PARP-1 inhibitor-AG14361 suppresses acute allograft rejection via stabilizing CD4+FoxP3+ regulatory T cells |
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| Affiliation: | 1. Department of Urology, Shanghai General Hospital, Shanghai Jiao Tong University School of Medicine, 100 Haining Road, Hongkou District, Shanghai, 200080, China;2. Shanghai Institute of Immunology, Shanghai Jiao Tong University School of Medicine, Shanghai, China;3. Shanghai Key Laboratory of Bio-energy Crops, School of Life Science, Shanghai University, Shanghai, China;1. Department of Pain, the First Affiliated Hospital of Fujian Medical University, No. 20 Chazhong Road, Taijiang District, Fuzhou, 350005, Fujian, China;2. Department of Anesthesiology, the First Affiliated Hospital of Fujian Medical University, No. 20 Chazhong Road, Taijiang District, Fuzhou, 350005, Fujian, China;3. Department of Anesthesiology, Quanzhou First Hospital Affiliated to Fujian Medical University, Quanzhou, 352000, Fujian, China;4. Department of Radiation Oncology, the First Affiliated Hospital of Fujian Medical University, No.20 Chazhong Road, Taijiang District, Fuzhou, 350005, Fujian, China;5. Department of Neurosurgery, the First Affiliated Hospital of Fujian Medical University, No.20 Chazhong Road, Taijiang District, Fuzhou, 350005, Fujian, China;1. Section of Immunology and Joint Immunology Program, Guangdong Provincial Academy of Chinese Medical Sciences, Guangzhou, Guangdong, China;2. Section of Nephrology, the Second Affiliated Hospital, Graduate School, Guangzhou University of Chinese Medicine, Guangzhou, Guangdong, China;3. Center for Regenerative and Translational Medicine, Guangdong Provincial Academy of Chinese Medical Sciences, Guangzhou, Guangdong, China;4. Department of Hepatobiliary Surgery, First Affiliated Hospital of Xi’an Jiaotong University, Xi׳an, Shaanxi, China;5. Department of Gastroenterology and Hepatology, Mayo Clinic, Rochester, Minnesota, USA;1. APHP HUPSSD GHU Avicenne, Bobigny, France;2. University Sorbonne Paris Nord, UFR SMBH, Bobigny, France;1. Institute for Inflammation Research, Center for Rheumatology and Spine Disease, Copenhagen University Hospital Rigshospitalet, Copenhagen, Denmark;2. Haematopoietic Cell Transplantation and Primary Immune Deficiency, Department of Paediatric and Adolescent Medicine, Copenhagen University Hospital Rigshospitalet, Copenhagen, Denmark;3. The Tissue Typing Laboratory, Department of Clinical Immunology, Copenhagen University Hospital Rigshospitalet, Copenhagen, Denmark;4. Department of Immunology and Microbiology, University of Copenhagen, Copenhagen, Denmark;5. Bioneer A/S, Hørsholm, Denmark;1. Translational Medicine Research Center, Affiliated Jiangning Hospital, and Liver Transplantation Center, First Affiliated Hospital, Nanjing Medical University, Nanjing 210029, China;2. Key Laboratory of Molecular Virology & Immunology, CAS Center for Excellence in Molecular Cell Science, Unit of Molecular Immunology, Institute Pasteur of Shanghai, University of Chinese Academy of Sciences, Shanghai 200031, China;3. Division of Rheumatology, Penn State Hershey College of Medicine, Hershey, PA 17033, USA |
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| Abstract: | Acute allograft rejection is the most common complication in organ transplantation leading to organ loss. Treg cells play an important role in preventing acute rejection, but they are unstable and easily lose function. Poly(ADP-ribose) polymerase 1(PARP-1) is involved in the differentiation stabilization of Treg cells, it has been suggested that PARP-1 inhibition could prevent acute rejection and prolong allograft survival. This study investigated AG14361 effects on acute allograft rejection. We used a fully MHC-mismatched murine heart transplantation model to compare the effect of PARP-1 inhibitor-AG14361 on alloimmunity to the control. Mice treated with PARP-1 inhibitors showed a longer median survival time of allografts (MS14 compared with the control group, MST was 8 days, and AG14361 was 6 days, P = 0.019). The combination of sirolimus and AG14361 significantly delayed allograft MST (AG14361 + sirolimus for 30 days, sirolimus for 16 days, P = 0.002). AG14361 markedly augmented the number of the CD25+FoxP3+ Treg cells in the graft and periphery. In addition, it could enhance the suppressive function of Treg cells by upregulating the level of CTLA-4, PD-1 and ICOS. In vivo, the Treg/Th17 ratio increased significantly in the AG14351 group compared to the control. In the combination with sirolimus treatment, AG14361 promoted the long-term allograft survival. Our results highlight novel effects of a PARP-1 inhibitor. PARP-1 inhibitor AG14361 may be a promising agent to attenuate acute allograft rejection as it can maintain the number and function of Treg cells in allografts. |
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| Keywords: | Organ transplantation Acute allograft rejection PARP-1 inhibitor AG14361 Regulatory T cells (Tregs) T helper type 17 (Th17) |
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