Role of CD47 in xenograft rejection by macrophages

CD47 在巨噬细胞异种移植排斥中的作用

• 批准号: 8436181
• 负责人: YONG-GUANG YANG
• 金额: $ 34.27万
• 依托单位: COLUMBIA UNIVERSITY HEALTH SCIENCES
• 依托单位国家: 美国
• 财政年份: 2007
• 资助国家: 美国
• 起止时间: 2007-12-01 至 2017-02-28
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8436181
• 关键词: Accounting; Address; Alloantigen; Allogenic; Antibodies; Attenuated; Binding; Biological Assay; CD47 gene; Cardiac; Cells; Clinical; Complement; Data; Dendritic Cells; Dendritic cell activation; Family suidae; Funding; Goals; Graft Rejection; Hematopoietic; Hepatocyte; Human; Immune; Immune Cell Activation; Immune response; Immune system; Immunosuppression; In Vitro; Inbred BALB C Mice; Ligands; Measures; Mediating; Membrane; Memory; Modeling; Molecular; Mus; Natural Immunity; Natural Killer Cells; Organ Donor; PTPNS1 gene; Pathway interactions; Phagocytosis; Play; Population; Regulation; Role; Signal Transduction; Solutions; T cell response; T-Cell Activation; T-Lymphocyte; Testing; Transfusion; Transgenic Organisms; Transplantation; Transplantation Tolerance; Wild Type Mouse; Xenograft procedure; allograft rejection; allotransplant; base; immune activation; improved; insight; macrophage; monocyte; mouse model; prevent; receptor; response; transgene expression

DESCRIPTION (provided by applicant): Xenotransplantation from pigs has the potential to resolve the growing shortage of human organ donors. Because of the extensive molecular incompatibilities between the donor and host, innate immunity plays a much greater role in xenograft rejection than in allograft rejection. CD47 is ubiquitously expressed and serves as a ligand of SIRP?, an inhibitory receptor on macrophages and DCs. During the current funding period, we demonstrated that the lack of cross-species interaction in CD47-SIRP? pathway largely accounts for macrophage-mediated rejection of hematopoietic and non-hematopoietic cellular xenografts. Transplantation of CD47-deficient cells induces rapid innate immune activation in syngeneic wild-type (WT) mice. Furthermore, CD47-SIRP? signal is required to repress recipient CD11hiCD8?- DC activation and induce tolerance after donor-specific transfusion (DST). Based on these and other data presented in the application, we hypothesize that the interaction between donor CD47 and host SIRP? is essential for controlling activation of SIRP?+ macrophages and DCs, and that the absence of this interaction activates host macrophages and DCs, hence stimulating anti-donor T cell responses. Here, we propose 3 specific aims to test our hypothesis. Aim 1 is to elucidate the role of CD47-SIPR? signaling in the regulation of SIRP?+ innate immune cell activation after hepatocyte xenotransplantation. We will transplant CD47 KO mouse hepatocytes into syngeneic WT mice to analyze innate immune cell activation and graft rejection induced solely by CD47 disparity. We will also transplant human CD47 transgenic vs. control pig hepatocytes into humanized mice to determine whether human CD47 expression may inhibit human innate immune responses to pig xenografts. Aim 2 is to determine the role of "missing CD47"-induced innate immune cell activation in T cell xenoresponses after hepatocyte transplantation. We will first address this question in allotransplant models, in which CD47 KO mice will be used to mimic CD47-incompatible xenogeneic donors. We will examine anti-donor T cell responses by in vitro and adoptive T cell transfer assays. We will then investigate the potential of human CD47 expression on pig hepatocytes to attenuate human T cell xenoimmune responses using humanized mice with a functional human immune system. Aim 3 is to determine the mechanisms by which CD47 on donor cells facilitates tolerance induction in DST plus costimulatory blockade-treated recipients. We will identify the DC and macrophage populations that are rapidly activated after CD47-deficient DST and their roles in T cell activation and tolerance induction. We will address these questions in a mouse model of CD47-deficient cardiac allotransplantation, and a pig-to-mouse xenotransplantation model that involves DST from human CD47-transgenic pigs into humanized mice. These studies are expected to provide significant insights into the mechanisms by which CD47 incompatibility activates innate and adaptive xenoimmune responses, and the potential of using human CD47 transgenic pigs as donors to facilitate xenotolerance induction and xenograft survival.

描述（由申请人提供）：猪的异种移植有可能解决人体器官捐献者日益增长的短缺。由于供体和宿主之间的分子不相容性，先天免疫在异种移植排斥中起着比同种异体移植排斥的作用要大得多。 CD47是普遍表达的，并用作SIRP的配体？，巨噬细胞和DC上的抑制受体。在当前的资金期间，我们证明了CD47-SIRP缺乏跨物种相互作用？途径在很大程度上说明了巨噬细胞介导的对造血和非造血性细胞异种移植的排斥。 CD47缺陷细胞的移植可诱导合成性野生型（WT）小鼠中的先天性免疫激活。此外，CD47-SIRP？抑制受体CD11HICD8需要信号？ - DC激活并在供体特异性输血（DST）后诱导公差。基于应用程序中提出的这些和其他数据，我们假设供体CD47和主机SIRP之间的相互作用？对于控制SIRP？+巨噬细胞和DC的激活至关重要，并且缺乏这种相互作用会激活宿主巨噬细胞和DC，从而刺激抗抑制T细胞反应。在这里，我们提出了3个特定旨在检验我们的假设的特定旨在。目标1是阐明CD47-SIPR的作用？肝脏异种移植后SIRP？+先天免疫细胞活化的信号传导。我们将将CD47 KO小鼠肝细胞移植到同步WT小鼠中，以分析仅由CD47差异引起的先天免疫细胞激活和移植排斥。我们还将移植人CD47转基因与对照猪肝细胞中的人源化小鼠，以确定人CD47表达是否可以抑制人类先天免疫对猪异种移植的反应。 AIM 2是确定“缺失CD47”诱导的肝细胞移植后T细胞Xenorespons中先天免疫细胞活化的作用。我们将首先在同种酶模型中解决这个问题，其中CD47 KO小鼠将用于模仿CD47不合时宜的异构供体。我们将通过体外和产物T细胞转移测定法检查抗抑制T细胞反应。然后，我们将研究人类CD47表达在猪肝细胞上使用具有功能性人体免疫系统的人源化小鼠来减轻人T细胞异种免疫性反应的潜力。 AIM 3是确定供体细胞上CD47促进DST Plus contimulation Blockade封锁处理的接受者的耐受性诱导的机制。我们将确定在CD47缺陷DST及其在T细胞激活和耐受性诱导中的作用后迅速激活的DC和巨噬细胞种群。我们将在CD47缺陷心脏同倍移植的小鼠模型中解决这些问题，以及涉及人类CD47-转基因猪的DST的猪到小鼠的异种移植模型。预计这些研究将为CD47不兼容激活先天和适应性异种免疫性反应的机制提供重要的见解，以及使用人CD47转基因猪作为供体促进异耐耐耐诱导和异种移植物存活的潜力。