What's hot,what's new: Report from the American Transplant Congress 2017

Significant advances in clinical practice as well as basic and translational science were presented at the American Transplant Congress this year. Topics included innovative clinical trials to recent advances in our basic understanding of the scientific underpinnings of transplant immunology. Key areas of interest included the following: clinical trials utilizing hepatitis C virus–positive (HCV⁺) donors for HCV^? recipients, the impact of the new allocation policies, normothermic perfusion, novel treatments for desensitization, attempts at precision medicine, advances in xenotransplantation, the role of mitochondria and exosomes in rejection, nanomedicine, and the impact of the microbiota on transplant outcomes. This review highlights some of the most interesting and noteworthy presentations from the meeting.     

Consideration of appropriate clinical applications for cardiac xenotransplantation

The field of cardiac xenotransplantation has entered an exciting era due to recent advances in the field. Although several hurdles remain, the use of rapidly evolving transgenic technology has the potential to address current allogeneic donor pool constraints and mechanical circulatory system device limitations. The success of xenotransplantation will undoubtedly be dependent on specific patient selection criteria. Defining these particular indications for xenotransplantation is important as we approach the possibility of clinical applications.     

National policies for xenotransplantation in the USA

An overview of xenotransplantation regulatory policies in the USA was presented at the Satellite Symposium, 'Xenotransplantation--Current Standards for Clinical Trials,' held in conjunction with the World Transplant Congress, Boston, MA, USA 2006. This article summarizes that overview.     

Pulmonary xenotransplantation: Rapidly progressing into the unknown

As one approach to circumventing the dire shortage of human lungs for transplantation, a handful of investigators have begun to probe the possibility of pulmonary xenotransplantation. The immunologic and perhaps physiologic barriers encountered by these investigators are considerable and progress in pulmonary xenotransplantation has lagged behind progress in cardiac and kidney xenotransplantation. However, during the last few years there have been substantial advances in the field of pulmonary xenotransplantation including, most noticeably, significant progress in attenuating hyperacute dysfunction. Progress has been made in understanding the barriers imposed by xenoreactive antibodies, complement, coagulation incompatibility and porcine pulmonary intravascular macrophages. Although our understanding of the barriers to pulmonary xenotransplantation is far from complete and the clinical application of pulmonary xenotransplantation is not yet in sight, current progress is fast paced. This progress provides a basis for future work and for a hope that the shortage of human lungs for transplantation will not always be a matter of life and death.     

Clinical xenotransplantation: past,present and future.

The ability to use animal organs, such as from the pig, for the purposes of transplantation in humans, would clearly overcome the major shortage of human organs that greatly restricts transplantation programmes worldwide. Recent experimental advances have raised the possibility of renewed attempts at organ xenotransplantation in humans within the near future. Previous clinical experience, dating back to 1906, is briefly reviewed. The problems that still require resolution include the immunological barrier, the risk of transferring infectious agents with the transplanted organ, and uncertainty as to whether the transplanted animal organ will function satisfactorily in the human environment. Ironically, the answers to some of these problems may only be provided when clinical xenotransplantation is undertaken.     

Genetic modification of pigs for solid organ xenotransplantation

Xenotransplantation of solid organs will only ever become a clinical reality with genetic modification of the pig, which is now widely accepted as the most likely donor species for humans. The understanding of the barriers to xenotransplantation has required advances in genetic technologies to resolve these problems. Hyperacute rejection has been overcome by overexpression of complement regulatory proteins or targeted disruption of the enzyme associated with the major carbohydrate xenoantigen. The subsequent barriers of disordered coagulation, induced antibody, and cell-mediated rejection remain challenging. The mechanisms for these incompatibilities are being deciphered, and multiple genetic manipulations to resolve these issues are currently in progress. Moreover, new technologies offer help to producing sizeable numbers of modified pigs in a timely manner. This article retraces the basis and foreshadows progress of the genetically modified pig for xenotransplantation as it advances toward the clinic.     

What's Hot,What's New From the 2016 American Transplant Congress

From June 11–15, 2016 the American Transplant Congress, the joint meeting of the American Society of Transplantation and the American Society of Transplant Surgeons, held its annual meeting in Boston, MA. The meeting, attended by 5200 registrants, included pre‐meeting conferences, focused topic sessions, and hundreds of high‐quality presentations from the transplant field. This meeting report highlights key findings from specific basic science, translational, and clinical research presentations deemed to have notable impact in thematic areas. In particular, there were a number of transformative studies indicating important advances in the understanding of alloimmunity, chronic rejection, tolerance, and organ‐specific outcomes. Many of these results are discussed in the context of the published literature to showcase rapid advances in the transplant field.     

Pigs as xenogeneic donors

The success and widespread acceptance of clinical allotransplantation has led to a shortage of cadaveric organs and a resurgence of interest in xenotransplantation. Although swine are generally regarded as the preferred source of xenogeneic organs, the severe immunologic response to swine organs has so far precluded their clinical use. However, the past 10 years have seen many advances in the field, especially the use of genetically modified swine. These include animals transgenic for human complement regulatory proteins, and most recently, animals not expressing the alpha 1,3-galactosyltransferase gene (GalT-KO swine), produced by nuclear transfer. The initial results using GalT-KO swine as donors to nonhuman primates demonstrated survival of a life-supporting renal graft for up to 83 days without rejection when combined with a regimen designed to induce tolerance by vascularized donor thymic grafts. Although the initial results are encouraging, further improvements will be needed to warrant a clinical trial of xenotransplantation. In this review, we discuss immunologic barriers to xenotransplantation and recent attempts to overcome them, strategies to induce tolerance across a xenogenic barrier, and issues that will need to be considered before a clinical trial is attempted.     

History of xenotransplantation

The present historical review reports the clinical experiences of transplantations from animal to human. The first transplantation attempts were made without any knowledge of the species barrier. The pioneers of xenotransplantation realized xenotransfusions as early as the 16th century, then cell and tissue xenotransplantations in the 19th century. At the beginning of the 20th century, xenotransplantation of testicles became the latest craze. At the same time, and later in the 1960s, organ xenotransplantations were attempted, with disappointing results. Mathieu Jaboulay, Serge Voronoff, Keith Reemtsma, James Hardy, Denton Cooley, Thomas Starzl, Christiaan Barnard and Leonard Bailey were among the pionneers of xenotransplantation. Recent trials concerned above all tissue and cell xenotransplantations. Nowadays, with encapsulation, transgenesis, and cloning, great advances have been made for controlling xenograft rejection, but ethical questions linked to the risk of infections have become a major pre-occupation within the scientific community and the general population.     

Clinical pig liver xenotransplantation: how far do we have to go?

As pigs are currently the preferred species for organ xenotransplantation, initial experience in liver xenotransplantation with wild-type (WT) pigs, advances in the development of genetically modified pigs, and recent studies using livers from them are reviewed. The xenotransplantation of livers from pigs transgenic for the human complement regulatory protein (CRP) CD55 or from α1,3-galactosyltransferase gene-knockout pigs+/- additionally transgenic for the CRP CD46 (GTKO/CD46 pigs) is associated with the survival of approximately 1 week. Satisfactory hepatic function has been documented, lending support to the concept that the pig liver might provide a bridge to allotransplantation. However, although significant features of rejection have not been documented, the development of an immediate thrombocytopenia after graft reperfusion is problematic and leads to spontaneous hemorrhage within the body cavities, native organs, and graft. Current studies are being directed to understand the factors causing the activation, aggregation, or phagocytosis of platelets, in particular the interaction between platelets and liver sinusoidal endothelial cells, hepatocytes, and Kupffer cells. If this problem can be resolved, a clinical trial of pig liver xenotransplantation as a bridge to allotransplantation may be both feasible and justified.     

Clinical lung xenotransplantation – what donor genetic modifications may be necessary?

Barriers to successful lung xenotransplantation appear to be even greater than for other organs. This difficulty may be related to several macro anatomic factors, such as the uniquely fragile lung parenchyma and associated blood supply that results in heightened vulnerability of graft function to segmental or lobar airway flooding caused by loss of vascular integrity (also applicable to allotransplants). There are also micro-anatomic considerations, such as the presence of large numbers of resident inflammatory cells, such as pulmonary intravascular macrophages and natural killer (NK) T cells, and the high levels of von Willebrand factor (vWF) associated with the microvasculature. We have considered what developments would be necessary to allow successful clinical lung xenotransplantation. We suggest this will only be achieved by multiple genetic modifications of the organ-source pig, in particular to render the vasculature resistant to thrombosis. The major problems that require to be overcome are multiple and include (i) the innate immune response (antibody, complement, donor pulmonary and recipient macrophages, monocytes, neutrophils, and NK cells), (ii) the adaptive immune response (T and B cells), (iii) coagulation dysregulation, and (iv) an inflammatory response (e.g., TNF-α, IL-6, HMGB1, C-reactive protein). We propose that the genetic manipulation required to provide normal thromboregulation alone may include the introduction of genes for human thrombomodulin/endothelial protein C-receptor, and/or tissue factor pathway inhibitor, and/or CD39/CD73; the problem of pig vWF may also need to be addressed. It would appear that exploration of every available therapeutic path will be required if lung xenotransplantation is to be successful. To initiate a clinical trial of lung xenotransplantation, even as a bridge to allotransplantation (with a realistic possibility of survival long enough for a human lung allograft to be obtained), significant advances and much experimental work will be required. Nevertheless, with the steadily increasing developments in techniques of genetic engineering of pigs, we are optimistic that the goal of successful clinical lung xenotransplantation can be achieved within the foreseeable future. The optimistic view would be that if experimental pig lung xenotransplantation could be successfully managed, it is likely that clinical application of this and all other forms of xenotransplantation would become more feasible.     

The International Xenotransplantation Association consensus statement on conditions for undertaking clinical trials of xenocorneal transplantation

To develop an international consensus regarding the appropriate conditions for undertaking clinical trials in xenocorneal transplantation, here we review specific ethical, logistical, scientific, and regulatory issues regarding xenocorneal transplantation, and propose guidelines for conduct of clinical xenocorneal transplantation trials. These proposed guidelines are modeled on the published consensus statement of the International Xenotransplantation Association regarding recommended guidelines for conduct of clinical islet xenotransplantation. It is expected that this initial consensus statement will be revised over time in response to scientific advances in the field, and changes in the regulatory framework based on accumulating clinical experience.     

What's New and Hot in Clinical Organ Transplantation: Report From American Transplant Congress 2012

Innovative and exciting advances in the clinical sciences in organ transplantation were presented at the American Transplant Congress 2012. The full spectrum of transplantation was covered with important advancements in many topics. Key areas covered by presentations included living donor outcomes, organ preservation, optimal allocation of deceased donors, new immunosuppression regimens, antibody mediated rejection and the regulatory environment. This review will highlight some of the most interesting and innovative clinical presentations from the meeting.     

Islet transplantation

Recently, significant advances have been made in the number and purity of islets that can be retrieved from the human pancreas, thus enabling several centers to initiate or resume clinical trials of islet transplantation in type I diabetic patients. Although the success rate of islet transplantation is lower than that of pancreas transplantation in terms of achievement of insulin-independence, islet transplantation has significant potential advantages over vascularized pancreas transplantation: it is a simple and safe procedure; it has the potential to be performed on an outpatient basis; it offers access to cell banking after cryopreservation; it offers the potential advantages of pre-transplant reduction of im-munogenecity; and it even offers the future feasibility of xenotransplantation. In this article, the current status of clinical trials and future perspectives of islet transplantation, including immunomodulation, immunotolerance, immunoisolation, and xenotransplantation, are reviewed. Received for publication on Feb. 24, 1999; accepted on March 28, 1999     

Attitude toward xenotransplantation of patients prior and after human organ transplantation

Stadlbauer V, Stiegler P, Müller S, Schweiger M, Sereingg M, Tscheliessnigg KH, Freidl W. Attitude toward xenotransplantation of patients prior and after human organ transplantation.
Clin Transplant 2011: 25: 495–503. © 2010 John Wiley & Sons A/S. Abstract: Xenotransplantation is a potential strategy to overcome the shortage of human donor organs. As this technique has a major medical and psychological impact on patients and their family and friends, the attitude of patients currently waiting for organ transplantation is important. Therefore, we conducted a survey on the attitude toward xenotransplantation of patients on the waiting list and already transplanted patients. Patients received detailed information before being asked to fill in the questionnaire. We found that 65% would accept xenotransplantation, irrespective of gender, education level or if the patients were on the waiting list or already transplanted. The most common concern was transmission of diseases or genetic material, followed by psychological concerns and ethical issues. More patients had a positive attitude toward accepting cell or tissue transplantation when compared to whole organs. Pig pancreas islet cell transplantation is generally well accepted, patients with diabetes mellitus show even higher acceptance rates than patients without diabetes. In conclusion, xenotransplantation seems to be well accepted in patients who are potential future candidates for organ transplantation. Informing patients about the current status of research tended to decrease acceptance rates slightly.     

First update of the International Xenotransplantation Association consensus statement on conditions for undertaking clinical trials of porcine islet products in type 1 diabetes—Executive summary

The International Xenotransplantation Association has updated its original “Consensus Statement on Conditions for Undertaking Clinical Trials of Porcine Islet Products in Type 1 Diabetes,” which was published in Xenotransplantation in 2009. This update is timely and important in light of scientific progress and changes in the regulatory framework pertinent to islet xenotransplantation. Except for the chapter on “informed consent,” which has remained relevant in its 2009 version, all other chapters included in the initial consensus statement have been revised for inclusion in this update. These chapters will not provide complete revisions of the original chapters; rather, they restate the key points made in 2009, emphasize new and under‐appreciated topics not fully addressed in 2009, suggest relevant revisions, and communicate opinions that complement the consensus opinion. Chapter 1 provides an update on national regulatory frameworks addressing xenotransplantation. Chapter 2 a, previously Chapter 2, suggests several important revisions regarding the generation of suitable source pigs from the perspective of the prevention of xenozoonoses. The newly added Chapter 2b discusses conditions for the use of genetically modified source pigs in clinical islet xenotransplantation. Chapter 3 reviews porcine islet product manufacturing and release testing. Chapter 4 revisits the critically important topic of preclinical efficacy and safety data required to justify a clinical trial. The main achievements in the field of transmission of all porcine microorganisms, the rationale for more proportionate recipient monitoring, and response plans are reviewed in Chapter 5. Patient selection criteria and circumstances where trials of islet xenotransplantation would be both medically and ethically justified are examined in Chapter 6 in the context of recent advances in available and emerging alternative therapies for serious and potentially life‐threatening complications of diabetes. It is hoped that this first update of the International Xenotransplantation Association porcine islet transplant consensus statement will assist the islet xenotransplant scientific community, sponsors, regulators, and other stakeholders actively involved in the clinical translation of islet xenotransplantation.     

The immense potential of xenotransplantation in surgery

There is a limited availability of deceased human organs and cells for the purposes of clinical transplantation. Genetically-engineered pigs may provide an alternative source. Although several immune barriers need to be overcome, considerable progress has been made in experimental models in recent years, largely through the increasing availability of pigs with new genetic modifications. Pig heterotopic heart graft survival in nonhuman primates has extended for 8 months, with orthotopic grafts supporting life for almost 2 months. Life-supporting kidney transplants have functioned for almost 3 months. The current barriers are related to coagulation dysfunction between pig and primate that results in thrombotic microangiopathy and/or a consumptive coagulopathy, which may in part be related to molecular incompatibilities in the coagulation systems of pigs and primates. Current efforts are concentrated on genetically-modifying the organ- or islet-source pigs by the introduction of 'anticoagulant' or 'anti-thrombotic' genes to provide protection from the recipient coagulation cascade and platelet activation. Progress with pig islet xenotransplantation has been particularly encouraging with complete control of glycemia in diabetic monkeys extending in one case for >12 months. Other areas where experimental data suggest the possibility of early clinical trials are corneal xenotransplantation and pig neuronal cell xenotransplantation, for example, in patients with Parkinson's disease. With the speed of advances in genetic engineering increasing steadily, it is almost certain that the remaining problems will be overcome within the foreseeable future, and clinical allotransplantation will eventually become of historical interest only.     

Attitudinal study of organ xenotransplantation in patients on the kidney and liver transplant waiting list in a country with a high rate of deceased donation

Martínez‐Alarcón L, Ríos A, Pons JA, González MJ, Ramis G, Ramírez P, Parrilla P. Attitudinal study of organ xenotransplantation in patients on the kidney and liver transplant waiting list in a country with a high rate of deceased donation. Xenotransplantation 2011; 18: 168–175. © 2011 John Wiley & Sons A/S. Abstract: Background: The organ transplant deficit is leading to an increase in the importance of solid organ xenotransplantation. However, the use of animals for human transplantation causes a certain amount of opposition in patients and the general public. The objective of this study was to analyze the attitude of patients on the kidney and liver waiting list toward xenotransplantation and the variables affecting this attitude. Methods: Patients on the kidney and liver waiting list (January 2003 – December 2005) were surveyed. Attitude toward xenotransplantation was assessed using a psychosocial questionnaire about the donation of organs of animal origin administered by a healthcare professional from the Transplant Unit. Results: A total of 373 patients were interviewed (kidney [n = 214] and liver patients [n = 158]). In the case of kidney patients, if the results of xenotransplantation were as effective as those attained using human organs, 76% (n = 162) would be in favor. If the results were worse, only 8% (n = 17) would be in favor. Two factors affected this attitude: a high level of education (P = 0.007) and a positive attitude toward organ donation upon death (P < 0.001). In the case of liver patients, 67% (n = 106) would be in favor if the results of xenotransplantation were as effective as those attained using human organs, decreasing to 16% (n = 25) if the results were worse. Attitude toward deceased organ donation also affected the attitude of these patients (P < 0.043). Conclusions: The attitude toward xenotransplantation of patients on the kidney and liver transplant waiting list was favorable and associated with a positive attitude toward human organ donation.     

Update regarding xenotransplantation in Japan

To overcome the donor shortage, a promising solution could be xenotransplantation. The pig is generally considered the most suitable donor species for xenotransplantation. A clinical xenotransplantation has not been conducted in Japan. However, many progresses have recently been made in this field. Japan has regulations for conducting cell xenotransplantation and guidelines to prevent zoonosis. Most Japanese patients and their family members have a positive opinion about islet xenotransplantation. A grant for clinical islet xenotransplantation research and development has been approved, and germ‐free pigs have been developed. Further research may bring the successful application of xenotransplantation closer to reality.     

ABO-incompatible allotransplantation as a basis for clinical xenotransplantation

The 8th Congress of the International Xenotransplantation Association (IXA), held in Goteborg in September, 2005, immediately followed the 2nd International Symposium on ABO-Incompatibility in Transplantation, both congresses organized by Michael Breimer and Lennart Rydberg. The Proceedings of the Symposium on ABO-Incompatibility in Transplantation have been published (Xenotransplantation 2006; 13 (2)). The present paper provides an overview of a workshop held at the 8th Congress of the IXA, and highlights the immunological concepts emerging from ABO-incompatible allotransplants and discusses them in relation to xenotransplantation. Using specified immunomodulatory protocols, ABO-incompatible solid organ allotransplantation has become a clinical reality for a small number of patients over the last two decades. ABO-incompatible adult kidney and infant heart transplants have similar patient and graft survivals as their ABO-compatible counterparts. In contrast, ABO-incompatibility is present in up to 30% of all patients receiving hematopoietic stem cell transplants in the absence of specific immunomodulation, without affecting overall survival. Consequently, ABO-incompatible solid organ transplants and hematopoietic stem cell transplants may serve as in vivo models to elucidate the immunological mechanisms of accommodation and/or tolerance in the clinical setting. Because of similarities in the immunological hurdles that need to be overcome, knowledge obtained from ABO-incompatible allotransplantation might further promote advances in the field of xenotransplantation. The similarities and differences between ABO-incompatible allotransplantation and xenotransplantation are discussed.