Donor-recipient mismatch at the SIRPA locus adversely affects kidney allograft outcomes

IF 14.6 1区 医学 Q1 CELL BIOLOGY
Daqiang Zhao, Hehua Dai, Camila Macedo, Steven M. Sanders, Charbel Elias, Andrew J. Friday, Mohamad Zaidan, Amanda L. Williams, Beth D. Elinoff, Martin H. Oberbarnscheidt, Jayne Danska, Adriana Zeevi, Parmjeet Randhawa, Amit D. Tevar, Sundaram Hariharan, David M. Rothstein, Khodor I. Abou-Daya, Aleksandar Senev, Anat R. Tambur, Diana Metes, Olivier Thaunat, Fadi G. Lakkis, Aravind Cherukuri
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Abstract

Donor-recipient mismatches in histocompatibility antigens recognized by lymphoid cells have been demonstrated to adversely affect allograft outcomes. In contrast, it remains unclear whether mismatches sensed by innate myeloid cells have a similar effect. We investigated the consequences of mismatch in the polymorphic gene encoding signal regulatory protein α (SIRPα) on kidney allograft pathology and survival in mice and humans. We found that SIRPα variants elicit monocyte activation by binding to CD47 and that eliminating SIRPα mismatch or recipient CD47 expression prevented chronic allograft pathology in mice receiving major histocompatibility complex (MHC)–mismatched renal allografts. Human genomic analysis identified two haplotype categories, A and B, encoding SIRPα variants with distinct CD47 binding interfaces. In kidney transplant recipients (N = 455), SIRPα mismatch was associated with increased acute rejection and graft fibrosis in the first posttransplant year, and A recipients of B kidneys had reduced long-term graft survival (hazard ratio, 3.2; 95% confidence interval, 1.5 to 6.9; P = 0.002), a finding that was confirmed in an independent validation cohort (N = 258). Moreover, monocytes in these graft recipients had an activated phenotype. The effects of SIRPα mismatch were independent of ancestry, human leukocyte antigen mismatch, donor-specific antibodies, and delayed graft function. Therefore, these data demonstrate that a donor-recipient mismatch that causes innate immune activation is a determinant of kidney transplantation outcomes.
在SIRPA位点供体-受体不匹配会对肾移植结果产生不利影响
淋巴样细胞识别的组织相容性抗原的供体-受体不匹配已被证明对同种异体移植的结果有不利影响。相比之下,尚不清楚先天骨髓细胞感知的错配是否有类似的效果。我们研究了编码信号调节蛋白α (SIRPα)的多态基因错配对小鼠和人类肾移植病理和存活的影响。我们发现SIRPα变异通过与CD47结合引起单核细胞活化,消除SIRPα错配或受体CD47表达可防止接受主要组织相容性复合体(MHC)错配肾移植的小鼠的慢性同种异体移植病理。人类基因组分析确定了两个单倍型类别,A和B,编码具有不同CD47结合界面的SIRPα变体。在肾移植受者(N = 455)中,SIRPα错配与移植后第一年急性排斥反应和移植物纤维化增加有关,A肾B肾受者长期移植存活率降低(风险比,3.2;95%置信区间为1.5 ~ 6.9;P = 0.002),这一发现在一个独立验证队列(N = 258)中得到了证实。此外,这些移植物受体中的单核细胞具有活化表型。SIRPα错配的影响与血统、人白细胞抗原错配、供体特异性抗体和移植物延迟功能无关。因此,这些数据表明,导致先天免疫激活的供体-受体错配是肾移植结果的决定因素。
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来源期刊
Science Translational Medicine
Science Translational Medicine CELL BIOLOGY-MEDICINE, RESEARCH & EXPERIMENTAL
CiteScore
26.70
自引率
1.20%
发文量
309
审稿时长
1.7 months
期刊介绍: Science Translational Medicine is an online journal that focuses on publishing research at the intersection of science, engineering, and medicine. The goal of the journal is to promote human health by providing a platform for researchers from various disciplines to communicate their latest advancements in biomedical, translational, and clinical research. The journal aims to address the slow translation of scientific knowledge into effective treatments and health measures. It publishes articles that fill the knowledge gaps between preclinical research and medical applications, with a focus on accelerating the translation of knowledge into new ways of preventing, diagnosing, and treating human diseases. The scope of Science Translational Medicine includes various areas such as cardiovascular disease, immunology/vaccines, metabolism/diabetes/obesity, neuroscience/neurology/psychiatry, cancer, infectious diseases, policy, behavior, bioengineering, chemical genomics/drug discovery, imaging, applied physical sciences, medical nanotechnology, drug delivery, biomarkers, gene therapy/regenerative medicine, toxicology and pharmacokinetics, data mining, cell culture, animal and human studies, medical informatics, and other interdisciplinary approaches to medicine. The target audience of the journal includes researchers and management in academia, government, and the biotechnology and pharmaceutical industries. It is also relevant to physician scientists, regulators, policy makers, investors, business developers, and funding agencies.
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