CXCR4 Antagonist Reduced the Incidence of Acute Rejection and Controlled Cardiac Allograft Vasculopathy in a Swine Heart Transplant Model Receiving a Mycophenolate-Based Immunosuppressive Regimen

Background CXCR4 blockade is pursued as an alternative to mesenchymal stem cell (MSC) treatment in transplantation based on our previous report that burixafor, through CXCR4 antagonism, mobilizes immunomodulatory MSCs. Here, we explored the efficacy of combining mycophenolate mofetil (MMF)-based immunosuppressants with repetitive burixafor administration. Methods Swine heterotopic cardiac allograft recipients received MMF and corticosteroids (control, n = 10) combined with burixafor as a 2-dose (burixafor2D, n = 7) or 2-dose plus booster injections (burixafor2D+B, n = 5) regimen. The efficacy endpoints were graft survival, freedom from first acute rejection, and the severity of intimal hyperplasia. Each specimen was sacrificed either at its first graft arrest or after 150 days. Results After 150 days, all specimens in the control group had died, but 28.5% of the burixafor2D group survived, and 60% of the burixafor2D+B group survived (P = 0.0088). Whereas the control group demonstrated acute rejection at a median of 33.5 days, the burixafor2D+B group survived without acute rejection for a median of 136 days (P = 0.0209). Burixafor administration significantly attenuated the incidence rate of acute rejection (P = 0.002) and the severity of intimal hyperplasia (P = 0.0097) at end point relative to the controls. These findings were associated with reduced cell infiltrates in the allografts, and modulation of C-reactive protein profiles in the circulation. Conclusions The augmentation of conventional MMF plus corticosteroids with a CXCR4 antagonist is potentially effective in improving outcomes after heart transplantation in minipigs. Future studies are warranted into optimizing the therapeutic regimens for humans. This is an open-access article distributed under the terms of the Creative Commons Attribution-Non Commercial-No Derivatives License 4.0 (CCBY-NC-ND), where it is permissible to download and share the work provided it is properly cited. The work cannot be changed in any way or used commercially without permission from the journal. chiiminglee@ntu.edu.tw Authorship Participated in research design: Wan-Tseng Hsu, Hsiang-Yiang Jui, Chii-Ming Lee. Participated in the writing of the paper: Wan-Tseng Hsu, Chia-Tung Shun, Kenneth Kun-Yu Wu, Chii-Ming Lee. Participated in the performance of the research: Wan-Tseng Hsu, Cheng-Hsin Lin, Ya-Hsuan Tseng, Chii-Ming Lee. Contributed new reagents: Ming-Chu Hsu. Participated in data analysis: Wan-Tseng Hsu, Ya-Hsuan Tseng. Disclosure: M.C.H is the cofounder and a shareholder of TaiGen Biotechnology Co., Ltd., Taipei, Taiwan. All other authors indicate no potential conflicts of interest. Funding: This study was supported by research grants from National Health Research Institutes (NHRI-CS-102-PP-15, NHRI-CS-103-PP-15, and NHRI-CS-104-PP-15) as well as Ministry of Science and Technology (MOST103-2321-B-002-101). Copyright © 2018 Wolters Kluwer Health, Inc. All rights reserved.

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