The evolutionary emergence of an efficient immune system has a fundamental role in our survival against pathogenic attacks. Nevertheless, this same protective mechanism may also establish a negative consequence in the...The evolutionary emergence of an efficient immune system has a fundamental role in our survival against pathogenic attacks. Nevertheless, this same protective mechanism may also establish a negative consequence in the setting of disorders such as autoimmunity and transplant rejection. In light of the latter, although research has long uncovered main concepts of allogeneic recognition, immune rejection is still the main obstacle to long-term graft survival. Therefore, in order to define effective therapies that prolong graft viability, it is essential that we understand the underlying mediators and mechanisms that participate in transplant rejection. This multifaceted process is characterized by diverse cellular and humoral participants with innate and adaptive functions that can determine the type of rejection or promote graft acceptance. Although a number of mediators of graft recognition have been described in traditional immunology, recent studies indicate that defining rigid roles for certain immune cells and factors may be more complicated than originally conceived. Current research has also targeted specific cells and drugs that regulate immune activation and induce tolerance. This review will give a broad view of the most recent understanding of the allogeneic inflammatory/tolerogenic response and current insights into cellular and drug therapies that modulate immune activation that may prove to be useful in the induction of tolerance in the clinical setting.展开更多
Organ transplantation is the ultimate treatment for end-stage diseases such as heart and liver failure.However,the severe shortage of donor organs has limited the organ transplantation progress.Xenogeneic stem cell tr...Organ transplantation is the ultimate treatment for end-stage diseases such as heart and liver failure.However,the severe shortage of donor organs has limited the organ transplantation progress.Xenogeneic stem cell transplantation provides a new strategy to solve this problem.Researchers have shown that xenogeneic stem cell transplantation has significant therapeutic effects and broad application prospects in treating liver failure,myocardial infarction,advanced type 1 diabetes mellitus,myelosuppression,and other end-stage diseases by replacing the dysfunctional cells directly or improving the endogenous regenerative milieu.In this review,the sources,problems and solutions,and potential clinical applications of xenogeneic stem cell transplantation will be discussed.展开更多
Xenotransplantation,involving animal organ transplantation into humans to address the human organ shortage,has been studied since the 17th century.Early attempts to obtain organs from animals such as goats,dogs,and no...Xenotransplantation,involving animal organ transplantation into humans to address the human organ shortage,has been studied since the 17th century.Early attempts to obtain organs from animals such as goats,dogs,and non-human primates proved unsuccessful.In the 1990s,scientists agreed that pigs were the most suitable donor animals for xenotransplantation.However,immune rejection between pig and human has hindered the application.To overcome these challenges,researchers developed genetically modified pigs that deactivate xenoreactive antigen genes and express human protective genes.These advances extended xenograft survival from days to years in non-human primates,resulting in the first human heart xenotransplant trial.Using genetically engineered pigs for the organ shortage is promising.This review provides an overview of potential incompatibilities of immunogenicity and functional proteins related to xenotransplantation between humans and pigs.Furthermore,it elucidates possible approaches for multiplex gene modification to breed better-humanized pigs for clinical xenotransplantation.展开更多
In order to investigate whether the non-classi- cal HLA-G classⅠmolecule protects the porcine endothelial cells (PECs) from the lysis mediated by human immune cells in pig to human discordant xenotransplantation, we ...In order to investigate whether the non-classi- cal HLA-G classⅠmolecule protects the porcine endothelial cells (PECs) from the lysis mediated by human immune cells in pig to human discordant xenotransplantation, we have cloned HLA-G cDNA from a human placenta by RT-PCR. Mammalian expression vector, pEFG-neo, was constructed by insertion of HLA-G cDNA in pEF-neo. We obtained effi-ciently expressed PECs by stable transfection. Cytotoxicity assay showed that overexpression of HLA-G on PECs was sufficient to inhibit human NK-92 cell lysis. The level of lysis was equal to or less than that of the lysis of human umbilical vein endothelial cells mediated by human NK-92 cells. It also indicated that HLA-G inhibited the lysis of PECs mediated by xeno-antigen specific T lymphocytes. The reduction of lysis ranged between 59.1% and 88.9%. These findings sug-gest that the transgenic approach to overexpress HLA-G is believed to be a new immunotherapy in overcoming the im-mune rejections in xenotransplantion, including delayed xenograft rejection and cell-mediated rejection.展开更多
Tissue engineering(TE)is promising for the regeneration of failed organs.However,immune rejection,shortage of seed cells,and unintegrated blood vessels restrict the development and clinical application of TE.The last ...Tissue engineering(TE)is promising for the regeneration of failed organs.However,immune rejection,shortage of seed cells,and unintegrated blood vessels restrict the development and clinical application of TE.The last factor is the most challenging and intractable.Harnessing the mature blood vessel network in existing dispensable organs could be a powerful approach to effectively overcome the obstacles.After being remodeled to harbor an immunosuppressive and proregenerative niche,these potential target organs can be transformed into other organs with specific physiological functions,compensating the latter's failed native functions.Organ transformation,such as a hepatized spleen,represents an effective and encouraging TE strategy.In this review,we discuss the current development and obstacles of TE and its feasibility and superiority in organ transformation.展开更多
基金Supported by Sao Paulo Research Foundation-FAPESP,Nos.2012/23347-3,2014/14147-6,2012/02270-2 and CNPq
文摘The evolutionary emergence of an efficient immune system has a fundamental role in our survival against pathogenic attacks. Nevertheless, this same protective mechanism may also establish a negative consequence in the setting of disorders such as autoimmunity and transplant rejection. In light of the latter, although research has long uncovered main concepts of allogeneic recognition, immune rejection is still the main obstacle to long-term graft survival. Therefore, in order to define effective therapies that prolong graft viability, it is essential that we understand the underlying mediators and mechanisms that participate in transplant rejection. This multifaceted process is characterized by diverse cellular and humoral participants with innate and adaptive functions that can determine the type of rejection or promote graft acceptance. Although a number of mediators of graft recognition have been described in traditional immunology, recent studies indicate that defining rigid roles for certain immune cells and factors may be more complicated than originally conceived. Current research has also targeted specific cells and drugs that regulate immune activation and induce tolerance. This review will give a broad view of the most recent understanding of the allogeneic inflammatory/tolerogenic response and current insights into cellular and drug therapies that modulate immune activation that may prove to be useful in the induction of tolerance in the clinical setting.
基金National Natural Science Foundation of China,No.81670951.
文摘Organ transplantation is the ultimate treatment for end-stage diseases such as heart and liver failure.However,the severe shortage of donor organs has limited the organ transplantation progress.Xenogeneic stem cell transplantation provides a new strategy to solve this problem.Researchers have shown that xenogeneic stem cell transplantation has significant therapeutic effects and broad application prospects in treating liver failure,myocardial infarction,advanced type 1 diabetes mellitus,myelosuppression,and other end-stage diseases by replacing the dysfunctional cells directly or improving the endogenous regenerative milieu.In this review,the sources,problems and solutions,and potential clinical applications of xenogeneic stem cell transplantation will be discussed.
基金supported by the National Key Research and Development Program of China(2022YFA1105404,2021YFF0702601 and 2021YFA0805300)the Research Unit of Generation of Large Animal Disease Models,Chinese Academy of Medical Sciences(2019I2M-5-025)+3 种基金the Science and Technology Program of Guangzhou(202201010409)the Key Research&Development Program of Hainan Province(ZDYF2021SHFZ052)the Major Science and Technology Project of Hainan Province(ZDKJ2021030)the 2020 Research Program of Sanya Yazhou Bay Science and Technology City(202002011)
文摘Xenotransplantation,involving animal organ transplantation into humans to address the human organ shortage,has been studied since the 17th century.Early attempts to obtain organs from animals such as goats,dogs,and non-human primates proved unsuccessful.In the 1990s,scientists agreed that pigs were the most suitable donor animals for xenotransplantation.However,immune rejection between pig and human has hindered the application.To overcome these challenges,researchers developed genetically modified pigs that deactivate xenoreactive antigen genes and express human protective genes.These advances extended xenograft survival from days to years in non-human primates,resulting in the first human heart xenotransplant trial.Using genetically engineered pigs for the organ shortage is promising.This review provides an overview of potential incompatibilities of immunogenicity and functional proteins related to xenotransplantation between humans and pigs.Furthermore,it elucidates possible approaches for multiplex gene modification to breed better-humanized pigs for clinical xenotransplantation.
基金This work was supported by the National Natural Science Foundation of China(Grant No.39993430)by the National?63?Project(Grant No.2001AA216071).
文摘In order to investigate whether the non-classi- cal HLA-G classⅠmolecule protects the porcine endothelial cells (PECs) from the lysis mediated by human immune cells in pig to human discordant xenotransplantation, we have cloned HLA-G cDNA from a human placenta by RT-PCR. Mammalian expression vector, pEFG-neo, was constructed by insertion of HLA-G cDNA in pEF-neo. We obtained effi-ciently expressed PECs by stable transfection. Cytotoxicity assay showed that overexpression of HLA-G on PECs was sufficient to inhibit human NK-92 cell lysis. The level of lysis was equal to or less than that of the lysis of human umbilical vein endothelial cells mediated by human NK-92 cells. It also indicated that HLA-G inhibited the lysis of PECs mediated by xeno-antigen specific T lymphocytes. The reduction of lysis ranged between 59.1% and 88.9%. These findings sug-gest that the transgenic approach to overexpress HLA-G is believed to be a new immunotherapy in overcoming the im-mune rejections in xenotransplantion, including delayed xenograft rejection and cell-mediated rejection.
基金Fundo para o Desenvolvimento das Ciências e da Tecnologia(the Science and Technology Development Fund,Macao SAR),Grant/Award Number:FDCT 0060/2020/AGJSpanish Ministry of Health–Instituto de Salud Carlos III,Grant/Award Number:FIS PI20/00220+4 种基金Universidade de Macao(the University of Macao Research Committee),Grant/Award Number:MYRG2020‐00084‐ICMSNatural Science Foundation of Jiangsu Province,Grant/Award Number:BK20200318Schweizerischer Nationalfonds zur Förderung der Wissenschaftlichen Forschung(the Swiss National Science Foundation),Grant/Award Number:310030_185219&320030_189252the Stiftung für Leberkrankheiten(Swiss Liver Foundation)National Natural Science Foundation of China,Grant/Award Numbers:31961160701,31971309,and 32001069。
文摘Tissue engineering(TE)is promising for the regeneration of failed organs.However,immune rejection,shortage of seed cells,and unintegrated blood vessels restrict the development and clinical application of TE.The last factor is the most challenging and intractable.Harnessing the mature blood vessel network in existing dispensable organs could be a powerful approach to effectively overcome the obstacles.After being remodeled to harbor an immunosuppressive and proregenerative niche,these potential target organs can be transformed into other organs with specific physiological functions,compensating the latter's failed native functions.Organ transformation,such as a hepatized spleen,represents an effective and encouraging TE strategy.In this review,we discuss the current development and obstacles of TE and its feasibility and superiority in organ transformation.
