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Nature Jun 2021Ageing of the immune system, or immunosenescence, contributes to the morbidity and mortality of the elderly. To define the contribution of immune system ageing to...
Ageing of the immune system, or immunosenescence, contributes to the morbidity and mortality of the elderly. To define the contribution of immune system ageing to organism ageing, here we selectively deleted Ercc1, which encodes a crucial DNA repair protein, in mouse haematopoietic cells to increase the burden of endogenous DNA damage and thereby senescence in the immune system only. We show that Vav-iCre;Ercc1 mice were healthy into adulthood, then displayed premature onset of immunosenescence characterized by attrition and senescence of specific immune cell populations and impaired immune function, similar to changes that occur during ageing in wild-type mice. Notably, non-lymphoid organs also showed increased senescence and damage, which suggests that senescent, aged immune cells can promote systemic ageing. The transplantation of splenocytes from Vav-iCre;Ercc1 or aged wild-type mice into young mice induced senescence in trans, whereas the transplantation of young immune cells attenuated senescence. The treatment of Vav-iCre;Ercc1 mice with rapamycin reduced markers of senescence in immune cells and improved immune function. These data demonstrate that an aged, senescent immune system has a causal role in driving systemic ageing and therefore represents a key therapeutic target to extend healthy ageing.
Topics: Aging; Animals; DNA Damage; DNA Repair; DNA-Binding Proteins; Endonucleases; Female; Healthy Aging; Homeostasis; Immune System; Immunosenescence; Male; Mice; Organ Specificity; Rejuvenation; Sirolimus; Spleen
PubMed: 33981041
DOI: 10.1038/s41586-021-03547-7 -
Transplant International : Official... Nov 2021The future clinical application of animal-to-human transplantation (xenotransplantation) is of importance to society as a whole. Favourable preclinical data relevant to... (Review)
Review
The future clinical application of animal-to-human transplantation (xenotransplantation) is of importance to society as a whole. Favourable preclinical data relevant to cell, tissue and solid organ xenotransplants have been obtained from many animal models utilizing genetic engineering and protocols of pathogen-free husbandry. Findings have reached a tipping point, and xenotransplantation of solid organs is approaching clinical evaluation, the process of which now requires close deliberation. Such discussions include considering when there is sufficient evidence from preclinical animal studies to start first-in-human xenotransplantation trials. The present article is based on evidence and opinions formulated by members of the European Society for Organ Transplantation who are involved in the Transplantation Learning Journey project. The article includes a brief overview of preclinical concepts and biology of solid organ xenotransplantation, discusses the selection of candidates for first-in-human studies and considers requirements for study design and conduct. In addition, the paper emphasizes the need for a regulatory framework for xenotransplantation of solid organs and the essential requirement for input from public and patient stakeholders.
Topics: Animals; Heterografts; Humans; Models, Animal; Organ Transplantation; Transplantation, Heterologous; Transplants
PubMed: 34459040
DOI: 10.1111/tri.14031 -
Frontiers in Immunology 2019The increasing life expectancy of humans has led to a growing numbers of patients with chronic diseases and end-stage organ failure. Transplantation is an effective... (Review)
Review
The increasing life expectancy of humans has led to a growing numbers of patients with chronic diseases and end-stage organ failure. Transplantation is an effective approach for the treatment of end-stage organ failure; however, the imbalance between organ supply and the demand for human organs is a bottleneck for clinical transplantation. Therefore, xenotransplantation might be a promising alternative approach to bridge the gap between the supply and demand of organs, tissues, and cells; however, immunological barriers are limiting factors in clinical xenotransplantation. Thanks to advances in gene-editing tools and immunosuppressive therapy as well as the prolonged xenograft survival time in pig-to-non-human primate models, clinical xenotransplantation has become more viable. In this review, we focus on the evolution and current status of xenotransplantation research, including our current understanding of the immunological mechanisms involved in xenograft rejection, genetically modified pigs used for xenotransplantation, and progress that has been made in developing pig-to-pig-to-non-human primate models. Three main types of rejection can occur after xenotransplantation, which we discuss in detail: (1) hyperacute xenograft rejection, (2) acute humoral xenograft rejection, and (3) acute cellular rejection. Furthermore, in studies on immunological rejection, genetically modified pigs have been generated to bridge cross-species molecular incompatibilities; in the last decade, most advances made in the field of xenotransplantation have resulted from the production of genetically engineered pigs; accordingly, we summarize the genetically modified pigs that are currently available for xenotransplantation. Next, we summarize the longest survival time of solid organs in preclinical models in recent years, including heart, liver, kidney, and lung xenotransplantation. Overall, we conclude that recent achievements and the accumulation of experience in xenotransplantation mean that the first-in-human clinical trial could be possible in the near future. Furthermore, we hope that xenotransplantation and various approaches will be able to collectively solve the problem of human organ shortage.
Topics: Animals; Animals, Genetically Modified; Biomarkers; Blood Coagulation Disorders; Disease Management; Gene Expression Regulation; Graft Rejection; Graft Survival; Haplorhini; Humans; Immunity, Cellular; Immunity, Humoral; Models, Animal; Species Specificity; Swine; Translational Research, Biomedical; Transplantation Immunology; Transplantation, Heterologous
PubMed: 32038617
DOI: 10.3389/fimmu.2019.03060 -
American Journal of Transplantation :... Feb 2023The American Society of Transplant Surgeons supports efforts to increase the number of organs that are critically needed for patients desperately awaiting... (Review)
Review
The American Society of Transplant Surgeons supports efforts to increase the number of organs that are critically needed for patients desperately awaiting transplantation. In the United States, transplantation using organs procured from donation after circulatory death (DCD) donors has continued to increase in number. Despite these increases, substantial variability in the utilization and practices of DCD transplantation still exists. To improve DCD organ utilization, it is important to create a set of best practices for DCD recovery. The following recommendations aim to provide guidance on contemporary issues surrounding DCD organ procurement in the United States. A work group was composed of members of the American Society of Transplant Surgeon Scientific Studies Committee and the Thoracic Organ Transplantation Committee. The following topics were identified by the group either as controversial or lacking standardization: prewithdrawal preparation, definition of donor warm ischemia time, DCD surgical technique, combined thoracic and abdominal procurements, and normothermic regional perfusion. The proposed recommendations were classified on the basis of the grade of available evidence and the strength of the recommendation. This information should be valuable for transplant programs as well as for organ procurement organizations and donor hospitals as they develop robust DCD donor procurement protocols.
Topics: Humans; United States; Tissue and Organ Procurement; Organ Transplantation; Tissue Donors; Cardiovascular System; Perfusion; Death; Organ Preservation
PubMed: 36695685
DOI: 10.1016/j.ajt.2022.10.009 -
Transplant International : Official... Nov 2021In donation after circulatory death (DCD), (thoraco)abdominal regional perfusion (RP) restores circulation to a region of the body following death declaration. We... (Meta-Analysis)
Meta-Analysis
In donation after circulatory death (DCD), (thoraco)abdominal regional perfusion (RP) restores circulation to a region of the body following death declaration. We systematically reviewed outcomes of solid organ transplantation after RP by searching PubMed, Embase, and Cochrane libraries. Eighty-eight articles reporting on outcomes of liver, kidney, pancreas, heart, and lung transplants or donor/organ utilization were identified. Meta-analyses were conducted when possible. Methodological quality was assessed using National Institutes of Health (NIH)-scoring tools. Case reports (13/88), case series (44/88), retrospective cohort studies (35/88), retrospective matched cohort studies (5/88), and case-control studies (2/88) were identified, with overall fair quality. As blood viscosity and rheology change below 20 °C, studies were grouped as hypothermic (HRP, ≤20 °C) or normothermic (NRP, >20 °C) regional perfusion. Data demonstrate that RP is a safe alternative to in situ cold preservation (ISP) in uncontrolled and controlled DCDs. The scarce HRP data are from before 2005. NRP appears to reduce post-transplant complications, especially biliary complications in controlled DCD livers, compared with ISP. Comparisons for kidney and pancreas with ISP are needed but there is no evidence that NRP is detrimental. Additional data on NRP in thoracic organs are needed. Whether RP increases donor or organ utilization needs further research.
Topics: Death; Graft Survival; Humans; Organ Preservation; Organ Transplantation; Perfusion; Retrospective Studies; Tissue Donors; Tissue and Organ Procurement
PubMed: 34570380
DOI: 10.1111/tri.14121 -
Current Biology : CB Mar 2016Animal communication, including that among humans, is fascinating in its efficiency, diversity and its complexity. The evolution of a communication signal requires that...
Animal communication, including that among humans, is fascinating in its efficiency, diversity and its complexity. The evolution of a communication signal requires that the encoded content sent by an organism (sender) is detected and decoded by a receiver, who then must respond in such a way that the fitness of the sender is increased. The signal could be visual, such as bright coloration or some stereotypical movement that attracts attention through the sense of sight. It could be chemical, such as a pheromone we detect by smell or taste, or it could be tactile, involving direct physical touch. It could be an acoustic wave, detected by an auditory organ as sound and perceived through the sense of hearing, or it could be a vibrational wave detected by a vibration receiver of another sort. The medium through which the signal is transmitted could be any that exists on the Earth (solid, liquid or gas), and each type of medium influences the type of signal that is able to most efficiently move through it.
Topics: Animal Communication; Animals
PubMed: 26954435
DOI: 10.1016/j.cub.2016.01.054 -
American Journal of Transplantation :... May 2015Use of organs from donors testing positive for hepatitis B virus (HBV) may safely expand the donor pool. The American Society of Transplantation convened a...
Use of organs from donors testing positive for hepatitis B virus (HBV) may safely expand the donor pool. The American Society of Transplantation convened a multidisciplinary expert panel that reviewed the existing literature and developed consensus recommendations for recipient management following the use of organs from HBV positive donors. Transmission risk is highest with liver donors and significantly lower with non-liver (kidney and thoracic) donors. Antiviral prophylaxis significantly reduces the rate of transmission to liver recipients from isolated HBV core antibody positive (anti-HBc+) donors. Organs from anti-HBc+ donors should be considered for all adult transplant candidates after an individualized assessment of the risks and benefits and appropriate patient consent. Indefinite antiviral prophylaxis is recommended in liver recipients with no immunity or vaccine immunity but not in liver recipients with natural immunity. Antiviral prophylaxis may be considered for up to 1 year in susceptible non-liver recipients but is not recommended in immune non-liver recipients. Although no longer the treatment of choice in patients with chronic HBV, lamivudine remains the most cost-effective choice for prophylaxis in this setting. Hepatitis B immunoglobulin is not recommended.
Topics: Antiviral Agents; Cost-Benefit Analysis; Heart Transplantation; Hepatitis B; Hepatitis B Antibodies; Hepatitis B Core Antigens; Hepatitis B virus; Humans; Kidney Transplantation; Lamivudine; Liver Transplantation; Societies, Medical; Tissue Donors; Tissue and Organ Procurement; United States
PubMed: 25707744
DOI: 10.1111/ajt.13187 -
Mechanisms of Ageing and Development Dec 2021Older organs provide a substantial unrealized potential with the capacity to close the gap between demand and supply in organ transplantation. The potential of... (Review)
Review
Older organs provide a substantial unrealized potential with the capacity to close the gap between demand and supply in organ transplantation. The potential of senolytics in improving age-related conditions has been shown in various experimental studies and early clinical trials. Those encouraging data may also be of relevance for transplantation. As age-differences between donor and recipients are not uncommon, aging may be accelerated in recipients when transplanting older organs; young organs may, at least in theory, have the potential to 'rejuvenate' old recipients. Here, we review the relevance of senescent cells and the effects of senolytics on organ quality, alloimmune responses and outcomes in solid organ transplantation. This article is part of the Special Issue - Senolytics - Edited by Joao Passos and Diana Jurk.
Topics: Aging, Premature; Cellular Senescence; Humans; Organ Transplantation; Senotherapeutics; Tissue Survival
PubMed: 34606875
DOI: 10.1016/j.mad.2021.111582