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allotransplantation of adult spinal cord tissues after complete transected spinal cord injury: long-term survival and functional recovery in canines

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Science China(Life Sciences) 2020年第12期63卷 1879-1886页

作者： He Shen Shuyu Wu Xi Chen Bai Xu Dezun Ma Yannan Zhao Yan Zhuang Bing Chen Xianglin Hou Jiayin Li Yudong Cao Xianyong Fu Jun Tan Wen Yin Juan Li Li Meng Ya Shi Zhifeng Xiao Xingjun Jiang Jianwu Dai Key Laboratory for Nano-Bio Interface Research Division of NanobiomedicineSuzhou Institute of Nano-Tech and Nano-BionicsChinese Academy of SciencesSuzhou 215123China State Key Laboratory of Molecular Developmental Biology Institute of Genetics and Developmental BiologyChinese Academy of SciencesBeijing 100101China Department of Neurosurgery Xiangya HospitalCentral South UniversityChangsha 410008China Shigatse Branch Xinqiao HospitalArmy Medical University(Third Military Medical University)Shigatse 857000China Department of Radiology Xiangyfa HospitalCentral South UniversityChangsha 410008China

Spinal cord injury(SCI), especially complete transected SCI, leads to loss of cells and extracellular matrix and functional impairments. In a previous study, we transplanted adult spinal cord tissues(aSCTs) to replace lost tissues and facilitate recovery in a rat SCI model. However, rodents display considerable differences from human patients in the scale, anatomy and functions of spinal cord systems, and responses after injury. Thus, use of a large animal SCI model is required to examine the repair efficiency of potential therapeutic approaches. In this study, we transplanted allogenic aSCTs from adult dogs to the lesion area of canines after complete transection of the thoracic spinal cord, and investigated the long-term cell survival and functional recovery. To enhance repair efficiency, a growth factor cocktail was added during aSCT transplantation, providing a favorable microenvironment. The results showed that transplantation of a SCTs, in particular with the addition of growth factors, significantly improves locomotor function restoration and increases the number of neurofilament-, microtubule-associated protein2-, 5-hydroxytryptamine-, choline acetyltransferase-and tyrosine hydroxylase-positive neurons in the lesion area at 6 months post-surgery. In addition, we demonstrated that donor neurons in a SCTs can survive for a long period after transplantation. This study showed for the first time that transplanting aSCTs combined with growth factor supplementation facilitates reconstruction of injured spinal cords, and consequently promotes long lasting motor function recovery in a large animal complete transected SCI model, and therefore could be considered as a possible therapeutic strategy in humans.

关键词： complete spinal cord injury allotransplantation adult spinal cord tissues(aSCTs) adult mammalian long-term survival functional restoration

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PARATHYROID GLAND allotransplantation IN RATS USING A NUDE MOUSE INTERIM HOST SYSTEM

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Chinese Medical Sciences Journal 1990年第1期8卷 41-42页

作者：何晓东朱预 PUMC Hospital CAMSBeijing

Donor rat parathyroid gland(PTG)was first transplanted into the nude mouse interim hostsystem.After 100 days the PTG was re-transplanted into eligible recipients.The resultsshow that mean survival time of recipient ra... 详细信息

关键词： parathyroid gland mean survival time allotransplantation

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Reviewing immunosuppressive regimens in animal models for vascularized composite allotransplantation

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Plastic and Aesthetic Research 2018年第3期5卷 17-26页

作者： Aline Yen Ling Wang Charles Yuen Yung Loh Center for Vascularized Composite allotransplantation Chang Gung Memorial HospitalTaoyuan 333Taiwan St Andrew’s Center for Burns and Plastic Surgery Chelmsford CM1 7THUK

The development of vascularized composite allotransplantation (VCA) and its clinical need has led to the need for more animal models to study and perform the research required to further this specialty in terms of functional recovery and immunomodulatory improvements. Much of the animal models are reported in individual series in the literature but there has not been a review as such of these models. Here we present a compilation of the animal models reported in the literature thus far in VCA. A comprehensive review of the literature was performed for any studies which involved the use of animal models in various aspects of VCA research. The models were organized according to the type of VCA transplant, whether they were orthotopic or heterotopic, immunosuppressive regimen each study used and investigation purpose. Twenty-one facial transplant models were reported, 3 abdominal wall transplants, 4 penile transplantations, 21 uterus transplantations, 12 hindlimb transplantations and 4 myocutaneous flap transplantation animal models were reported. Primates, swine, rats, mice, rabbits, sheep and dog animal models in VCA were also reported. The most used immunosuppressive drugs are calcineurin inhibitor such as cyclosporin A and tacrolimus in these VCA animal models. They can significantly suppress lymphocyte function by blocking the phosphatase activity of calcineurin of lymphocytes. They are sometimes used combined with mycophenolate mofetil or steroids or antilymphocyte serum. The review of existing animal models will allow further research to be focused in other areas of VCA where there is a current paucity of literature. The immunosuppressive regimens used in each animal model can also be reviewed to determine which regimen works in which type of animal model which will save time and resources for future research.

关键词： Animal models vascularized composite allotransplantation immunosuppressive regimens

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Recovery of nigrostriatal dopaminergic system insufficiency by allotransplantation of embryonic brain tissue

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World Journal of Neuroscience 2013年第4期3卷 240-245页

作者： Olga Berchenko Yelena Usmentseva The Laboratory of Neurophysiology Immunology and Biochemistry Institute of Neurology Psychiatry and Narcology of the NAMS Kharkiv Ukraine

In an experiment in rats with electrolytic lesion of the compact part of substantia nigra (SN) and after allotransplantation of the embryonic tissue of SN in the caudate nucleus the features of movement and emotional behavior in the Open Field Test (OFT), the rotation movements caused by an administration of amphetamine, a content of catecholamines in the caudate nucleus, hypothalamus and blood plasma have been investigated. It is shown that the electrolytic lesion causes violations of the statokinetic reflexes, the horizontal and the vertical movement activity, enhances the rotatory behavior, slow the orienttate-searching and the emotional reactions that combined with disbalance in dopamine-and noradrenalinetransmitter systems functioning. allotransplantation of the embryonic dofaminsynthesizing brain tissue contributes to the restoration of movement activeity and its specific neurotransmitter ensuring.

关键词： Movement Violations Catecholamines allotransplantation Embryonic Tissue

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rFliC prolongs allograft survival in association with the activation of recipient Tregs in a TLR5-dependent manner

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Cellular & Molecular Immunology 2014年第2期11卷 206-214页

作者： Jing Hao Chao Zhang Jing Song Guihua Hou Key Laboratory for Experimental Teratology of the Ministry of Education and Institute of Experimental Nuclear Medicine Shandong University MedicalSchool Jinan 250012 China

AIIorejection remains an obstacle for successful organ transplantation. Although different types of immunosuppressive agents are effective for controlling rejection and prolonging graft survival, drug treatment is limited because of side effects and toxicity. Therefore, it is necessary and urgent to identify new candidate drugs for inducing allotolerance. Recently, it has been reported that bacterial flagellin induces the immunosuppressive activity of regulatory T cells （Tregs） in humans in vitro. In the present study, we analyzed the effects of recombinant flagellin （rFliC） on allograft survival and explored the underlying mechanisms associated with the activation of recipient Tregs in a murine skin allotransplantation model. The results showed that rFliC administration （3 mg/kg, once per day for 3 days, i.p.） prolonged allograft survival （mean survival time： 18.4--.1.1 days） compared to the control group （10___0.7 days, P〈O.01）. Additionally, higher positive expression of Toll-like receptor 5 （TLR5） was detected within the allograft administered with rFliC. The frequency of CD4＋CD25＋Foxp3＋ Tregs; the expression of Treg-related factors TLR5, Foxp3, TGF-I^I and IL-IO; and the proliferation and suppression of Tregs were increased following rFliC administration compared to the control. Moreover, the increased expression of tolerance-related molecules and the proliferation of Tregs induced by rFliC were attenuated by an anti-TLR5 blocking antibody both in vivo and in vitro. In conclusion, rFliC administration prolongs the survival of allografts, which is associated with the activation of recipient Tregs in a TLR5-dependent manner, rFliC may be a new candidate for anti-allorejection therapy.

关键词： allotransplantation flagellin regulatory T cells TLR5

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Immunological protection of small bowel by simultaneously transplanted liver graft in pigs

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Hepatobiliary & Pancreatic Diseases International 2009年第4期8卷 363-369页

作者： Yin, Zhen-Yu Li, Ning Wang, Xiao-Ming Ni, Xiao-Dong Jiang, Feng Li, You-Sheng Li, Jie-Shou Nanjing Univ Sch Med Jinling Hosp Inst Gen Surg Nanjing 210002 Peoples R China Xiamen Univ Zhongshan Hosp Dept Hepatobiliary Surg Xiamen 361004 Peoples R China

BACKGROUND: A simultaneously transplanted liver shields a bowel graft from immunologic attack in small animals, while the possible immuno-tolerance induced by the liver in liver and small bowel transplantation (LSBT) is uncertain in large animal models. To investigate the clinically suspected beneficial effect of the liver on small bowel allograft, we developed a new model of composite LSBT in the pig. METHODS: Seventy outbred long-white pigs were randomized into four groups. LSBT without immunosuppressive treatment (n=10, group A); LSBT with routine immunosuppressive treatment (n=10, group B); LSBT with a lower dose of immunosuppressive treatment (n=10, group C); and small bowel segment allotransplantation without immunosuppressive treatment (n=10, group D). RESULTS: There was no remarkable difference in survival time between groups A and D (10.33 vs. 12.89 days, P>0.05), but the initial time of acute rejection of the intestinal graft in group A was clearly delayed when compared to group D (8.22 vs. 4.33 days, P0.05), initial acute rejection time (25.40 vs. 22.13 days, P>0.05) or rejection score did not differ between groups B and C within one postoperative month. CONCLUSIONS: Compared to isolated segment small bowel allotransplantation, the intestinal graft in LSBT (group A) had a delayed initial time of acute rejection and a lower postoperative acute rejection score, and a lower dose of immunosuppressive treatment led to persistent graft immuno-tolerance in LSBT. Thus the simultaneously transplanted liver graft may reduce the risk of intestinal rejection and protect the bowel graft from sever

关键词： liver transplantation small bowel transplantation porcine allotransplantation rejection immuno-tolerance

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I-2190A Is a Potent Immunosuppressive Drug for Vascularized Heart Transplantation in Rats

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Journal of Huazhong University of Science and Technology(Medical Sciences) 1998年第1期18卷 37-38,41页

作者：刘斌李锦文郭晖马绪娴陈实 Institute of Organ Transplantation Tongji Medical University Wuhan

The effect of a new immunosuppressant -I-2190A was tested in a rodent heart allograft model. Grafts were transplanted to recipients heterotopcally.There were 5 groups: group 1 received no immunosuppressive agents; group 2 was given CsA (2. 0 mg/kg, i. p.); group 3 was administered I-2190A (0. 1 mg/kg, i. p. ) in carboxymethyl cellulose (CMC); group 4 received injection of I-2190A (0. 5 mg/kg, i. p. in CMC) ; group 5 received the combination treatment of I-2190A (0. 1rug/kg) and CsA (2. 0 mg/kg). Immunosuppressants were discontinued 14 days after operation. No statistically significant difference in grafts median survival time (MST) was found between group 2 (9. 5 days) and group 1 (9days ). The MSTs of grafts in group 3 (22 days, P 100 days, PRO. of ) and group 5 (M100 days, P< 0. 01 ) were significantly prolonged compared with control group 1 (9 days ). Our results suggest that I-2190A is a potent immunosuppressant able to significantly prolong heart allograft survival in rats after a short time treatment. Low-dose I-2190A could potentiate the effect of sub-therapeutic dose of CsA as well.

关键词： I-219QA immunosuppressant allotransplantation

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Rapamycin enhanced autophagy favors tolerance induction in allotransplantation model through mTORC1/ULK1 pathway

Rapamycin enhanced autophagy favors tolerance induction in a...

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第十三届全国免疫学学术大会

作者： Shanshan Zhao Guihua Hou Shandong University

Background and purspose: Autophagy is a homeostatic process facilitating either cellular survival or death which is tightly correlated with allotransplantation. This study aimed to investigate whether autophagy affects allotransplantation in allotransplanted mice model.Methods and results: We performed rapamycin(autophagy activator) and 3 MA(autophagy inhibitor) injection in vivo, observed alloskin survival in allograft mouse model, and isolated allograft skin and splenic CD4+T cell on day 12. We found that autophagy molecules Beclin 1 and ATG5 both apparently increased in rapamycin group with prolonged survival and toleranced allograft. ATG5 expression was co-related with T cell distribution in allograft. Rapamycin facilitated autophagy through mTORC1/ULK1 pathway. To understand the effect of autophagy on recipient CD4+ T cell, we detected autophagy of splenic CD4+ T cells, and found that rapamycin enhanced autophagy in vivo led to higher expression of IL-10, Foxp3, TGF-β and the ratio of Treg cells. However, rapamycin-prolonged allograft survival was not apparently affected by autophagy inhibition and this effect may mainly depend on mTORC1/p70 S6 K.Conclusion: Rapamycin enhanced autophagy favors tolerance induction in allotransplantation model, while long-term tolerance by rapamycin may mainly depend on mTORC1/p70 S6 K, not autophagy pathway.

关键词： Autophagy Rapamycin allotransplantation CD4+T cells,Th2 cytokine

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Face transplantation:Anesthetic challenges

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World Journal of Transplantation 2016年第4期6卷 646-649页

作者： Aparna Dalal Department of Anesthesiology Icahn School of Medicine at Mount Sinai

Face transplantation is a complex vascular composite allotransplantation(VCA) surgery. It involves multiple types of tissue, such as bone, muscles, blood vessels, nerves to be transferred from the donor to the recipient as one unit. VCAs were added to the definition of organs covered by the Organ Procurement and Transplantation NetworkFinal Rule and National Organ Transplant Act. Prior to harvest of the face from the donor, a tracheostomy is usually performed. The osteotomies and dissection of the midface bony skeleton may involve severe hemorrhagic blood loss often requiring transfusion of blood products. A silicon face mask created from the facial impression is used to reconstruct the face and preserve the donor's dignity. The recipient airway management most commonly used is primary intubation of an existing tracheostoma with a flexometallic endotracheal tube. The recipient surgery usually averages to 19-20 h. Since the face is a very vascular organ, there is usually massive bleeding, both in the dissection phase as well as in the reperfusion phase. Prior to reperfusion, often, after one sided anastomosis of the graft, the contralateral side is allowed to bleed to get rid of the preservation solution and other additives. Intraoperative product replacement should be guided by laboratory values and point of care testing for coagulation and hemostasis. In face transplantation, bolus doses of pressors or pressor infusions have been used intraoperatively in several patients to manage hypotension. This article reviews the anesthetic considerations for management for face transplantation, and some of the perioperative challenges faced.

关键词： Face transplantation Vascular composite allotransplantation Organ harvest Facial reconstruction

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TLR5 Specific Ligand, Flagellin, Prolonged Allograft Survival via Activating Regulatory T Cells in MAPKdependent Pathway

TLR5 Specific Ligand, Flagellin, Prolonged Allograft Surviva...

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第八届全国免疫学学术大会

作者： Jing Hao Chao Zhang Ting Liang Jing Song Guihua Hou Key Laboratory for Experimental Teratology of the Ministry of Education and Institute of Experimental Nuclear Medicine School of Medicine Shandong University

BACKG ROUND and Purpose:It has been well documented that Regulatory T cells(Tregs) play an important role in immuno-tolerance keeping, and activating of Tregs would be a practicable way to overcome the allorejection.In current research, the effect of recombinant flagellin(fli C) on allograft survival and its mechanisms were explored with murine skin allotransplantation models.Methods:Herein, recombinant flagellin was expressed and purified firstly, then murine skin allotransplantation models were established and the effects of fli C on allograft survival and recipients Treg were studied in vivo and in vitro.Blocking experiments were performed using anti-TLR5 blocking antibody or JNK- / p38 MAPKsignaling inhibitors(SP600125/SB203580).Results:It was shown that the fli C(3mg/kg)-administration in vivo obviously prolonged graft survival(MST 18.4±1.1 day) than control(10±0.7 day), p<0.01;and apparently increased the frequency of CD25+Foxp3+ cells in CD4+ splenocytes(from 9.3±1.6% to 15.25±1.6%), p<0.01;the suppressive effect of Tregs on T effector cells(Teffs) was increased by 93.9%(p<0.01) with fli C(3mg/kg)-stimulation compared with control.Meanwhile, expression of TLR5, Foxp3, TGF-β1 and IL-10 on splenocytes was significantly enhanced by fli C stimulus;suppressive capacity of fli C-treated Tregs in vitro was notably enhanced and these fli C-arousedeffects could be partially neutralized by anti-TLR5 blocking antibody.Furthermore, we found that flagellinTLR5 signaling pathway was JNK- and MAPK- dependent;expression of transcription factor Foxp3 was partially prevented by pharmacological inhibiting MAPK signaling.CONCLUSIONS:Together, these data demonstrate that flagellin administration could significantly prolong allograft survival through activating and expanding Treg subset via TLR5 pathway specifically, by a mechanism partially dependent on the activation of p38 MAPK;thereby flagellin may become a promising new candidate to down-regulate allograft rejection.

关键词： flagellin TLR5 allotransplantation regulatory T cells

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