Regulatory T cells: from the bench to the clinic and back Purpose of review
The main objective of this review is to briefly highlight how we gradually came to understand regulatory T cells (Tregs) and forkhead box p3 (FoxP3) biology, including their function and regulation. We will also discuss how this knowledge is being translated into the clinical setting and the significant challenges that need to be overcome.
CD4+FoxP3+ Tregs are key players in immune regulation. Their deficiency and dysfunction have been implicated in the pathogenesis of many autoimmune diseases. This has led towards extensive work across the years to figure out the biology and suppressive mechanisms of these cells. Furthermore, Tregs’ ability to suppress immune responses makes the idea of their utilization in adoptive immunotherapy appealing. Work has been underway to establish ideal methods to integrate Tregs into the management of autoimmune diseases and alloimmunity, either by treatment with IL-2 or infusion of ex-vivo expanded Tregs. Despite Tregs’ scarcity and increased tendency for Activation-induced cell death, many groups have developed effective methods to expand them ex vivo.
Although clinical trials are ongoing to test the safety and efficacy of regulatory cells in transplant recipients, it is vital to continue exploring the cellular and molecular mechanisms that control their stability and homeostasis.
Active targeted delivery of immune therapeutics to lymph nodes Purpose of review
Organ transplantation is a life-saving procedure and the only option for patients with end-organ failure. Immune therapeutics have been key to the success of organ transplantation. However, immune therapeutics are still unable to eliminate graft rejection and their toxicity has been implicated in poorer long-term transplant outcomes. Targeted nanodelivery has the potential to enhance not only the therapeutic index but also the bioavailability of the immune therapeutics. One of the key sites of immune therapeutics delivery is lymph node where the priming of immune cells occur. The focus of this review is on nanomedicine research to develop the targeted delivery of immune therapeutics to lymph nodes for controlling immune activation.
As nanomedicine creates its niche in clinical care, it provides novel immunotherapy platforms for transplant recipients. Draining lymph nodes are the primary loci of immune activation and represent a formidable site for delivery of wide variety of immune therapeutics. There have been relentless efforts to improve the properties of nanomedicines, to have in-depth knowledge of antigen and drug loading, and, finally, to explore various routes of passive and active targeted delivery to lymph nodes.
The application of nanotechnology principles in the delivery of immune therapeutics to the lymph node has created enormous excitement as a paradigm shifting approach that enables targeted delivery of a gamut of molecules to achieve a desired immune response. Therefore, innovative strategies that improve their efficacy while reducing their toxicity are among the highest unmet needs in transplantation.
Biomimetic nanoparticles for transplantation tolerance Purpose of review
The current review aims to provide a current landscape and future trends of biomimetic nanoparticles which have the potential to revolutionize the field of transplantation in the next decade.
Currently, the inability to safely induce robust donor-specific immunological tolerance makes it difficult to achieve immunosuppression-free graft survival. Despite progresses in the development of nanotherapeutics for antigen-specific immunomodulation in autoimmune diseases and in cancer treatments, few have been proposed and tested in transplantation with success. The complexity of parallel rejection mechanisms, multitude of antigen epitopes, and potential epitope spreading have challenged conventional nanodelivery systems in transplant models. Overcoming such challenges, biomimetic nanotherapeutics represent a promising alternative, as they allow better recapitulation of the complexity of the main biological players involved in tolerance. Within biomimetic nanodelivery systems, we envision that hybrid systems mimicking extracellular vesicles have the potential to bridging the gap between cell-based therapies, which are effective but costly and difficult to translate in clinical practice, and fully synthetic systems which are relatively easy to manufacture but lack the capacity to recapitulate the complexity of transplant antigens and tolerance mechanisms.
Next-generation nanotherapeutics for tolerance delivery is evolving toward biomimetic systems capable of capturing an increasing level of antigen complexity and exploiting multiple tolerance pathways.
Emerging role of exosomes in allorecognition and allograft rejection Purpose of review
This article reviews recent literature on the nature of extracellular vesicles released by allogeneic transplants and examine their role in T-cell alloimmunity involved in rejection and tolerance of these grafts.
Donor cells release extracellular vesicles, including exosomes, after transplantation of allogeneic organs and tissues. Consequently, recipient APCs take up these exosomes and present donor MHC antigens on their surface (allo-MHC cross-dressing) thus, activating some alloreactive T cells via a mechanism called semi-direct pathway of allorecognition. In addition, one study shows that exosomes carrying noninherited maternal antigens are associated with maternal microchimerism and tolerance in offspring. Finally, a few studies describe potential utilization of exosomes as modulators of alloimmunity and biomarkers of rejection in allotransplantation.
Extracellular vesicles, including exosomes, released by allografts contribute to recognition of donor antigens by T cells after allotransplantation. This occurs through cross-dressing of recipient APCs with donor MHC antigens and subsequent activation of T cells, a process called semi-direct alloreactivity. The relevance of this phenomenon in rejection and tolerance of allografts and the potential utilization of exosomes as biomarkers in transplantation are discussed.
Mechanisms of rejection in vascular composite allotransplantation Purpose of review
For patients with devastating injuries in whom standard reconstruction is not an option, vascularized composite allotransplantation (VCA) has become a viable means of restoring form and function. However, immunological rejection continues to be a problem in VCA and has not yet been fully characterized. As the field is relatively new, much of the data on rejection and immunosuppression have been extrapolated from that of solid organ transplantation. In this review, we cover the basic mechanisms of rejection as they relate specifically to VCA with analysis of recent literature and future directions.
Recent clinical studies have supported previously postulated T-cell-mediated mechanism of acute rejection and have also made strides in differentiating rejection from inflammation from other skin conditions and with different treatment regimens. Antibody-mediated rejection has been described in recent cases as well as treatment of presensitized patients receiving VCAs. With more long-term grafts, chronic changes, including vasculopathy, are being reported.
Clinically observed types of rejection in VCA include mainly cell-mediated, antibody-mediated and chronic rejection. Advances in diagnosis and treatment of rejection have been made, but there is still much to be learned about VCA-specific rejection.
ATP and T-cell-mediated rejection Purpose of review
Purine nucleosides and nucleotides are released in the extracellular space following cell injury and act as paracrine mediators through a number of dedicated membrane receptors. In particular, extracellular ATP (eATP) significantly influences T-lymphocyte activation and phenotype. The purpose of this review is to discuss the role of ATP signaling in the T-cell-mediated alloimmune response.
In various animal models of solid transplantation, the purinergic axis has been targeted to prevent acute rejection and to promote long-term graft tolerance. The inhibition of ATP-gated P2X receptors has been shown to halt lymphocyte activation, to downregulate both Th1 and Th17 responses and to promote T-regulatory (Treg) cell differentiation. Similarly, the inhibition of ATP signaling attenuated graft-versus-host disease in mice undergoing hematopoietic cell transplantation. Significantly, different drugs targeting the purinergic system have been recently approved for human use and may be a viable therapeutic option for transplant patients.
The inhibition of eATP signaling downregulates the alloimmune response, expands Treg cells and promotes graft survival. This robust preclinical evidence and the recent advances in pharmacological research may lead to intriguing clinical applications.
Diverse roles of TIM4 in immune activation: implications for alloimmunity Purpose of review
T-cell immunoglobulin and mucin domain-containing molecule (TIM)4 is a costimulatory molecule and phosphatidylserine receptor. Its dominant function varies according to the expressing cell and site of activation. In recent years, studies have identified its role in diverse disease processes and increasingly in alloimmunity. Herein, we will comprehensively review the literature on TIM4 and outline its function in shaping the alloimmune response.
TIM4 expression on dendritic cells increases following transplantation. Blockade of TIM4 in vivo leads to increased differentiation of regulatory T cells and improved allograft survival. TIM4 binds phosphatidylserine-expressing apoptotic cells. Previously thought of as a tethering molecule, recent studies have demonstrated that TIM4 interacts with integrins to mediate uptake of apoptotic cells. TIM4+ B cells have recently been identified, which produce high levels of IFNγ and promote allograft rejection. Targeting these B cells improved allograft survival and promoted the development of TIM1+ regulatory B cells.
TIM4 is expressed in niche compartments and has many immunological effects. However, inhibition of TIM4 has been demonstrated to prolong allograft survival, through varied mechanisms. A unifying explanation for the role of TIM4 in alloimmunity remains to be found, but this pathway appears to hold considerable promise in transplantation.
Significance of biologics in renal transplantation: past, present, and future Purpose of review
Finding the right immunosuppressive approach for the individual transplant patient is of utmost importance. In truth, a ‘one size fits all’ does not exist, and as patients differ, so should therapeutic suppression of the immune system be individualized. For over three decades, biologics have been a central component of transplant immunosuppression. Our growing knowledge of immunological processes combined with biotechnological advances is leading to promising new therapeutic concepts and possibilities including novel biologics. Use of biologics may be appropriate at various phases of kidney transplantation, from desensitization and induction to maintenance therapy and management of acute rejection. Their mechanisms of action include depleting or modulating immune cells, eliminating preformed antibodies, and inhibiting the complement system. Herein, we summarize the current approaches to applying ‘established’ biologics to prevent and treat allograft rejection in kidney transplantation. We also provide insights into new developments and possible future directions.
A number of candidate biologics were found to be efficacious in more recent preclinical and early phase clinical trials. Their properties are outlined and their potential for future utilization discussed.
The extraordinary capabilities of biologics are undisputed and our technological progress offers unprecedented opportunities to devise new agents and refine old ones. However, the rationale for their use in kidney allograft recipients must be rigorously examined in every case and, given the significant risk of early and late-onset adverse effects, the risk-to-benefit ratio carefully balanced. We also need to expand and use our knowledge of the underlying physiology of allograft rejection to adjust the characteristics of therapeutic biologics and thus harness their full potential for the benefit of our patients.
Micro-RNAs in transplant tolerance Purpose of review
Micro-RNAs (miRNAs) are highly conserved small RNA molecules that have selective gene-regulatory functions. This posttranscriptional regulation by miRNAs is critical for many immunological processes. Many developments in establishing the biological role of miRNAs in solid organ transplantation have been generated in the last decade. Discoveries of immune regulation by miRNAs, resulting in graft prolongation and transplant tolerance, are rapidly advancing and are the subject of this review.
Many elegant experimental studies have revealed intriguing associations between transplant tolerance and specific miRNA profiles. These findings have provided insight into the miRNAs critical for sustaining immune suppression, and have revealed common miRNA pathways that should be further investigated and/or targeted therapeutically. Further reports have strategized and corroborated different methods of manipulating miRNA expression for prolonging allograft survival, yielding promising preclinical evidence of the efficacy of miRNA-based therapies.
The review covers these recent developments in miRNA research that can revolutionize how we implement diagnostics and prognostics and how we can strategize transplantation therapies.
Harnessing the lymph node microenvironment Purpose of review
To evaluate role of the lymph node in immune regulation and tolerance in transplantation and recent advances in the delivery of antigen and immune modulatory signals to the lymph node.
Lymph nodes are a primary site of immune cell priming, activation, and modulation, and changes within the lymph node microenvironment have the potential to induce specific regulation, suppression, and potentially tolerance. Antigen enters the lymph node either from tissues via lymphatics, from blood via high endothelial venules, or directly via injection. Here we review different techniques and materials to deliver antigen to the lymph node including microparticles or nanoparticles, ex-vivo antigen presenting cell manipulation, and use of receptor conjugation for specific intralymph node targeting locations.
The promising results point to powerful techniques to harness the lymph node microenvironment and direct systemic immune regulation. The materials, techniques, and approaches suggest that translational and clinical trials in nonhuman primate and patients may soon be possible.
Revisiting the phenotypic and genetic profiling of anergic T cells mediating long-term transplant tolerance Purpose of review
Herein our focus will be to revisit peripheral tolerance mechanisms and in particular ‘active’ or ‘dominant’ tolerance as originally defined and mediated by regulatory CD4+FoxP3+ T lymphocytes (Treg) and also T-cell anergy that appears as a major mainstay to support long-term allograft survival.
It is at the same time interesting and rewarding that the tool that recently guided our efforts along this path is the in-vivo use of CD3 antibody, the first monoclonal introduced in the clinic (Orthoclone OKT3) about 35 years ago to treat and prevent rejection of renal allografts. Beyond their immunosuppressive activity, whenever administered judiciously, CD3 antibodies promote robust allograft tolerance through selective purging of alloreactive effectors, resetting Treg-mediated active tolerance and promoting a unique subset of anergic CD8+ T cells.
The new findings discussed open up new perspectives from both a fundamental and a clinical point of view. In basic research, concrete molecular signaling paths are now spotted to finely dissect the conditions that lead to the establishment and maintenance of robust T-lymphocyte anergy mediating allograft tolerance. In the clinic, this may rapidly translate into novel biomarkers to be used in parallel to the ones already available, to better adapt posttransplant immunotherapy and monitor for long-term allograft acceptance.
Are donor lymphocytes a barrier to transplantation tolerance? Purpose of review
Following solid organ transplantation (SOT), populations of donor lymphocytes are frequently found in the recipient circulation. Their impact on host alloimmunity has long been debated but remains unclear, and it has been suggested that transferred donor lymphocytes may either promote tolerance to the graft or hasten its rejection. We discuss possible mechanisms by which the interaction of donor passenger lymphocytes with recipient immune cells may either augment the host alloimmune response or inhibit it.
Recent work has highlighted that donor T lymphocytes are the most numerous of the donor leukocyte populations within a SOT and that these may be transferred to the recipient after transplantation. Surprisingly, graft-versus-host recognition of major histocompatibility complex class II on host B cells by transferred donor CD4 T cells can result in marked augmentation of host humoral alloimmunity and lead to early graft failure. Killing of donor CD4 T cells by host natural killer cells is critical in preventing this augmentation.
The ability of passenger donor CD4 T cells to effect long-term augmentation of the host humoral alloimmune response raises the possibility that ex-vivo treatment or modification of the donor organ prior to implantation may improve long-term transplant outcomes.
Equipping the islet graft for self defence: targeting nuclear factor κB and implications for tolerance Purpose of review
Clinical islet transplantation does not enjoy the success seen for solid organ transplants, indicating a need for new therapeutic approaches to improve patient outcomes. This has prompted investigation into islet autonomous factors and pathways that may represent druggable targets. These have the potential to synergize with approaches aimed at generating graft-specific tolerance.
There are emerging data that nuclear factor κB (NF-κB) activation can prevent and or overcome tolerance, whereas dampening NF-κB activation in immune cells is associated with prolonged allograft survival. In islet cells, NF-κB plays a central role in triggering the inflammatory transcriptional response that is often associated with reduced islet function and contributes to poor transplant outcomes.
Targeting intraislet NF-κB represents a promising target in islet transplantation. Here we will discuss the current state of the knowledge on the role of NF-κB activation in the context of islet transplantation and the implications of targeting NF-κB for tolerance induction.
Guiding regulatory T cells to the allograft Purpose of review
The application of regulatory T cell (Treg) therapy in organ transplantation is actively being pursued using unmodified, typically polyclonal cells. As the results of these ongoing clinical trials emerge, it is time to plan the next wave of clinical trials of Tregs. Here we will review a key strategy to improve Treg effectiveness and reduce side effects, namely increasing Treg specificity – both in terms of antigen recognition and localization to the allograft.
Study of chemokine signatures accompanying acute rejection has revealed several chemokines that could be targeted to increase Treg homing. For example, Tregs possessing a Th1-like phenotype and expressing CXCR3 are better able to migrate towards local inflammation. Allografts themselves can be modified to increase Treg-attracting chemokines and Tregs themselves can produce chemokines, facilitating local proximity to their targets of suppression. Finally, tailoring Treg antigen specificity by T-cell or chimeric antigen receptor engineering is another approach to increase the specificity of suppression and optimize localization.
Treg localization to the graft is important, but the important role of lymph node and germinal center homing cannot be overlooked. There is an opportunity to learn from advances made in cancer immunotherapy to optimize Treg therapy for transplantation.
Determination of death in donation after circulatory death: an ethical propriety Purpose of review
The recently developed donation after circulatory death (DCD) heart transplant technique, pioneered by Papworth Hospital in the UK, involves the use of extracorporeal perfusion technologies to restart the donor heart in situ and thereby restore the donor's own circulation, after first isolating the donor's cerebral circulation. By restoring the circulation in the deceased donor, even if the cerebral circulation is excluded, the Papworth technique challenges the acceptability of death determination in DCD.
This study uses as its exemplar case the Papworth DCD heart technique to review and make wider comment about death determination in DCD. We seek to answer three challenges to ethical propriety raised by the Papworth technique: death determination using the permanence standard (common to all DCD practice); restoration of heart contractility and circulation in the body; and active prevention of the restoration of brain circulation by use of a cross-clamp to isolate the cerebral circulation.
The Papworth technique for heart DCD does not compromise the permanence standard for declaring death and therefore respects the dead donor rule in the UK, but perhaps elsewhere the law would need to change to refer to the cessation of circulation in the brain.
Donation after circulatory death and its expansion in Spain Purpose of review
Donation after circulatory death (DCD) is still performed in a limited number of countries. This article summarizes the development of DCD in Spain and presents recent Spanish contributions to gain knowledge on the potential benefits and the practical use of normothermic regional perfusion (nRP).
DCD now contributes to 24% of deceased donors in Spain. The development of DCD has been based on an assessment of practices in the treatment of cardiac arrest and end-of-life care to accommodate the option of DCD; the creation of an adequate regulatory framework; and institutional support, professional training and public education. Appropriate posttransplant outcomes have been obtained with organs from both uncontrolled and controlled DCD donors. nRP is increasingly used, with preliminary data supporting improved results compared with other in-situ preservation/recovery approaches. Mobile teams with portable extracorporeal membrane oxygenation devices are making nRP possible in hospitals without these resources. To avoid the possibility of reestablishing brain circulation after the determination of death, a specific methodology has been validated.
DCD has been successfully developed in Spain following a streamlined process. nRP may become a standard in DCD, although further evidence on the benefits of this technology is eagerly awaited.
The evolution of donation after circulatory death donor kidney repair in the United Kingdom Purpose of review
The increasing reliance on marginal donors has driven research to investigate ways to repair and improve the quality of kidneys for transplantation. Normothermic perfusion technologies provide an opportunity for improved preservation, organ assessment and resuscitation/repair of damaged kidneys. This review describes the evolution of normothermic perfusion in kidney transplantation in the United Kingdom.
One hour of normothermic perfusion can be used to restore function and improve early graft function of extended criteria donor kidneys. A large multicentre trial is investigating the impact of normothermic perfusion on delayed graft function in a series of donation after circulatory death kidneys. Normothermic perfusion is also a platform for the delivery of therapies to the kidney to upregulate and modulate repair mechanisms or prevent injurious processes, such as activation of caspase-3 with the delivery of caspase-3 targeted small interfering RNAs. Normothermic perfusion can also be used to assess the quality and anatomical structure of a kidney to judge suitability for transplantation.
Normothermic perfusion technology is a useful adjunct in kidney transplantation. It can improve early graft function by upregulating protective mechanisms. It also has the advantage of providing a functional assessment of the kidney and as a platform for the delivery of therapies or graft manipulation to target ischaemia reperfusion injury or the immune response. This technology can be used to expand the organ donor pool and prevent the unnecessary discard of kidneys.
The need and opportunity for donation after circulatory death worldwide Purpose of review
The global shortage of organ donors will not be resolved solely by relying on deceased donation following a brain death determination (DBD). Expansion of deceased donation after circulatory death (DCD) will be needed to address the shortfall of organs for transplantation. Approximately 120 000 organ transplants are performed each year; however, the WHO estimates that this number of transplants only resolves 10% of the annual worldwide transplant need.
The report addresses the opportunity of DCD expansion by evaluating the DCD potential that is not being realized, the utility of DCD enabling DBD to emerge in some clinical situations, by the effectiveness of a donor registry in achieving DCD, and by the current clinical research of heart, lung, and liver transplantation from DCD.
The future of deceased donation must include DCD and ex-vivo organ repair if the organ shortage is to be reconciled even partially to the ongoing demand. Although the religious and legal impediments have been overcome to determine brain death, the possibility of DCD has not been addressed. A program of DCD is feasible in all countries with transplantation services. The excellent results following kidney and lung transplantation suggest opportunities of heart and liver transplantation should be the focus of needed DCD accomplishment in the near future.
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