Precise treatment of acute antibody-mediated cardiac allograft rejection in rats using C4d-targeted microbubbles loaded with nitric oxide

Tao Liao; Qiaojia Li; Yannan Zhang; Zhe Yang; Zhengyu Huang; Fei Han; Xiaolong Chen; Tinghui Yin; Jie Ren; Qiquan Sun

doi:10.1016/j.healun.2020.02.002

Precise treatment of acute antibody-mediated cardiac allograft rejection in rats using C4d-targeted microbubbles loaded with nitric oxide

J Heart Lung Transplant. 2020 May;39(5):481-490. doi: 10.1016/j.healun.2020.02.002. Epub 2020 Feb 13.

Authors

Tao Liao¹, Qiaojia Li², Yannan Zhang¹, Zhe Yang¹, Zhengyu Huang¹, Fei Han¹, Xiaolong Chen¹, Tinghui Yin², Jie Ren², Qiquan Sun³

Affiliations

¹ Research Institute of Organ Transplantation, the Third Affiliated Hospital of Sun Yat-sen University, Guangzhou, Guangdong, China.
² Department of Medical Ultrasound, the Third Affiliated Hospital of Sun Yat-sen University, Guangzhou, Guangdong, China.
³ Research Institute of Organ Transplantation, the Third Affiliated Hospital of Sun Yat-sen University, Guangzhou, Guangdong, China. Electronic address: sunqiq@mail.sysu.edu.cn.

PMID: 32115364
DOI: 10.1016/j.healun.2020.02.002

Abstract

Background: Antibody-mediated rejection (AMR) constitutes an important cause of cardiac allograft loss; however, all current therapeutic strategies represent systemic applications with unsatisfactory efficacy. Previously, we successfully non-invasively detected C4d, a specific marker for AMR diagnosis, in allografts using C4d-targeted microbubbles (MB_C4d). In this study, we extended this approach by incorporating nitric oxide (NO), as high NO levels manifest immunosuppressive and anti-thrombotic effects.

Methods: We designed novel MB_C4d loaded with NO (NO-MB_C4d). A rat model of AMR was established by pre-sensitization with skin transplantation. Contrast-enhanced ultrasound (CEUS) images were obtained and quantitatively analyzed following NO-MB_C4d injection. Allograft survival and histologic features were analyzed to evaluate the therapeutic effect and underlying mechanism of NO-MB_C4d toward AMR.

Results: We successfully obtained CEUS images following NO-MB_C4d injection and demonstrated that the ultrasound signal intensity of the myocardial area and clearance time of NO-MB_C4d both increased with increased C4d grade, thereby realizing non-invasive diagnosis of AMR. Furthermore, allograft survival was significantly prolonged, and rejection was obviously attenuated following NO-MB_C4d injection through significant suppression of thrombosis and reduction of inflammatory cell infiltrates. Overall, the therapeutic efficacy was significantly improved in the NO-MB_C4d group compared with the control NO-MB group, demonstrating that precise treatment could significantly improve the therapeutic efficacy compared with that afforded by systemic applications.

Conclusions: This study presented a novel tool to provide simultaneous non-invasive diagnosis and precise treatment of AMR using NO-MB_C4d CEUS imaging, which may be expected to provide a better option for recipients with AMR in clinic.

Keywords: C4d; antibody-mediated rejection; contrast-enhanced ultrasound; non-invasive diagnosis; precise treatment.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Allografts
Animals
Biopsy
Complement C4b / therapeutic use*
Disease Models, Animal
Graft Rejection / diagnosis
Graft Rejection / immunology
Graft Rejection / therapy*
Heart Transplantation*
Immunologic Factors / therapeutic use
Isoantibodies / immunology*
Microbubbles
Nitric Oxide / pharmacology*
Rats

Substances

Immunologic Factors
Isoantibodies
Nitric Oxide
Complement C4b