不同线粒体DNA编码的次要组织相容性抗原的克隆小型猪中，猪白细胞抗原匹配的肾脏同种异体移植后的急性排斥反应。

Acute rejection after swine leukocyte antigen-matched kidney allo-transplantation in cloned miniature pigs with different mitochondrial DNA-encoded minor histocompatibility antigen.

作者信息

Kwak H-H, Park K-M, Teotia P K, Lee G-S, Lee E-S, Hong S-H, Yang S-R, Park S-M, Ahn C, Park C-K, Lee K-W, Woo H-M

机构信息

Stem Cell Institute, Kangwon National University, Chuncheon, South Korea.

出版信息

Transplant Proc. 2013 Jun;45(5):1754-60. doi: 10.1016/j.transproceed.2013.02.103.

DOI:10.1016/j.transproceed.2013.02.103

PMID:23769038

Abstract

INTRODUCTION

Graft rejection remains a major cause of morbidity and mortality following renal transplantation. One of the main determinants of success after renal transplantation is histocompatibility between donor and recipient. Most of the research on this topic has addressed human leukocyte antigen (HLA), but the roles played by minor histocompatibility antigens (mHAgs), such as mitochondrially transmitted antigens, are poorly understood. In this study, we evaluated immune responses induced by minor antigens originating from mitochondrial DNA (mtDNA) in a large animal model.

METHODS

To characterize whole swine leukocyte antigen (SLA) allele in 8 cloned pigs, we performed SLA genotyping for SLA-1, SLA-2, SLA-3, SLA-DQB1, and SLA-DRB1 as well as the hypervariable region 1 (HV1) of mtDNA. Renal transplantation was performed using SLA-matched pigs with different mtDNA as well as SLA-mismatched cloned animals. Cytokine profiling was performed by incubating peripheral leukocytes with cellular components from SLA-matched different mtDNA and SLA-mismatched cells to evaluate mtDNA-mediated immune response.

RESULTS

SLA types were confirmed to be identical, but mtDNA sequences of HV1 varied among cloned pigs. Rejection episodes in the SLA-matched group with different mtDNA were similar to those in the SLA-mismatched group; that is, plasma creatinine and BUN levels were increased and mononuclear cell infiltration was observed in perivascular regions in the matched and SLA-mismatched groups. Furthermore, in vitro studies showed interleukin (IL)-1β expression to be elevated in SLA-matched and SLA-mismatched groups.

CONCLUSION

Cloned pigs are a useful preclinical model to evaluate the immunogenicity of mtDNA encoding minor antigens. The mtDNA originating from nongenomic DNA induced cell-mediated immune rejection after kidney transplantation.

摘要

引言

移植肾排斥反应仍然是肾移植后发病和死亡的主要原因。肾移植成功的主要决定因素之一是供体和受体之间的组织相容性。关于这一主题的大多数研究都集中在人类白细胞抗原（HLA）上，但对次要组织相容性抗原（mHAgs），如线粒体传递抗原所起的作用了解甚少。在本研究中，我们在大型动物模型中评估了源自线粒体DNA（mtDNA）的次要抗原诱导的免疫反应。

方法

为了鉴定8头克隆猪的全猪白细胞抗原（SLA）等位基因，我们对SLA-1、SLA-2、SLA-3、SLA-DQB1和SLA-DRB1以及mtDNA的高变区1（HV1）进行了SLA基因分型。使用具有不同mtDNA的SLA匹配猪以及SLA不匹配的克隆动物进行肾移植。通过将外周血白细胞与来自SLA匹配的不同mtDNA和SLA不匹配细胞的细胞成分孵育来进行细胞因子分析，以评估mtDNA介导的免疫反应。

结果

SLA类型被确认为相同，但HV1的mtDNA序列在克隆猪之间有所不同。具有不同mtDNA的SLA匹配组中的排斥反应与SLA不匹配组中的排斥反应相似；也就是说，血浆肌酐和尿素氮水平升高，并且在匹配组和SLA不匹配组的血管周围区域观察到单核细胞浸润。此外，体外研究表明，SLA匹配组和SLA不匹配组中白细胞介素（IL）-1β的表达均升高。