的生存率。相比之下，用CTLA4-Ig的治疗促进了年轻但不是老年接受者的移植物生存。在此应用中，我们将剖析特异性同种免疫反应的机制。在特定目标1中，我们将确定衰老是否会增强供体树突状细胞（DC）的免疫原性。此外，我们将定义与使用DTR转基因小鼠衰老相关的同种异体移植排斥中旧DC的作用，并识别激活信号通路。在特定的目标2中，我们将评估老鼠和年轻小鼠中CD4+和CD8+ T细胞的功能变化。此外，我们将使用FOXP3-GFP报告基因转基因小鼠测试效应T细胞中的体内增殖和效应T细胞转化。在特定的目标3中，我们将定义对雷帕霉素和ctla4-ig的特定年龄反应。随着我们的社会拥抱不断增长的人口，我们的研究将具有相当大的意义，并允许在器官移植中和超越器官移植中创建有效的治疗方案。