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: 8850764
• 负责人: Stefan Gunther Tullius
• 金额: $ 29.74万
• 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 2016-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8850764
• 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; Health; 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; 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）：在候补名单或接受器官移植的人群中，老年人的比例增幅最高。日益增长的需求至少部分是通过利用较旧的供体器官得到补偿的。衰老与免疫系统的显着变化有关，但人们对器官移植中免疫反应的潜在机制及其潜在影响知之甚少。此外，人们对器官年龄如何影响免疫反应知之甚少。我们在一项大规模临床研究中表明，老年肾移植受者的急性排斥反应较少，移植物存活率较高（死亡审查）。相比之下，较旧器官的移植与更严重的排斥反应有关。在从床到台的方法中，我们最近报告的实验数据表明，高龄供体年龄与活化 T 细胞频率显着升高、T 细胞增殖增强和同种异体 IFNg 产生相关。我们现在还建立了一个实验性移植模型，该模型显示旧同种异体移植物的存活率显着缩短。在我们的实验研究中，受者年龄会延迟移植物排斥反应，并与 T 细胞反应受损、T 细胞增殖减少和 IFNg 产生有限有关。同时，我们观察到旧同种异体抗原特异性 CD4+CD25+FoxP3+ T 细胞保存完好的抑制功能。我们在老年接受者中的初步实验数据还显示，CD8+ TCR 信号机制的改变与 CD122 的下调相关。我们还能够通过实验证明免疫抑制剂具有年龄特异性效应：用雷帕霉素或 CTLA4-Ig 治疗老年和年轻受体小鼠，这两种具有不同作用机制的临床相关免疫抑制剂对同种异体移植物的存活表现出年龄依赖性效应。雷帕霉素促进老年受者的长期移植功能，而年轻受者的同种异体心脏移植物的存活率显着降低。相比之下，CTLA4-Ig 治疗可促进年轻受者而非老年受者的移植物存活。在此应用中，我们将剖析年龄特异性同种免疫反应的机制。在具体目标 1 中，我们将确定衰老是否会增强供体树突状细胞 (DC) 的免疫原性能力。此外，我们将使用 DTR 转基因小鼠来定义老树突状细胞在与衰老相关的同种异体移植排斥中的作用，并确定激活的信号通路。在具体目标 2 中，我们将评估老年和年轻小鼠 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体内增殖和效应 T 细胞向 Tregs 的转化。在具体目标 3 中，我们将定义对雷帕霉素和 CTLA4-Ig 的年龄特异性反应。随着我们的社会正在接受不断扩大的人口老龄化，我们的研究将具有相当大的意义，并将有助于制定与器官移植内外相关的有效治疗方案。