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immunosuppression for in vivo research： state-of-the-at protocols and experimental approaches

Cellular & Molecular Immunology 2017年第2期14卷 146-179页

作者： Rita Diehl Fabienne Ferrara Claudia Müller Antje Y Dreyer Damian D McLeod Stephan Fricke Johannes Boltze Fraunhofer-lnstitute for Cell Therapy and Immunology Leipzig 04103 Germany Institute of Vegetative Physiology Charite University Medicine and Center for Cardiovascular Research Berlin 10115 Germany University of Newcastle Callaghan NSW 2308 Australia Fraunhofer Research Institution for Marine Biotechnolegy and Institute for Medical and Marine Bietechnolegy University of LObeck LObeck 23562 Germany These authors contributed equally to this work

Almost every experimental treatment strategy using non-autologous cell, tissue or organ transplantation is tested in small and large animal models before clinical translation. Because these strategies require immunosuppression in most cases, immunosuppressive protocols are a key element in transplantation experiments. However, standard immunosuppressive protocols are often applied without detailed knowledge regarding their efficacy within the particular experimental setting and in the chosen model species. Optimization of such protocols is pertinent to the translation of experimental results to human patients and thus warrants further investigation. This review summarizes current knowledge regarding immunosuppressive drug classes as well as their dosages and application regimens with consideration of species-specific drug metabolization and side effects. It also summarizes contemporary knowledge of novel immunomodulatory strategies, such as the use of mesenchymal stem cells or antibodies. Thus, this review is intended to serve as a state-of-the-art compendium for researchers to refine applied experimental immunosuppression and immunomodulation strategies to enhance the predictive value of preclinical transplantation studies.

关键词： animal models immunomodulation immunosuppression transplantation translational research

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Expert consensus on the monitoring and treatment of sepsis-induced immunosuppression

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Military Medical Research 2023年第3期10卷 281-298页

作者： Fei Pei Ren‑Qi Yao Chao Ren Soheyl Bahrami Timothy RBilliar Irshad HChaudry De‑Chang Chen Xu‑Lin Chen Na Cui Xiang‑Ming Fang Yan Kang Wei‑Qin Li Wen‑Xiong Li Hua‑Ping Liang Hong‑Yuan Lin Ke‑Xuan Liu Ben Lu Zhong‑Qiu Lu Marc Maegele Tian‑Qing Peng You Shang Lei Su Bing‑Wei Sun Chang‑Song Wang Jian Wang Jiang‑Huai Wang Ping Wang Jian‑Feng Xie Li‑Xin Xie Li‑Na Zhang Basilia Zingarelli Xiang‑Dong Guan Jian‑Feng Wu Yong‑Ming Yao Department of Critical Care Medicine the First Affiliated Hospital of Sun Yat-Sen University58 Zhongshan Er RoadYuexiu DistrictGuangzhou 510080GuangdongChina Translational Medicine Research Center Medical Innovation Research Division and Fourth Medical Center of the Chinese PLA General Hospital28 Fuxing RoadHaidian DistrictBeijing 100853China Department of Burn Surgery the First Affiliated Hospital of Naval Medical UniversityShanghai 200433China Ludwig-Boltzmann Institute for Experimental and Clinical Traumatology 1200 ViennaAustria Department of Surgery University of Pittsburgh Medical CenterPittsburghPA 15213USA Center for Surgical Research and Department of Surgery University of Alabama at BirminghamBirminghamAL 35294USA Department of Critical Care Medicine Ruijin HospitalShanghai Jiaotong UniversityShanghai 200025China Department of Burns the First Affiliated Hospital of Anhui Medical UniversityHefei 230022China Department of Critical Care Medicine Peking Union Medical College HospitalChinese Academy of Medical Science and Peking Union Medical CollegeBeijing 100730China Department of Anesthesiology the First Affiliated HospitalZhejiang University School of MedicineHangzhou 31003China Department of Critical Care Medicine West China Hospital of Sichuan UniversityChengdu 610041China Department of Critical Care Medicine General Hospital of Eastern Theater Command of Chinese PLANanjing 210002China Department of Surgical Intensive Critical Unit Beijing Chao‑Yang HospitalCapital Medical UniversityBeijing 100020China State Key Laboratory of Trauma Burns and Combined InjuryResearch Institute of SurgeryDaping HospitalArmy Medical UniversityChongqing 400042China Department of Critical Care Medicine Fourth Medical Center of the Chinese PLA General HospitalBeijing 100048China Department of Anesthesiology Nanfang HospitalSouthern Medical UniversityGuangzhou 510515China Department of Critical Care Medicine and Hematology the Third Xiangya HospitalCentral South UniversityChangs

Emerged evidence has indicated that immunosuppression is involved in the occurrence and development of sepsis.To provide clinical practice recommendations on the immune function in sepsis,an expert consensus focusing on the monitoring and treatment of sepsis-induced immunosuppression was developed.Literature related to the immune monitoring and treatment of sepsis were retrieved from PubMed,Web of Science,and Chinese National Knowledge Infrastructure to design items and expert opinions were collected through an online questionnaire.Then,the Delphi method was used to form consensus opinions,and RAND appropriateness method was developed to provide consistency evaluation and recommendation levels for consensus opinions.This consensus achieved satisfactory results through two rounds of questionnaire survey,with 2 statements rated as perfect consistency,13 as very good consistency,and 9 as good consistency.After summarizing the results,a total of 14 strong recommended opinions,8 weak recommended opinions and 2 non-recommended opinions were produced.Finally,a face-to-face discussion of the consensus opinions was performed through an online meeting,and all judges unanimously agreed on the content of this consensus.In summary,this expert consensus provides a preliminary guidance for the monitoring and treatment of immunosuppression in patients with sepsis.

关键词： Sepsis Immune function monitoring Immunomodulatory therapy immunosuppression

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Sepsis-induced immunosuppression:mechanisms,diagnosis and current treatment options

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Military Medical Research 2023年第2期10卷 242-261页

作者： Di Liu Si-Yuan Huang Jian-Hui Sun Hua-Cai Zhang Qing-Li Cai Chu Gao Li Li Ju Cao Fang Xu Yong Zhou Cha-Xiang Guan Sheng-Wei Jin Jin Deng Xiang-Ming Fang Jian-Xin Jiang Ling Zeng Department of Trauma Medical Center Daping HospitalState Key Laboratory of TraumaBurns and Combined InjuryArmy Medical UniversityChongqing 400042China Department of Respiratory Disease Daping HospitalArmy Medical UniversityChongqing 400042China Department of Laboratory Medicine the First Affiliated Hospital of Chongqing Medical UniversityChongqing 400016China Department of Critical Care Medicine the First Affiliated Hospital of Chongqing Medical University400016 ChongqingChina Department of Physiology School of Basic Medicine ScienceCentral South UniversityChangsha 410078China Department of Anesthesia and Critical Care the Second Affiliated Hospital and Yuying Children’s Hospital of Wenzhou Medical UniversityZhejiang 325027 WenzhouChina Department of Emergency the Affiliated Hospital of Guizhou Medical UniversityGuizhou Medical University550001 GuiyangChina Department of Anesthesiology the First Affiliated HospitalZhejiang University School of MedicineHangzhou 310052China.

Sepsis is a common complication of combat injuries and trauma,and is defined as a life-threatening organ dysfunction caused by a dysregulated host response to infection.It is also one of the significant causes of death and increased health care costs in modern intensive care units.The use of antibiotics,fluid resuscitation,and organ support therapy have limited prognostic impact in patients with sepsis.Although its pathophysiology remains elusive,immunosuppression is now recognized as one of the major causes of septic death.Sepsis-induced immunosuppression is resulted from disruption of immune homeostasis.It is characterized by the release of antiinflammatory cytokines,abnormal death of immune effector cells,hyperproliferation of immune suppressor cells,and expression of immune checkpoints.By targeting immunosuppression,especially with immune checkpoint inhibitors,preclinical studies have demonstrated the reversal of immunocyte dysfunctions and established host resistance.Here,we comprehensively discuss recent findings on the mechanisms,regulation and biomarkers of sepsis-induced immunosuppression and highlight their implications for developing effective strategies to treat patients with septic shock.

关键词： Sepsis immunosuppression Immune monitoring Immunomodulatory therapy

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Gypenosides ameliorate morphine-induced immunosuppression with an increased proportion of thymic T lymphocyte subsets and are involved in the regulation of the cAMP-CREM/CREB-IL-2 pathway

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Genes & Diseases 2024年第3期11卷 120-123页

作者： Hui Wang Zhonghao Li Qisheng Wang Weixin Lin Ziting Zhou Xinru Mu Yongwei Jiang Shengfeng Lu Shaodong Chen Zhigang Lu Jiangsu Collaborative Innovation Center of Traditional Chinese Medicine in Prevention and Treatment of Tumor Nanjing University of Chinese MedicineNanjingJiangsu 210023China Key Laboratory of Acupuncture and Medicine Research of Ministry of Education Nanjing University of Chinese MedicineNanjingJiangsu 210023China College of Pharmacy Nanjing University of Chinese MedicineNanjingJiangsu 210023China School of Medicine Xiamen UniversityXiamenFujian 361102China

Opioid abuse can suppress the lymphatic system function,and produce severe immunosuppression that poses a significant risk of opportunistic infections such as methicillinresistant Staphylococcus aureus(MRSA)pneumonia.^(1,2)Gypenosides(Gps)are the most important immunomodulator components in the Chinese herbal medicine Gynostemma pentaphyllum.

关键词： herbal Gypenosides immunosuppression

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Metabolic reprogramming in the immunosuppression of tumor-associated macrophages

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Chinese Medical Journal 2022年第20期135卷 2405-2416页

作者： Ying Wang Dan Wang Li Yang Yi Zhang Biotherapy Center and Cancer Center The First Affiliated Hospital of Zhengzhou UniversityZhengzhouHenan 450052China School of Life Sciences Zhengzhou UniversityZhengzhouHenan 450001China Henan Key Laboratory for Tumor Immunology and Biotherapy ZhengzhouHenan 450052China State Key Laboratory of Esophageal Cancer Prevention&Treatment Zhengzhou UniversityZhengzhouHenan 450052China

Tumor-associated macrophages(TAMs)are an essential proportion of tumor-infiltrating immune cells in the tumor microenvironment(TME)and have immunosuppressive functions.The high plasticity and corresponding phenotypic transformation of TAMs facilitate oncogenesis and progression,and suppress antineoplastic responses.Due to the uncontrolled proliferation of tumor cells,metabolism homeostasis is regulated,leading to a series of alterations in the metabolite profiles in the TME,which have a commensurate influence on immune cells.Metabolic reprogramming of the TME has a profound impact on the polarization and function of TAMs,and can alter their metabolic profiles.TAMs undergo a series of metabolic reprogramming processes,involving glucose,lipid,and amino acid metabolism,and other metabolic pathways,which terminally promote the development of the immunosuppressive phenotype.TAMs express a pro-tumor phenotype by increasing glycolysis,fatty acid oxidation,cholesterol efflux,and arginine,tryptophan,glutamate,and glutamine metabolism.Previous studies on the metabolism of TAMs demonstrated that metabolic reprogramming has intimate crosstalk with anti-tumor or pro-tumor phenotypes and is crucial for the function of TAMs themselves.Targeting metabolism-related pathways is emerging as a promising therapeutic modality because of the massive metabolic remodeling that occurs in malignant cells and TAMs.Evidence reveals that the efficacy of immune checkpoint inhibitors is improved when combined with therapeutic strategies targeting metabolism-related pathways.In-depth research on metabolic reprogramming and potential therapeutic targets provides more options for anti-tumor treatment and creates new directions for the development of new immunotherapy methods.In this review,we elucidate the metabolic reprogramming of TAMs and explore how they sustain immunosuppressive phenotypes to provide a perspective for potential metabolic therapies.

关键词： Immune checkpoint inhibitors immunosuppression Metabolism Tumor-associated macrophages Tumor microenvironment

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De novo malignancies after liver transplantation: The effect of immunosuppression-personal data and review of literature

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World Journal of Gastroenterology 2019年第35期25卷 5356-5375页

作者： Tommaso Maria Manzia Roberta Angelico Carlo Gazia Ilaria Lenci Martina Milana Oludamilola T Ademoyero Domiziana Pedini Luca Toti Marco Spada Giuseppe Tisone Leonardo Baiocchi HPB and Transplant Unit Department of Surgery University of Rome Tor Vergata Rome 00133 Italy Division of Abdominal Transplantation and HPB Surgery Bambino Gesù Children's Hospital IRCCS Rome 00165 Italy Wake Forest Institute for Regenerative Medicine Winston-Salem NC 27101 United States Hepatology and Liver Transplant Unit University of Tor Vergata Rome 00133 Italy

BACKGROUND immunosuppression has undoubtedly raised the overall positive outcomes in the post-operative management of solid organ transplantation. However, long-term exposure to immunosuppression is associated with critical systemic morbidities. De novo malignancies following orthotopic liver transplants (OLTs) are a serious threat in pediatric and adult transplant individuals. Data from different experiences were reported and compared to assess the connection between immunosuppression and de novo malignancies in liver transplant patients. AIM To study the role of immunosuppression on the incidence of de novo malignancies in liver transplant recipients. METHODS A systematic literature examination about de novo malignancies and immunosuppression weaning in adult and pediatric OLT recipients was described in the present review. Worldwide data were collected from highly qualified institutions performing OLTs. Patient follow-up, immunosuppression discontinuation and incidence of de novo malignancies were reported. Likewise, the review assesses the differences in adult and pediatric recipients by describing the adopted immunosuppression regimens and the different type of diagnosed solid and blood malignancy.RESULTS Emerging evidence suggests that the liver is an immunologically privileged organ able to support immunosuppression discontinuation in carefully selected recipients. Malignancies are often detected in liver transplant patients undergoing daily immunosuppression regimens. Post-transplant lymphoproliferative diseases and skin tumors are the most detected de novo malignancies in the pediatric and adult OLT population, respectively. To date, immunosuppression withdrawal has been achieved in up to 40% and 60% of well-selected adult and pediatric recipients, respectively. In both populations, a clear benefit of immunosuppression weaning protocols on de novo malignancies is difficult to ascertain because data have not been specified in most of the clinical experiences. CONCLUSION The selected populations of toleran

关键词： Pediatric liver transplant immunosuppression weaning Clinical operational tolerance Adult liver transplant Graft rejection Immune system De novo malignancies immunosuppression minimization Cancer

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T-cell Co-inhibitory Molecules in Sepsis-induced immunosuppression： From Bench to Bedside

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Chinese Medical Journal 2017年第10期130卷 1249-1252页

作者： Jian-Feng Xie Hai-Bo Qiu Yi Yang Department of Critical Care Medicine Nanjing Zhongda Hospital School of Medicine Southeast University Nanjing Jiangsu 210009 China

Sepsis, which is defined as life-threatening organ dysfunction caused by a dysregulated host response to infection, is a leading cause of death in the Intensive Care Unit （ICU） Epidemiological studies have shown tha... 详细信息

关键词： Co-inhibitory Molecules immunosuppression Sepsis T-cell

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Mechanisms of myeloid-derived suppressor cell-mediated immunosuppression in colorectal cancer and related therapies

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World Journal of Gastrointestinal Oncology 2024年第5期16卷 1690-1704页

作者： Shu-Chang Nie Yan-Hua Jing Lu Lu Si-Si Ren Guang Ji Han-Chen Xu Institute of Digestive Diseases Longhua HospitalChina-Canada Center of Research for Digestive DiseasesShanghai University of Traditional Chinese MedicineShanghai 200032China Shanghai Frontiers Science Center of Disease and Syndrome Biology of Inflammatory Cancer Transformation Shanghai 200032China State Key Laboratory of Integration and Innovation of Classic Formula and Modern Chinese Medicine(Shanghai University of Traditional Chinese Medicine) Shanghai 200032China

Severe immunosuppression is a hallmark of colorectal cancer(CRC).Myeloid-derived suppressor cells(MDSCs),one of the most abundant components of the tumor stroma,play an important role in the invasion,metastasis,and immune escape of CRC.MDSCs create an immunosuppressive microenvironment by inhibiting the proliferation and activation of immunoreactive cells,including T and natural killer cells,as well as by inducing the proliferation of immunosuppressive cells,such as regulatory T cells and tumor-associated macrophages,which,in turn,promote the growth of cancer cells.Thus,MDSCs are key contributors to the emergence of an immunosup-pressive microenvironment in CRC and play an important role in the breakdown of antitumor immunity.In this narrative review,we explore the mechanisms through which MDSCs contribute to the immunosuppressive microenvironment,the current therapeutic approaches and technologies targeting MDSCs,and the therapeutic potential of modulating MDSCs in CRC treatment.This study provides ideas and methods to enhance survival rates in patients with CRC.

关键词： Myeloid-derived suppressor cells Tumor microenvironment Colorectal cancer Therapy immunosuppression

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Solid,non-skin,post-liver transplant tumors:Key role oflifestyle and immunosuppression management

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World Journal of Gastroenterology 2016年第1期22卷 427-434页

作者： Christophe Carenco Stéphanie Faure JoséUrsic-Bedoya Astrid Herrero Georges Philippe Pageaux Liver Transplant Unit CHRU Montpellier34090 MontpellierFrance

Liver transplantation has been the treatment of choice for end-stage liver disease since 1983.Cancer has emerged as a major long-term cause of death for liver transplant recipients.Many retrospective studies that have explored standardized incidence ratio have reported increased rates of solid organ cancers postliver transplantation;some have also studied risk factors.Liver transplantation results in a two to five-fold mean increase in the rate of solid organ cancers.Risk of head and neck,lung,esophageal,cervical cancers and Kaposi’s sarcoma is high,but risk of colorectal cancer is not clearly demonstrated.There appears to be no excess risk of developing breast or prostate cancer.Environmental risk factors such as viral infection and tobacco consumption,and personal risk factors such as obesity play a key role,but recent data also implicate the role of calcineurin inhibitors,whose cumulative and dose-dependent effects on cell metabolism might play a direct role in oncogenesis.In this paper,we review the results of studies assessing the incidence of non-skin solid tumors in order to understand the mechanisms underlying solid cancers in post-liver transplant patients and,ultimately,discuss how to prevent these cancers.Immunosuppressive protocol changes,including a calcineurin inhibitor-free regimen,combined with dietary guidelines and smoking cessation,are theoretically the best preventive measures.

关键词： Liver transplantation Tumors Calcineurininhibitors immunosuppression Risk factors Tacrolimus Review Incidence

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Impact of STAT-signaling pathway on cancer-associated fibroblasts in colorectal cancer and its role in immunosuppression

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World Journal of Gastrointestinal Oncology 2024年第5期16卷 1705-1724页

作者： Damián Sánchez-Ramírez Mónica G Mendoza-Rodríguez Omar R Alemán Fernando A Candanedo-González Miriam Rodríguez-Sosa Juan JoséMontesinos-Montesinos Mauricio Salcedo Ismael Brito-Toledo Felipe Vaca-Paniagua Luis I Terrazas Unidad de Investigacion en Biomedicina Facultad de Estudios Superiores IztacalaUniversidad Nacional Autonoma de MexicoTlalnepantla 54090Estado de MexicoMexico Department of Biology Facultad de QuimicaUniversidad Nacional Autonoma de MexicoCiudad UniversitariaMexico City 04510Mexico Department of Pathology National Medical Center Century XXIInstituto Mexicano del Seguro SocialMexico City 06720Mexico Laboratorio de Células Troncales Mesenquimales Unidad de Investigación Médica en Enfermedades OncológicasHospital de Oncología Centro Medico Nacional Siglo XXIInstituto Mexicano del Seguro SocialMexico City 06720Mexico Unidad de Investigacion en Biomedicina y Oncologia Genomica Instituto Mexciano del Seguro SocialMexico City 07300Mexico Servicio de Colon y Recto Hospital de Oncología Centro Medico Nacional Siglo XXIInstituto Mexicano del Seguro SocialMexico City 06720Mexico Laboratorio Nacional en Salud Facultad de Estudios Superiores IztacalaUniversidad Nacional Autónoma de MéxicoTlalnepantla 54090Estado de MexicoMexico

Colorectal cancer(CRC)remains one of the most commonly diagnosed and deadliest types of cancer worldwide.CRC displays a desmoplastic reaction(DR)that has been inversely associated with poor prognosis;less DR is associated with a better prognosis.This reaction generates excessive connective tissue,in which cancer-associated fibroblasts(CAFs)are critical cells that form a part of the tumor microenvironment.CAFs are directly involved in tumorigenesis through different mechanisms.However,their role in immunosuppression in CRC is not well understood,and the precise role of signal transducers and activators of transcription(STATs)in mediating CAF activity in CRC remains unclear.Among the myriad chemical and biological factors that affect CAFs,different cytokines mediate their function by activating STAT signaling pathways.Thus,the harmful effects of CAFs in favoring tumor growth and invasion may be modulated using STAT inhibitors.Here,we analyze the impact of different STATs on CAF activity and their immunoregulatory role.

关键词： Cancer-associated fibroblasts Signal transducer and activator of transcription signaling Colorectal cancer Immunity immunosuppression

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