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.

/pdf/xenotransplantation-current-status-in-preclinical-research-4uwbiepa2m.pdf

Xenotransplantation: Current Status in Preclinical Research.

Pluripotent stem cell-based therapy for Parkinson’s disease: Current status and future prospects

Purpose of review To review the progress in the field of xenotransplantation with special attention to most recent encouraging findings which will eventually bring xenotransplantation to the clinic in the near future. Recent findings Starting from early 2000, with the introduction of galactose-α1,3-galactose (Gal)-knockout pigs, prolonged survival especially in heart and kidney xenotransplantation was recorded. However, remaining antibody barriers to non-Gal antigens continue to be the hurdle to overcome. The production of genetically engineered pigs was difficult requiring prolonged time. However, advances in gene editing, such as zinc finger nucleases, transcription activator-like effector nucleases, and most recently clustered regularly interspaced short palindromic repeats (CRISPR) technology made the production of genetically engineered pigs easier and available to more researchers. Today, the survival of pig-to-nonhuman primate heterotopic heart, kidney, and islet xenotransplantation reached more than 900, more than 400, and more than 600 days, respectively. The availability of multiple-gene pigs (five or six genetic modifications) and/or newer costimulation blockade agents significantly contributed to this success. Now, the field is getting ready for clinical trials with an international consensus. Summary Clinical trials in cellular or solid organ xenotransplantation are getting closer with convincing preclinical data from many centers. The next decade will show us new achievements and additional barriers in clinical xenotransplantation.

Xenotransplantation: past, present, and future.

The number of donated human organs and tissues for patients with terminal organ failure falls far short of the need. According to the United Network for Organ Sharing (www.unos.org), more than 113,000 candidates for transplant are currently on the U.S. national waiting list, but only 36,527 organ transplants could be performed in 2018. Alternative sources, such as organs and tissues from animals, are therefore urgently needed. For a number or reasons, including size, anatomical, and physiological similarities with humans, the pig is the preferred donor species (reviewed in Cooper et al., 2016). Importantly, pigs can be optimized by genetic engineering as a source of cells, tissues, and organs for xenotransplantation. Recent advances in gen(om)e editing are speeding up progress in this field. Numerous genetically (multi-)modified pig lines have been generated to prevent immune rejection of xenotransplants, to overcome physiological incompatibilities, and to reduce the risk of transmitting zoonotic pathogens (Table 1; reviewed in Kemter et al., 2018).

Table 1.

Selection of genetic modifications of donor pigs for xenotransplantation

Genetically modified pigs as donors of cells, tissues, and organs for xenotransplantation.

Porcine endogenous retroviruses (PERVs) are integrated in the genome of all pigs, and some of them are able to infect human cells. Therefore, PERVs pose a risk for xenotransplantation, the transplantation of pig cells, tissues, or organ to humans in order to alleviate the shortage of human donor organs. Up to 2021, a huge body of knowledge about PERVs has been accumulated regarding their biology, including replication, recombination, origin, host range, and immunosuppressive properties. Until now, no PERV transmission has been observed in clinical trials transplanting pig islet cells into diabetic humans, in preclinical trials transplanting pig cells and organs into nonhuman primates with remarkable long survival times of the transplant, and in infection experiments with several animal species. Nevertheless, in order to prevent virus transmission to the recipient, numerous strategies have been developed, including selection of PERV-C-free animals, RNA interference, antiviral drugs, vaccination, and genome editing. Furthermore, at present there are no more experimental approaches to evaluate the full risk until we move to the clinic.

Porcine Endogenous Retroviruses and Xenotransplantation, 2021

https://onlinelibrary.wiley.com/doi/pdf/10.1111/ajt.13704

Cell Therapy for Parkinson's Disease: A Translational Approach to Assess the Role of Local and Systemic Immunosuppression.

A Pig Model of Hemivascular Liver Occlusion for The Study of Ischemia-Reperfusion Injury: Use of an Infrared System for Detecting Ischemic Areas

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Cell Therapy for Parkinson's Disease: A Translational Approach to Assess the Role of Local and Systemic Immunosuppression.

A Pig Model of Hemivascular Liver Occlusion for The Study of Ischemia-Reperfusion Injury: Use of an Infrared System for Detecting Ischemic Areas