Successful Organ Transplantation Research Articles

Total Recall: Can We Reshape T Cell Memory by Lymphoablation?

Despite recent advances in immunosuppression, donor-reactive memory T cells remain a serious threat to successful organ transplantation. To alleviate damaging effects of preexisting immunologic memory, lymphoablative induction therapies are used as part of standard care in sensitized recipients. However, accumulating evidence suggests that memory T cells have advantages over their naive counterparts in surviving depletion and expanding under lymphopenic conditions. This may at least partially explain the inability of existing lymphoablative strategies to improve long-term allograft outcome in sensitized recipients, despite the well-documented decrease in the frequency of early acute rejection episodes. This minireview summarizes the insights gained from both experimental and clinical transplantation as to the effects of existing lymphoablative strategies on memory T cells and discusses the latest research developments aimed at improving the efficacy and safety of lymphoablation.

The Biological Effects of IL-21 Signaling on B-Cell-Mediated Responses in Organ Transplantation.

Antibody-mediated rejection has emerged as one of the major issues limiting the success of organ transplantation. It exerts a highly negative impact on graft function and outcome, and effective treatment is lacking. The triggers for antibody development, and the mechanisms leading to graft dysfunction and failure, are incompletely understood. The production of antibodies is dependent on instructions from various immunocytes including CD4 T-helper cells that secrete interleukin (IL)-21 and interact with antigen-specific B-cells via costimulatory molecules. In this article, we discuss the role of IL-21 in the activation and differentiation of B-cells and consider the mechanisms of IL-21 and B-cell interaction. An improved understanding of the biological mechanisms involved in antibody-mediated complications after organ transplantation could lead to the development of novel therapeutic strategies, which control humoral alloreactivity, potentially preventing and treating graft-threatening antibody-mediated rejection.

Anesthetic Considerations for the Parturient After Solid Organ Transplantation.

Over the past 40 years, the success of organ transplantation has increased such that female solid organ transplant recipients are able to conceive and carry pregnancies successfully to term. Anesthesiologists are faced with the challenge of providing anesthesia care to these high-risk obstetric patients in the peripartum period. Anesthetic considerations include the effects of the physiologic changes of pregnancy on the transplanted organ, graft function in the peripartum period, and the maternal side effects and drug interactions of immunosuppressive agents. These women are at an increased risk of comorbidities and obstetric complications. Anesthetic management should consider the important task of protecting graft function. Optimal care of a woman with a transplanted solid organ involves management by a multidisciplinary team. In this focused review article, we review the anesthetic management of pregnant patients with solid organ transplants of the kidney, liver, heart, or lung.

Looking Outside: Summer Camp for Children Who Have Undergone a Solid-Organ Transplant.

A high-quality critical care team is an essential component of any successful organ transplant program. From pretransplant care to the crucial postoperative period, its importance cannot be discounted. However, because of the focused nature of work in an intensive care unit (ICU), all too often members of the ICU team are not able to see and appreciate the ultimate fruits of their labor. These are factors that can contribute to the high rates of burnout and turnover among ICU teams. This article presents the concept of a summer camp for children who have received a solid-organ transplant. We discuss a vehicle by which ICU staff as well as other members of a patient's care team can gain a better appreciation of the full nature of both medical and, perhaps more importantly in this situation, nonmedical goals and outcomes in pediatric transplantation. We review our institutional experience running a summer camp for these children, discuss some of the important points in making such a camp successful, and discuss potential benefits to the campers as well as those taking care of them.

Travel to High Altitude Following Solid Organ Transplantation.

Luks, Andrew M. Clinician's corner: travel to high altitude following solid organ transplantation. High Alt Med Biol. 17:147-156, 2016.-As they regain active lifestyles following successful organ transplantation, transplant recipients may travel to high altitude for a variety of activities, including skiing, climbing, and trekking. This review is intended to provide information for medical providers who may encounter transplant patients seeking advice before planned high altitude travel or care for medical issues that develop during the actual sojourn. There is currently limited information in the literature about outcomes during high-altitude travel following solid organ transplantation, but the available evidence suggests that the physiologic responses to hypobaric hypoxia are comparable to those seen in nontransplanted individuals and well-selected transplant recipients with no evidence of organ rejection can tolerate ascents as high as 6200 m. All transplant recipients planning high-altitude travel should undergo pretravel assessment and counseling with an emphasis on the recognition, prevention, and treatment of altitude illness, as well as the importance of preventing infection and limiting sun exposure. Transplant recipients can use the standard medications for altitude illness prophylaxis and treatment, but the choice and dose of medication should take into account the patient's preexisting medication regimen and current renal function. With careful attention to these and other details, the healthy transplant recipient can safely experience the rewards of traveling in the mountains.

Motivations for Deceased Organ Donation Among Volunteers in China: A Qualitative Research Study.

BACKGROUND To align with guiding principles on human organ and tissue transplantation published by the World Health Organization (WHO), the Red Cross Society of China (RCSC) launched a new nationwide organ donation program in 2010 to recruit organ donation volunteers. Despite severe shortage of donated organs, there is a very low rate of volunteering for organ donation among the Chinese population (only 0.03 donors per million population) in the national program. Motivating organ donation is the key to the success of organ transplantation in China. MATERIAL AND METHODS Semi-structured 45- to 60-min interviews were conducted among 34 volunteers. Data analysis was performed with Nvivo 8.0 software. RESULTS Six motivations for organ donation were identified: helping others/altruism, fulfilling long-cherished wishes, reducing the burdens, making the best use of everything, giving back to society, and life extension. Factors affecting the motivation of organ donation among volunteers in China included traditional values, personal experiences, role model effect, family support, and problems in the donation system. Possible strategies to improve organ donation included fostering a scientific concept of the body and death, focusing donation promotion efforts on certain groups, and simplifying the process of organ donation. CONCLUSIONS There are multiple reasons for Chinese people to register for organ donation, with helping others as the central motivation.

Social world of organ transplantation, trafficking, and policies.

Although success of organ transplants reflects advances in medical procedures, the success has generated debates about the ethical standards and policies that govern transplants, especially the acquisition of organs for transplants. We focus on laws, policies, and organ trafficking to highlight the interdisciplinary perspectives that can shape our understanding of transplantation as a social phenomenon. We discuss international policies and country-specific legislation from Pakistan to point to gaps and their implications for protecting vulnerable people who are exploited for organ removal. International collaboration and the legal framework need to be strengthened to fight the menace globally and to deal with the cases of organ trafficking within the legal ambit of human trafficking so that the rights of victims are upheld by states, justice systems, and ultimately medical establishments and practitioners.

Understanding Luminal Microorganisms and Their Potential Effectiveness in Treating Intestinal Inflammation.

The human intestine contains 10¹⁴ bacteria, which outnumber the mammalian cells 10-fold. Certain other commensal or infectious agents, like helminthic parasites, become members of this microbial ecosystem, especially in populations living under less hygienic conditions. Intestinal microbes, also called the microbiome or microbiota, shape the host immune reactivity to self and nonself throughout life. Changes in microbiome composition may impair the maturation of immune regulatory pathways and predispose the host to develop various forms of inflammatory disorders, like Crohn's disease or ulcerative colitis. The microbiome is also critical to successful transplantation of organs or grafts. After allogeneic hematopoietic stem cell transplantation, when the new donor cells, such as T lymphocytes learn to discriminate "the new self from nonself" in the transplant recipient, they need healthy microbiota-derived signals to preserve the immune homeostasis. Restoring microbiota through intestinal delivery of bacterial strains, helminths, fecal microbiota transplantation, or stool substitutes have the potential to improve and correct aberrant immune reactivity in various disorders.

Improving medication adherence among kidney transplant recipients: Findings from other industries, patient engagement, and behavioral economics-A scoping review.

The immune system is a powerful barrier to successful organ transplantation, but one that has been routinely thwarted through modern pharmacotherapeutics. Despite the benefits of immunosuppressive therapy, medication non-adherence leads to an increased risk of graft rejection, higher hospital utilization and costs, and poor outcomes. We conduct a scoping review following Arksey and O’Malley’s five-stage framework methodology to identify established or novel interventions that could be applied to kidney transplant recipients to improve medication adherence. As the desired outcome is a behavior (taking a pill), we assess three areas: behavioral-focused interventions in other industries, patient engagement theories, and behavioral economic principles. Search strategies included mining business, social sciences, and medical literature with additional guidance from six consultative interviews. Our review suggests that no intervention stands out as superior or likely to be more effective than any other intervention; yet promising strategies and interventions were identified across all three areas examined. Based on our findings, we believe there are five strategies that transplant centers and other organizations can implement to improve medication adherence: (1) Build a foundation of trust; (2) Employ multiple interventions; (3) Stratify the population; (4) Develop collaborative partnerships; and (5) Embed medication adherence into the organization’s culture. The effectiveness of these interventions will need to be investigated further, but we believe they are a step in the right direction for organizations to consider in their efforts to improve medication adherence.

Ridge augmentation in an organ transplant patient

With the continuing progress in medicine, the number of successful organ transplantations has continued to increase, a fact that also concerns dentists and implantologists. Implantology after organ transplantation remains controversial due to the patient's immunocompromised situation and the corresponding risk of infection. Only a few studies on this topic have been reported, with all of them showing the dental implant success rates in transplant patients to be similar to those in healthy subjects. However, immunosuppression has been identified as a contraindication to bone augmentation. Consequently, there is still a lack of knowledge regarding pre-implantology bone grafting procedures. The following case report describes the use of ridge augmentation and extended bilateral sinus lift procedures in a liver transplant patient. The patient was treated with an implant-supported fixed prosthesis in the upper jaw and was followed up for a total of 28 months after implant insertion. According to the findings presented, pre-implantology augmentation procedures may be performed successfully in immunosuppressed organ transplant patients. Stable peri-implant conditions were shown over a period of more than 2 years. Nevertheless, further investigations are needed to define a safe treatment protocol for these high-risk patients.

The role of genetically engineered pigs in xenotransplantation research.

There is a critical shortage in the number of deceased human organs that become available for the purposes of clinical transplantation. This problem might be resolved by the transplantation of organs from pigs genetically engineered to protect them from the human immune response. The pathobiological barriers to successful pig organ transplantation in primates include activation of the innate and adaptive immune systems, coagulation dysregulation and inflammation. Genetic engineering of the pig as an organ source has increased the survival of the transplanted pig heart, kidney, islet and corneal graft in non-human primates (NHPs) from minutes to months or occasionally years. Genetic engineering may also contribute to any physiological barriers that might be identified, as well as to reducing the risks of transfer of a potentially infectious micro-organism with the organ. There are now an estimated 40 or more genetic alterations that have been carried out in pigs, with some pigs expressing five or six manipulations. With the new technology now available, it will become increasingly common for a pig to express even more genetic manipulations, and these could be tested in the pig-to-NHP models to assess their efficacy and benefit. It is therefore likely that clinical trials of pig kidney, heart and islet transplantation will become feasible in the near future.

From Kidney Transplants to Vascularized Composite Allografts: The Role of the Plastic Surgeon in Transplantation

In 1954, plastic surgeon Dr Joseph Murray performed the first successful organ transplant between identical twins. Today solid organ transplants are performed routinely and offer a curative option for patients with end stage organ failure. For his pioneering work in transplantation biology, Dr Murray remains the only plastic surgeon to have been awarded the Nobel Prize in Medicine.The success of modern day transplants has allowed transplantation to be applied more broadly. In particular, vascularized composite allografts (VCAs), including face and hand transplants, have emerged over the past 15 y. These have been used for reconstruction of patients with extensive disfigurements. Despite these great successes, the use of chronic immunosuppression by transplant recipients is accompanied by the risk of malignancy, organ toxicity and infection. Current research efforts by transplant physicians and plastic surgeons are aimed at reducing and subsequently eliminating the burden of life-long immunosuppression.Thi...

Diagnostic workup of brain-dead organ donors and organ retrieval

Renal transplantation is well established as the best and often the only treatment for many patients with end-stage kidney failure. Because of an increasing shortfall between the diminishing number of deceased donor organs available and the increasing waiting list of patients in need of transplantation the shortage of suitable donors remains one of the most pressing challenges. The success of organ transplantation can be attributed to many factors but ultimately depends upon retrieval and preservation techniques to maintain the quality of an organ. Although the literature on organ retrieval is extensive, the level of evidence provided is mainly low. But as techniques and treatments improve, it may be possible to use organs from donors who were previously thought to be unsuitable. This article provides the reader an overview on the topic of organ donation.

Hypodermin A, a potential agent for prevention of allogeneic acute rejection

Immunosuppressive agents play an important role in the success of organ transplantation, however the chronic toxicity of these agents is a major issue over the long-term. Hypodermin A (HA) is an enzyme secreted by the larvae of Hypoderma lineatum (Diptera: Oestridae), and has been implicated in immunosuppression in cattle. Malassagne et al. have demonstrated that HA can degrade the C3 protein, and could be used to prevent hyperacute xenogeneic rejection. We found that overexpression of HA in RAW264.7 cells induced significant secretion of prostaglandin E2 (PGE2), which mediates a variety of innate and adaptive immune responses through four E-type prostanoid (EP) receptor subtypes (EP1–4). PGE2 is useful in the management of allogeneic acute rejection. In addition, we found that induction of PGE2 expression downregulates the expression of interferon (IFN)-γ and interleukin (IL)-2, and promotes the secretion of IL-10 in vitro through the EP4 receptor. It was previously shown that activation of IL-2 and IFN-γ is involved in allograft acute rejection. IL-10 is known to prevent inflammation, and can improve allograft survival rates. We concluded that besides preventing hyperacute xenogeneic rejection, HA might also be a potential therapeutic candidate for ameliorating acute rejection during allotransplantation.

HLA Antibody testing- it’s not a one stop assay

HLA laboratories rely on single antigen (SA) assays to determine unacceptable antigens and perform virtual crossmatches (vXM) that can immunologically guide clinicians in the identification of an appropriate donor. Although solid phase antibody detection assays are sensitive, specific and robust-instances arise when further testing is needed to verify results or resolve inconsistencies between these tests. Patient S.T. is a 50 year old male diagnosed with heart failure. Routine work-up in our laboratory is to evaluate % FlowPRA and compare those results to solid phase assays on a Luminex platform which measures the breadth and strength of antibodies in a patient’s sera. Patient S.T. had two samples tested three months apart with a class I FlowPRA of 58% and 62%, respectively. However, The Luminex SA results consistently demonstrated only 5 class I (all B15) antibodies in the positive MFI range leading to a cPRA of about 15%. Moreover, the internal negative control values were > 2500 MFI leading us to believe that there may be additional specificities masked by the high background. How should we deal with these contradictory test results? Can we rely on a vXM to accept a heart for this patient? To reconcile these seemingly contradictory results and to determine if the antibodies detected by Luminex assays were relevant, surrogate FCXM were performed. Surrogate Donor 1 (B15 positive) was FCXM positive. Surrogate donor 2 (B15 negative) was FCXM negative indicating that non-specific binding/false-positivity due to high background should not affect FCXM interpretation, Importantly, testing using phenotype beads were not affected by high background and further confirmed the presence of B15 antibodies. Due to the presence of HLA antibodies and the high background exhibited by this patient, a prospective FCXM must be performed prior to accepting an organ. In conclusion, this is an example in which different tests provide contradictory (or non-consistent) results - and our approach to resolve these ambiguities to support successful organ transplantation.

Role of Sphingosine-1-Phosphate in Transplant Vasculopathy Evoked by Anti-HLA Antibody

Transplant vasculopathy (TV) represents the main cause of late graft failure and limits the long-term success of organ transplantation. Cellular and humoral immune responses contribute to the pathogenesis of the concentric and diffuse intimal hyperplasia of arteries of the grafted organ. We recently reported that the mitogenic signaling, evoked in human vascular smooth muscle cells (hmSMC) by the anti-HLA class I monoclonal antibody W6/32, implicates neutral sphingomyelinase-2, suggesting a role for sphingolipids in intimal hyperplasia of TV. Here, we investigated whether the mitogenic sphingolipid, sphingosine-1-phosphate (S1P), is involved in intimal hyperplasia elicited by W6/32. Studies were done on cultured hmSMC and on an in vivo model of TV, consisting of human mesenteric arteries grafted into SCID/beige mice, injected weekly with W6/32. hmSMC migration and DNA synthesis elicited by W6/32 were inhibited by the sphingosine kinase-1 (SK1) inhibitor dimethylsphingosine, the anti-S1P antibody Sphingomab and the S1PR1/R3 inhibitor VPC23019. W6/32 stimulated SK1 activity, while siRNA silencing SK1, S1PR1 and S1PR3 inhibited hmSMC migration. In vivo, Sphingomab significantly reduced the intimal thickening induced by W6/32. These data emphasize the role of S1P in intimal hyperplasia elicited by the humoral immune response, and open perspectives for preventing TV with S1P inhibitors.

Addressing organ shortage: are nudges the way forward?

ABSTRACTThis paper examines the use of nudges in organ donation, against a background of organ shortage. This is a complex and contested area of public policy where questions of legitimacy loom large. The legitimacy of nudges is assessed by reference to function, values-based and democratic criteria. Analysis of normative claims made about nudges revealed that such criteria were not fulfilled. Findings from UK experimental studies showed that nudge interventions had a short-term effect, limited to increasing organ donation registration rates. It was unclear how this might translate into donation of organs after death or successful organ transplants. One of the studies also revealed the importance attached to reciprocity in motivating people to register as organ donors. This calls into question whether there should more of a focus on developing a reciprocity model to encourage human tissue donation, rather than relying on altruistic intent as embodied in the gift relationship.

Refractive surgery following corneal graft.

To review the different surgical procedures for management of postkeratoplasty refractive errors after total suture removal. There are different surgical options to address residual refractive errors that frequently occur after corneal transplantation. The correction can be done on the corneal surface or intraocular with intraocular lens (IOL) implantation which requires complete tectonic and refractive stability after suture removal. The most commonly used procedures are photorefractive keratectomy, laser in-situ keratomileusis and Phakic IOLs. Keratoplasty has been profited by recent advances in refractive surgery. Custom excimer laser ablation is an alternative way to treat irregular errors. New IOL modalities are good practical options for a wide range of errors. Femtosecond laser, as a new option in the toolbox, can modify corneal grafting refractive results and assist corrective refractive procedures. Although being the most successful organ transplantation, keratoplasty is usually followed by significant ametropia. Different corrective modalities exist and the choice should fit ocular conditions, patient requirements, surgeon skills and the available technologies. Recent advances in ophthalmic surgery have improved the outcomes.

Pericytes, microvasular dysfunction, and chronic rejection.

Chronic rejection of transplanted organs remains the main obstacle in the long-term success of organ transplantation. Thus, there is a persistent quest for development of antichronic rejection therapies and identification of novel molecular and cellular targets. One of the potential targets is the pericytes, the mural cells of microvessels, which regulate microvascular permeability, development, and maturation by controlling endothelial cell functions and regulating tissue fibrosis and inflammatory response. In this review, we discuss the potential of targeting pericytes in the development of microvasular dysfunction and the molecular pathways involved in regulation of pericyte activities for antichronic rejection intervention.

Transplantation of Epcam+Ve Human Hepatic Stem Cells in Liver Cirrhosis Patient and Cellular Immune Response Running Title: Transplantation and Cellular Immune Response

Liver transplant is considered is the only treatment for liver cirrhosis. Despite the success of organ transplantation, the treatment requires lifelong immunosuppression and major limitation is the availability of donor liver. Hepatic progenitor cell transplantation (HSCT) offers novel but challenging alternatives therapy to liver transplantation for management of liver cirrhosis. In this study, we investigated the cellular immune response by monitoring T-cell, NK-cell and cytokines which play major role in cellular rejection. A total of 5 patients with decompensated liver cirrhosis were enrolled in the study. T-cell (CD3, CD4 and CD8), NK-cells (CD16) was monitored before (Day-1) and after transplantation (Day 1, 7, 15, 30) of human fetal liver-derived EPCAM+Ve cell by flowcytometry. Before and after transplantation, Cytokinelevels (IL2, TNFβ, IFNα, IFNγ and INFβ) were also measured by ELISA. Study has demonstrated that after HSCT patient showed marked clinical recovery and decline in the MELD score and there was no significant increase found in cell mediated response and cytokine levels between pre and post transplantation. Hence this preliminary study demonstrated human fetal liver- derived EPCAM+Ve stem cell transplantation is safety for end stage liver cirrhosis.