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Xenotransplantation holds the promise of being used to address the imbalance between organ supply and demand for clinical transplantation. Pigs have natural features that make them more suitable donors for transplant organs than non-human primates. A series of biological barriers that arise after pig organ transplantation have been overcome by genetic engineering and pharmacological suppression. Mean- while, the gradual maturity of the genetic engineering technology has been significantly optimized for suit- able pigs for xenotransplantation, and promoted the development of pig organ transplantation research. Although it will take time for pig organ xenotransplantation to enter the clinical trial stage, recent studies conducted in a few brain-dead or critically ill patients have exhibited the great potential of porcine xeno- transplantation in solving the imbalance between supply and demand of organs for clinical transplantation.
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BACKGROUND: Skin transplantation is one of the most effective methods for treating large-area burns. How to effectively suppress the immune rejection after allogeneic skin transplantation is a problem that needs to be solved urgently. OBJECTIVE: To investigate the effect of human adipose derived mesenchymal stem cells (hADSCs) on the immunoregulation of skin grafts in different strains of mice. METHODS: Isolated hADSCs were cultured to the 3rd generation. Sixty ICR neonatal mice, 2-4 days of age, were randomly divided into four groups (n=15). The skin tissues of ICR neonatal mice were transplanted into adult C57BL/6 mice to establish a different strain of mouse skin graft immune rejection model. PBS and low dose (5×104), medium dose (10×104), high dose (20×104) hADSCs were injected into the model mice through tail vein, and the survival time of transplanted skin in each group was recorded. On the 7th day after operation, five mice from each group were randomly selected to remove their spleen and serum, and the expression of immune factors interleukin-10, tumor necrosis factor-α and interferon-γ were detected by RT-PCR and ELISA respectively. The transplanted part of the skin was taken to make pathological sections for observing the infiltration of lymphocytes. RESULTS AND CONCLUSION: Compared with the PBS group, the survival time of the skin was prolonged in the low dose hADSCs group; however, there was no significant difference between the two groups (P > 0.05). Compared with the PBS and low dose hADSCs groups, the survival time of the skin was significantly increased in the medium and high dose groups (P 0.05). Compared with the PBS group, the relative expression of tumor necrosis factor-α and interferon-γ in the spleen and serum was significantly decreased in the low, medium and high dose hADSCs groups (P < 0.05), whereas the level of interleukin-10 was significantly elevated in the medium and high dose hADSCs groups (P < 0.05). To conclude, the appropriate dose of hADSCs can significantly prolong the survival time of transplanted skin between different strains of mice, by regulating the expression of related immune factors in the recipient mice.
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@#AIM: To explore the mechanism of rejection of bioengineered keratoplasty by the laser confocal microscope and immunopathological studies.<p>METHODS: Retrospective case study. Five patients(5 eyes)who underwent bioengineered keratoplasty for infectious keratitis from Sep.2018 to Dec.2020 and were immunologically rejected included. All observers were monocular. Slit-lamp was used to examine corneal transparency and corneal neovascularization. The cornea was dynamically observed under laser confocal microscopy, the density of subepithelial langerhans cells and stromal inflammatory cells was recorded after graft rejection, and the contralateral eye was used as the control group for statistical analysis. The infiltration and distribution of CD4<sup>+</sup> cells, CD8<sup>+</sup> cells and inflammatory cells were observed after immunohistochemical staining of bioengineered corneas during corneal allograft.<p>RESULTS: Confocal laser microscopy showed that a large number of langerhans cells were activated under the corneal epithelium of the intraoperative eye, and the activation ratio was significantly different from that of the contralateral eye(χ<sup>2</sup>=38.29, <i>P</i><0.001). The stromal layer was rich in inflammatory cells, which was significantly different from that of the contralateral eye(<i>t</i>=32.5, <i>P</i><0.05). Immunohistochemical staining and HE staining were performed on the bioengineering corneal tissue. CD4<sup>+</sup> and CD8<sup>+</sup> cells were observed in all corneal stromal layers, and only one case had a large number of eosinophils.<p>CONCLUSION: Immunopathology of rejection after bioengineered keratoplasty confirmed that T-cell-mediated cellular immunity plays an important role in the pathogenesis, and hypersensitivity to xenoantigen may be involved in it.
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The application of microsurgery and immunosuppressive agents have led to remarkable progress in uterus allotransplantation for patients with absolute uterine infertility. At present, more than 40 cases of human uterus transplantation have been successfully carried out worldwide, and 12 healthy newborn babies have been delivered using cesarean section. However, selection of transplant donors and recipient, in vitro uterine perfusion, the immunosuppressive therapy and characteristics of graft rejection after uterus allotransplantation are worthy of attention. This article reviews the research progress in uterus allotransplantation.
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Objective To explore the relationship between cellular rejection and the development of allo-or xenografted primordia from different gestational ages .Methods Whole rat metanephroi from embryonic day E14～ E19 were transplanted into omenta of outbred (SD → SD ,6 groups ,n≥10 each ;E15-E17SDCsA ,3 groups ,n=15 each) ,syngeneic (Lewis→Lewis ,5 groups ,n=8 each) ,allogeneic (Lewis→BN ,E15BN n= 6 each E15BNCsA n= 10 each ,E16BNCsA n= 10 each) rats and xenogeneic (Lewis→C57groups ,E15C57 n=10 each ,E15C57CsA ,n=8 each ;Lewis→Balb/c nude mice ,3 groups ,n=10 each) recipients .Histopathology ,Banff's grading and electron microscopy (EM ) were utilized for assessing the graft development .Similarly ,biochemical indicators and creatinine clearances were measured .Results At 4 weeks post-transplantation , in SD → SD groups ,E14-E17SD metanephroi developed with Banff ' s rejections . E14/E15SD was significantly lighter than E16/E17SD ( P< 0 .01 );E18/E19SD barely developed . After cyclosporine A (CsA , 8 mg·kg -1·d-1 )dosing ,Banff's rejection of E15-E17SDCsA group lessened significantly .In Lewis→BN ,E15BN metanephroi were completely rejected .After dosing CsA (12 mg·kg -1·d-1 ) ,E15BNCsA and E16BNCsA Banff ' s rejections became alleviated . Upon a discontinuation of CsA , both metanephroi were rejected . In Lewis → Lewis , E15 ～ E17Lewis metanephroi developed well . No significant difference existed in Banff's classification (P>0 .05) .E14Lewis and E18Lewis rats had significantly poorly differentiated metanephroi than those in E16 Lewis group .In Lewis→C57BL/6 , E15 metanephroi were rejected at Day 14 post-transplantation (n= 10) and no improvement was evident after CsA dosing (15 mg·kg -1·d-1 ,n=8) .In Lewis→Balb/c nude mice ,all E15～E17Balb/c metanephroi developed well .Both light microscopy and EM examination showed normal nephrons and collecting ducts and wet weight ,creatinine or urea nitrogen of effusion showed no significant difference (P>0 .05) .E15Lewis and E16Lewis had significantly different values of wet weight and creatinine clearances from those of E15SDCsA and E16SDCsA .E15SDCsA had the greatest wet weight and the lowest creatinine clearance rate (P< 0 .01) .Conclusions After controlling rejection during allo-and xenotransplantations ,E15 ,E16 and E17 rat metanephros have similar development characteristics . And cellular immunogenic factors still remain the major barriers to their developments .
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AIM:To observe the sustained-release effect of compound betamethasone by subconjunctival injection on immunological rejection after ostrich-rabbit lamellar keratoplasty.METHODS:Sixteen healthy New Zealand white rabbits with 6wk old received corneal lamellar keratoplasty,and the corneal graft was ostrich acellular corneal stroma.After surgery all subjects were divided into two groups,Group A (experimental group) were administrated with subconjunctival injection of compound betamethasone injection (once every 7d),and Group B (control group) were administrated with subconjunctival injection of dexamethasone sodium phosphate (once every 7d).At 1,2wk,1,2mo after the surgery,rabbit corneas were taken for paraffin sections,and were observed with H-E staining,in the meantime changes of CD4+ and CD8+ T lymphocytes were observed by immunofluorescence.RESULTS:Two months after surgery,in Group A corneal grafts remained transparenct,and showed little neovascularization;HE staining and indirect immunofluorescence showed that only a few neutrophil infiltration,no CD4+ and CD8+T lymphocytes.In Group B,the inflammatory reaction was observable at different time points,the corneal graft was turbid;and the tissue sections and indirect immunofluorescence staining showed that neutrophil infiltration was predominant,and CD4+,CD8+T lymphocytes were also seen.CONCLUSION:Compound betamethasone is able to inhibit the ostrich-rabbit corneal transplantation immune rejection,prolong the survival time of the grafts.The present study lay the foundation for further research and clinical application.
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Objective To investigate the effect of tripterygium glycosides on the resistance to immune rejection after allogeneic islet transplantation in mice.Methods Twenty C57BL/6 mice were treated with STZ diabetes mellitus and transplanted the islets from Balb/c mice donor,then recipient mice were randomly divided into two groups:triptolide group and model control group(n=10),and were intraperitoneal injected with tripterygium glycoside solutin and equivalent solvent of 5 mg·kg-1·d-1 for 14 days.Blood glucose and body weight were measured within 4 weeks after transplantation.Two weeks later,two groups of grafted islets were stained by HE staining and immunohistochemical staining,the expression of IL-2 protein were detected by Western blotting.Results The level of blood glucose were decreased to normal in the triptolide group and model control group after islet transplantation,but blood glucose gradually increased in the model control group after two weeks.Compared with the model control group,the inflammatory cells were less infiltrated and the immunohistochemical staining of insulin was deeper in the triptolide group.The expression of IL-2 in the triptolide group was significantly decreased(P<0.05).Conclusion Tripterygium glucoside could significantly decrease the inflammatory cell infiltration and inflammation factor expression in the allogeneic islet recipients to reduce the immune rejection and improve graft survival.
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Objective To investigate the extraction and purification methods of serum specific endothelial cell antibody of renal transplant recipients with rejection after renal transplantation.Methods Human umbilical vein endothelial cell (HUVEC)was isolated and cultured.The serum samples of the renal transplant recipients with poor renal function after renal transplantation were collected.Specific endothelial cell antibody was screened out with flow cytometry;antibodies against human leukocyte antigen (HLA)and major histocompatibility complex class Ⅰ-related chain A (MICA)were detected by Luminex platform.After the existence of specific endothelial cell antibody in the serum sample was confirmed,specific endothelial cell antibody was absorbed with HUVEC.The cell was washed and then the absorbed antibody was eluted from the cell membrane.Antibody IgG in the eluent was purified and concentrated again with Protein-A /G magnetic beads.Antibody activity in the eluent was detected by flow cytometry and the purified specific endothelial cell antibody (IgG)was identified by SDS-polyacrylamide gel (SDS-PAGE)and Western blot.Results In the serum of 386 renal transplant recipients,the serum samples of 5 renal transplant recipients with serum creatinine (Scr) >400 μmoI /L,negative anti-HLA antibody,negative anti-MICA antibody and median fluorescence intensity (MFI) >16 were selected.Purified specific endothelial cell antibody IgG showed immunoglobulin heavy chain (purity > 95%)by SDS-PAGE gel.Flow cytometry showed that the purified antibody had the feature of rebinding with the surface antigen of vascular endothelial cell.Conclusions The purification method of using human umbilical vein endothelial cell to absorb specific endothelial cell antibody in the serum of renal transplant recipients may obtain good effect.
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Objective To modify the techniques for establishment of an abdominal working heart transplantation model in rats and to sum up the key factors to success.Methods A total of 180 12-week old Brown Norway rats ( donor) and Lewis rats ( recipient) were used in this study:50 BN rats and 50 Lewis rats for pilot experiment, and 40 BN rats and 50 Lewis rats for the formal experiment.The rat model of working heart heterotopic transplantation was adopted and estab-lished by Wiedemann’ s mode.We transplanted the heart from BN rats to Lewis rats and analyzed the survival rate, causes of death and histological changes of the heart ( HE staining) in this experiment.Results After exercise and modification, the survival rate was increased to 77.5%, and the mean total duration of operation was 71 ±11 min, and the mean ische-mic time of the donor hearts was 34 ±5 min.Histological examination ( HE staining) of the cardiac allograft showed a mild inflammatory cell infiltration in the graft at 24 h after transplantation, indicating that the model was reliable.Conclusions A variety of factors may affect the final operation success rate in the establishment of this heart transplantation model.A-mong them, the major affecting factors include: healthy animals, donor heart protection, rapid and effective vascular su-ture, and postoperative animal management.
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Objective To study the clinical effects and immunological rejection of allogenic bone as autologous bone graft substitute materials in the treatment of developmental dislocation of the hip.Methods Selected 36 chlidren 40 hip joint undergoing Salter innominate osteotomy,shortening and derotational of the femur bone cutting,Allogeneic bone implantation.Results According to the clinical evaluation criteria of Mckay,excellent 32,good 6,satisfaction 87.5％.All 40 cases of hip bone graft healing,complications such as postoperative incisional drainage response,and no obvious immune rejection.Conclusions Allogeneic bone implantion in the treatment of developmental dislocation of the hip is safe.
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BackgroundAllogenic immunological rejection is still the common cause of keratoplasty failure.Organ culture is a good choice for gradually attenuating corneal antigeniciy.However,the complicated regulatory mechanism of such allogenic rejection with organ culture gratts is unclear until now.ObjectiveTo investigate the changes of several Thl/Th2 cytokines and T lymphocyte subsets in the rat corneal allogenic transplantation rejection with organ culture grafts.MethodsThirty-six SPF Wistar rats served as donors,and 72 SPF SD rats served as recipients in this study.Seventy-two SD rats were divided into two groups randomly.Organ culture and fresh grafts from Wistar rats were performed on 36 recipients SD rats,respectively.Six normal SD rats were served as the normal control.After transplantation,graft survival time was observed ; Aqueous humor levels of IL-2,IFN-γ,IL-4 and TNF-α were measured by enzyme linked immunosorbent assay.Immunohistochemistry was performed to examine CD25 expressions in grafts.Levels of TNF-αmRNA,IFN-γmRNA,IL-4mRNA and CD25mRNA in grafts were detected by using reverse transcription polymerase chain reagction.The levels of CD28subsets in peripheralblood were determined by Flow Cytometry.The use of experimental animals followed the Statement of ARVO.Results The mean rat graft survival time was longer in the organ culture grafts group( 13.78 d) than that with fresh gratts( 10.56 d)(t=14.945,P =0.000 ).The aqueous humor levels of IL-2,IFN-γ,IL-4 and TNF-α were higher in two allograft groups at day 6,day 13 and day 24 after transplantation than that in the normal control,which peaked at day 13,and the fresh grafts group had the highest level( F=324.891,416.416,240.661,364.533,P=0.000).At day 13,CD25 was weakly expressed in frozen section of two operation groups.The expression of TNF-α and IFN-γmRNA in organ culture grafts group was markedly less than in fresh grafts group at day 13 after surgeries (t =2.464,P =0.039;t=5.438,P=0.001 ),whereas there was no significient difference in IL-4 and CD25 mRNA levels between them (t=-0.782,P =0.457,t =0.712,P =0.497).The percentages of CD28 of the fresh graft group increased significantly and more weakly expressed in organ culture grafts group (P =0.016 ). Conclusions Th1/Th2 cytokines and CD28 lymphocyte subsets may play important roles during corneal allograft rejection with organ culture grafts.
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ObjectiveTo compare the capability of optimized acellular(OA) allograft and xenograft reparing rat sciatic nerve defect by observing the immunological rejection, early functional recovery and nerve regeneration in the adult rats, which had been made a 1.0cm long gap in the continuity of the sciatic nerve.MethodsThe right sciatic nerve of adult Sprague-Dawley(SD) rats were exposed and 1.0cm long segment of the nerves were removed and repaired by fresh rabbit nerve and autofrafts, OA rat and rabbit nerve. After 1 and 3 months respectively,sciatic functional index (SFI),electrophysiological and histology studies were detected to evaluate immunological rejection,early functional recovery and nerve regeneration. ResultsThe immunological rejection, functional recovery and nerve regeneration in OA xenografts were compared with that in OA allografts, autografts and fresh allografts. One month after the surgery, the levels of CD8+ T cells and macrophages that infiltrated the grafts,the SFI and the axon density at the midpoints of them were similar within OA grafts and autografts(P ＞ 0.05),but all statistically distinguishable from fresh allografts(P ＜ 0.05).And better results were got after 2 months(P ＜ 0.05).ConclusionsThe results imply that OA xenografts is as good as OA allografts,which can be immunologically tolerated and that the removal of cellular material and preservation of the matrix are beneficial for promoting regeneration and functional recovery through an OA procedure.And this gives another promising option to repair peripheral nerve defect.
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Xenotransplantation can probably overcome the critical shortage of human organ donors for clinical transplantation.Recently,research progresses in the biology of xenograft rejection and zoonotic infections,and the generation of α1,3-galactosyltransferase-deficient pigs have moved this approach closer to clinical application,but immunological rejection is also the primary barrier in the study of xenotransplantation.This review sumarries the research progress of immunological rejection of xenotransplantation,providing some advices for the future of clinical xenotransplantation.
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Objective To investigate the inhibitive effect of mesenchymal stem cells (MSCs) on the immunological rejection in rats after liver transplantation. Methods The recipients and donors were female SD rats and Wistar rats. All rats were randomly divided into 3 groups (28 rats in each group). Rats in group A were infused with normal saline; rats in group B received FK506 (0.25 mg/kg) every 2 days for 2 weeks after liver transplantation; rats in group C were injected with MSCs from male Wistar rats during liver transplantation. The pathological changes, expression of TGF-β1 and IL-10, Y chromosome location, changes of liver function and the survival of the recipients were detected on postoperative day 10. The levels of ALT and AST were analyzed by com-pletely randomised design analysis of variance, and the difference among the 3 groups were analyzed by LSD. Ridit was used to analyze the pathological grading. The survival was analyzed by Log-rank test after the Kaplan-Meier survival curve was drawn. Results The values of ALT and AST were (756±104)U/L and (635±134)U/L in group A, (197±49)U/L and (331±78) U/L in group B, (103±31)U/L and (150±38) U/L in group C, respectively. The difference in the level of ALT and AST among the 3 groups had statistical significance (F = 158, 265, P < 0.05). The liver function of rats in group B and C was better than those in group A (P < 0.01), and the liver function of rats in group C was better than those in group B. The mean values of ridit in group A, B and C were 0.8333, 0.4583 and 0.2083, respectively. The expression rates of TCG-β1 in group A, B and C were 18%±5% , 69%±20% and 85%±24% , with statistical difference among the 3 groups (F=191, P <0.01). There was a significant difference in IL-10 expression among group A (21%±5%), group B (75%±14%) and group C (91%±21%) (F=672, P<0.01). The TCG-β1 and IL-10 had strong positive expression in group B and C, and the expression of TCG-β1 and IL-10 was much stronger in group C than in group B; while the expres-sion of TCG-β1 and IL-10 was weak positive in group A. MSCs cells with Y chromosome were positively stained and were concentrated at the portal area in group C. The 50-day survival rate of rats in group A, B and C were 0, 10% and 90% , respectviely, with significant difference (χ~2=36, P < 0.01). The median survival time of rats in group C was 63 days, which was longer than that in group A and B. Conclusion Simultaneous injection of MSCs from donors during liver transplantation can inhibite the immunological rejection of recipients to the liver graft.
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0.05),but all statistically distinguishable from fresh allografts(P
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It is considered that the central nervous system (CNS) is an immunologically privileged organ, but its immunological privilege is not complete, and immunological rejection may also occurred after tissue transplantation. Neural stem cell (NSC) transplantation has developed a brand-new approach for the treatment of various CNS diseases. Despite the low immunogenicity of NSC, there are also troubles of immunological rejection. This article reviews the immunological characteristics of CNS, the mechanisms of immunological response and immunological rejection in CNS, as well as the problems of immunological rejection of NSC transplantation.
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The incidence of primary nonfunction in the early period of liver transplantation,is reported to be 2%-23%,which is the main cause of death of liver transplant patients.It can be induced by many complicated factors and is particularly associated with the pathological changes caused by acute immunological rejection.Current studies of liver transplantation are focused on how to reduce the injury and improve the function of the liver graft and raise the success rate of liver transplantation.
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Objective:To investigate the effect of intrathymic injection of allogenic antigen to sciatic nerve transplantation.Methods:C57BL/6(H-2b) mice were used as donors and BALB/c(H-2d) as recipients. The recipients were divided into four groups: auto-transplantation group, allogenic transplantation group, allogenic transplantation and using immunosuppressive drugs,intrathymic injection group: 3 mol/L KCl MHC antigen extractions were injected into the recipients’ thymus before two weeks before the sciatic nerves were transplanted. In the third week all the recipients underwent immunological detections for IL-2R,TNF-?,mixed lymphocytes culture and apoptosis.Results:All the detections indicated that it was of significant difference between intrathymic injection group and those in allogenic transplantation group.Conclusion:The immunological rejection of allogenic peripheral nerve transplantation can be somewhat inhibited by intrathymic injection of allogenic MHC antigen.
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The shortage of human hearts has brought the current research focus on finding an animal source as substitute hearts.The immunological barriers to cardiac xenotransplantation are now more clearly defined,allowing retrospective interpretation of past clinical experience in humans.Due to physiological compatibilities as well as ethical and infectious considerations,pigs have now emerged as the most likely source of future xenografts.With the introduction of transgenic pigs expressing human complement regulatory proteins and new immunosuppressive strategies have shown early promise in the laboratory,cardiac xenotransplantation has been the social focus.This article explores ethical issues that surround developments in this field.