EditorialXenotransplantation: The Way beyond and Ahead towardClinical Application

Laura Iop ,1,2 Vered Padler-Karavani,3 and Emanuele Cozzi4

1Cardiovascular Regenerative Medicine Group, Department of Cardiac, Thoracic and Vascular Surgery, University of Padua,Padua, Italy2Venetian Institute of Molecular Medicine, Padua, Italy3Department of Cell Research & Immunology, The George S. Wise Faculty of Life Sciences, Tel Aviv University, 69978 Tel Aviv, Israel4Transplant Immunology Unit, Department of Cardiac, Thoracic and Vascular Sciences, Padua University Hospital, Padua, Italy

Correspondence should be addressed to Laura Iop; laura.iop@unipd.it

Received 28 February 2018; Accepted 5 March 2018; Published 4 April 2018

Copyright © 2018 Laura Iop et al. This is an open access article distributed under the Creative Commons Attribution License, whichpermits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

Instigated at the beginning of the 20th century, moderntransplantation has triggered an unprecedented era for med-ical therapeutics. Indeed, the feasibility to successfully trans-plant cells, tissues, or organs derived from an allogeneicdonor has opened the way to novel approaches to rescueand prolong the life of patients with end-stage organ failure.However nowadays, due to an increasing gap between thedemand for organs and the limited number of humandonors, allogeneic transplantation is, unfortunately, a thera-peutic option that is not always available to those in need.

In the dramatic scenario of human donor shortage andincreasing transplantation waiting lists, transplanting organsfrom other species such as the pig into man, a conditionknown as xenotransplantation, might represent an appealingtherapeutic solution for a larger population of patientsaffected by organ failure. Despite the well-established sim-ilarities with regards to some aspects of anatomy andphysiology between pigs and humans, transplanting pigtissues and organs into man is known to elicit an aggres-sive immune reaction that commonly results in prematurefailure of the graft.

Breakthroughs in the understanding of the mechanismsunderlying xenograft rejection, that include advancementsin glycoimmunology, proteomics, and molecular signaling,have enabled the development of novel modalities to pre-vent or delay the development of antixenograft immuneresponses. In fact, innovative strategies have been devised tomodulate the recipient’s immune response to xenografts, to

reduce the immunogenic power of transplanted cells, tissues,and organs, or to create a physical barrier between thehuman blood and the xenograft. However, the route to theclinical application of xenotransplantation still presentsmany hurdles that will need to be overcome before reachingits ambitious therapeutic goal.

In this special issue, we aim to offer an overview of thestate of the art of xenotransplantation with reference to thecontinuous innovation and potential issues in this challeng-ing medical field. In particular, G. P. Yung and colleaguesreview the role of human natural killer (NK) cells in the path-ophysiological mechanisms leading to xenograft rejection (inThe Role of NK Cells in Pig-to-Human Xenotransplantation).In this context, the authors accurately describe specificmolecular strategies to overcome the human NK responsedirected against porcine endothelial cells. As previously evi-denced for NK immune responses, costimulatory moleculesrepresent a key target of intervention to optimize immuno-modulation in xenotransplantation. In the review by K. P.Samy et al. (in The Role of Costimulation Blockade in SolidOrgan and Islet Xenotransplantation), the central role ofsuch approaches is illustrated in enabling xenotransplanta-tion of solid organs, as kidney, heart, and liver, as well asof islets. Specifically, advancements in terms of survivalachieved in preclinical models with the introduction ofmonoclonal antibodies against CD154, CD40, and CTLA-4are discussed. E. Montanari et al. cover another strategy thatmight possibly improve xenograft durability. This approach

HindawiJournal of Immunology ResearchVolume 2018, Article ID 6191359, 2 pageshttps://doi.org/10.1155/2018/6191359

is represented by the protection offered to hepatocytes bycotransplantation with multipotent mesenchymal stem cells(MSCs) (in Beneficial Effects of Human MesenchymalStromal Cells on Porcine Hepatocyte Viability and AlbuminSecretion). In fact, alginate-encapsulated hepatocytes dem-onstrated higher viability and albumin secretion upon cocul-ture with MSCs thanks to the paracrine effect of theirsecreted cytokines CCL2, CXCL12, and macrophage migra-tion inhibitory factor (MIF). Such original results are ofgreat interest for the success of cell transplantation in thesetting of acute liver failure and once again, confirm thepowerful immunomodulatory and protective abilities ofMSCs when applied as ancillary therapies or alone.

Besides immune response, other pitfalls in the clinicalapplication of xenotransplantation could be represented byinappropriate organ function and growth adaptation, alsodeveloped in the long term. J. A. Shah and colleagues analyzethe possible causes of post-transplant proteinuria in preclin-ical renal xenotransplantation and summarize the preventivestrategies that are currently being tested/applied (in PotentialPathways behind Proteinuria as well as Factors Related toGrowth Discrepancies following Pig-to-Kidney Xenotrans-plantation). In addition, they highlight the importance oforgan size match since discrepancies may ultimately be acause of xenograft failure. Lastly, in their review, C. G. A.McGregor and G. W. Byrne examine the current barriershindering access of heart xenotransplantation in the clinicalarena (in Porcine to Human Heart Transplantation: Is Clini-cal Application Now Appropriate?). Following an accuratedescription of the technological progress that has enabledthe current preclinical results in nonhuman models, theremaining key preclinical studies indispensable to ensurethe efficacy and safety of clinical cardiac xenotransplantationare discussed.

In this continuous cross talk between fundamentaland applied research, progress is very encouraging andclinical translation of novel therapeutic solutions based onthe use of animal-derived cells, tissue, or organs appearsincreasingly closer.

Laura IopVered Padler-Karavani

Emanuele Cozzi

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