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Personalizing immunosuppression is a major objective in transplantation. Transplant recipients are heterogeneous regarding their immunological memory and primary alloimmune susceptibility. This biomarker‐guided trial investigated whether in low immunological‐risk kidney transplants without pretransplant DSA and donor‐specific T cells assessed by a standardized IFN‐γ ELISPOT, low immunosuppression (LI) with tacrolimus monotherapy would be non‐inferior regarding 6‐month BPAR than tacrolimus‐based standard of care (SOC). Due to low recruitment rates, the trial was terminated when 167 patients were enrolled. ELISPOT negatives (E−) were randomized to LI (n= 48) or SOC (n= 53), E+ received the same SOC. Six‐ and 12‐month BPAR rates were higher among LI than SOC/E− (4/35 [13%] vs. 1/43 [2%], p= .15 and 12/48 [25%] vs. 6/53 [11.3%], p= .073, respectively). E+ patients showed similarly high BPAR rates than LI at 6 and 12 months (12/55 [22%] and 13/66 [20%], respectively). These differences were stronger in per‐protocolanalyses. Post‐hoc analysis revealed that poor class‐II eplet matching, especially DQ, discriminated E− patients, notably E−/LI, developing BPAR (4/28 [14%] low risk vs. 8/20 [40%] high risk, p= .043). Eplet mismatch also predicted anti‐class‐I (p= .05) and anti‐DQ (p< .001) de novoDSA. Adverse events were similar, but E−/LI developed fewer viral infections, particularly polyoma‐virus‐associated nephropathy (p= .021). Preformed T cell alloreactivity and HLA eplet mismatch assessment may refine current baseline immune‐risk stratification and guide immunosuppression decision‐making in kidney transplantation. In a multicenter, randomized, biomarker‐guided trial assessing pretransplant donor‐reactive memory T cells for immunosuppression minimization in kidney transplant recipients, both absence of preformed cellular alloreactivity and optimal HLA class II molecular matching identified patients who could be maintained on tacrolimus monotherapy at 1 year after transplantation.

Personalizing immunosuppression is a major objective in transplantation. Transplant recipients are heterogeneous regarding their immunological memory and primary alloimmune susceptibility. This biomarker-guided trial investigated whether in low immunological-risk kidney transplants without pretransplant DSA and donor-specific T cells assessed by a standardized IFN-γ ELISPOT, low immunosuppression (LI) with tacrolimus monotherapy would be non-inferior regarding 6-month BPAR than tacrolimus-based standard of care (SOC). Due to low recruitment rates, the trial was terminated when 167 patients were enrolled. ELISPOT negatives (E–) were randomized to LI (n= 48) or SOC (n= 53), E+ received the same SOC. Six- and 12-month BPAR rates were higher among LI than SOC/E– (4/35 [13%] vs. 1/43 [2%], p= .15 and 12/48 [25%] vs. 6/53 [11.3%], p= .073, respectively). E+ patients showed similarly high BPAR rates than LI at 6 and 12 months (12/55 [22%] and 13/66 [20%], respectively). These differences were stronger in per-protocolanalyses. Post-hoc analysis revealed that poor class-II eplet matching, especially DQ, discriminated E– patients, notably E–/LI, developing BPAR (4/28 [14%] low risk vs. 8/20 [40%] high risk, p= .043). Eplet mismatch also predicted anti-class-I (p= .05) and anti-DQ (p< .001) de novoDSA. Adverse events were similar, but E–/LI developed fewer viral infections, particularly polyoma-virus-associated nephropathy (p= .021). Preformed T cell alloreactivity and HLA eplet mismatch assessment may refine current baseline immune-risk stratification and guide immunosuppression decision-making in kidney transplantation.

Short‐term outcomes in kidney transplantation are marred by progressive transplant failure and mortality secondary to immunosuppression toxicity. Immune modulation with autologous polyclonal regulatory T cell (Treg) therapy may facilitate immunosuppression reduction promoting better long‐term clinical outcomes. In a Phase I clinical trial, 12 kidney transplant recipients received 1–10 × 106Treg per kg at Day +5 posttransplantation in lieu of induction immunosuppression (Treg Therapy cohort). Nineteen patients received standard immunosuppression (Reference cohort). Primary outcomes were rejection‐free and patient survival. Patient and transplant survival was 100%; acute rejection‐free survival was 100% in the Treg Therapy versus 78.9% in the reference cohort at 48 months posttransplant. Treg therapy revealed no excess safety concerns. Four patients in the Treg Therapy cohort had mycophenolate mofetil withdrawn successfully and remain on tacrolimus monotherapy. Treg infusion resulted in a long‐lasting dose‐dependent increase in peripheral blood Tregs together with an increase in marginal zone B cell numbers. We identified a pretransplantation immune phenotype suggesting a high risk of unsuccessful ex‐vivo Treg expansion. Autologous Treg therapy is feasible, safe, and is potentially associated with a lower rejection rate than standard immunosuppression. Treg therapy may provide an exciting opportunity to minimize immunosuppression therapy and improve long‐term outcomes. Immune modulation with autologous polyclonal regulatory T cells is feasible, safe, and allows successful living donor kidney transplantation with reduced immunosuppression.

The International Workshop on Clinical Transplant Tolerance is a biennial meeting that aims to provide an update on the progress of studies of immunosuppression minimization or withdrawal in solid organ transplantation. The Fourth International Workshop on Clinical Tolerance was held in Pittsburgh, Pennsylvania, September 5‐6, 2019. This report is a summary of presentations on the status of clinical trials designed to minimize or withdraw immunosuppressive drugs in kidney, liver, and lung transplantation without subsequent evidence of rejection. All protocols had in common the use of donor or recipient cell therapy combined with organ transplantation. The workshop also included presentations of mechanistic studies designed to improve understanding of the cellular and molecular basis of tolerance and to identify potential predictors/biomarkers of tolerance. Strategies to enhance the safety of hematopoietic cell transplantation and to improve patient selection/risk stratification for clinical trials were also discussed. This report summarizes the status of trials designed to minimize or withdraw immunosuppressive drugs in kidney, liver, and lung transplantation.

Use of cell-based medicinal products (CBMPs) represents a state-of-the-art approach for reducing general immunosuppression in organ transplantation. We tested multiple regulatory CBMPs in kidney transplant trials to establish the safety of regulatory CBMPs when combined with reduced immunosuppressive treatment.

Adoptive transfer of autologous regulatory T cells (Tregs) is a promising therapeutic strategy aimed at enabling immunosuppression minimization following kidney transplantation. In our phase 1 clinical trial of Treg therapy in living donor renal transplantation, the ONE Study (ClinicalTrials.gov: NCT02129881), we observed focal lymphocytic infiltrates in protocol kidney transplant biopsies that are not regularly seen in biopsies of patients receiving standard immunosuppression.

Recent progress in deciphering the mechanisms underlying the concepts of tumor immunosurveillance and immunoevasion has opened new opportunities for the development of effective antitumor therapies. Transplant physicians and immunologists have much to learn from those direct clinical translations of basic science. The 2016 Beaune Seminar in Transplant research brought together researchers from both fields to explore and discuss significant advances in cancer biology, immunotherapies and their potential impacts for the management of cancer in transplant recipients.The same mechanisms that favor immunoediting in cancer could be used to induce immune tolerance in transplantation. Successful immunotherapies in cancer exploiting costimulatory pathways or CAR T cells are beginning to be used in transplantation. Certain cancers in transplanted patients can be reduced by adapting immunosuppressive regimes.

Following in vitro expansion with tacrolimus, CD4+CD127-/loCD25+CD45RA- Treg had a greater suppressive capacity vs the CD45RA+ counterpart Treg. Nevertheless, CD45RA+ Treg had a more stable TSDR demethylated FOXP3+ phenotype vs the CD45RA- Treg counterpart. CD4+CD127-/loCD25+CD45RA+ Treg offer the best compromise following expansion. Supplemental digital content is available in the text.

Overlooked for decades, the humoral alloimmune response is increasingly recognized as a leading cause of graft loss after transplantation. However, improvement in the diagnosis of antibody-mediated rejection has not yet translated into better outcomes for transplanted patients. After an update on B cell physiology and antibody generation, the 2015 Beaune Seminar in Transplant Research challenged the conventional view of antibody-mediated rejection pathophysiology and discussed the latest promising therapeutic approaches.A summary of the 2015 Beaune Seminars in Transplant Research discussing issues related to B cell physiology and antibody generation, current state in diagnosing pathogenic DSA and antibody-mediated rejection, and new treatment strategies.

Vascularized composite allograft (VCA) transplantation restores defects to a degree not possible by conventional techniques. However, it is limited by the need for long-term immunosuppression and high rates of acute rejection directed against skin. There is therefore a need for a therapy that may shift the risk-benefit ratio in favour of VCA transplantation. Regulatory T cells (Tregs) are a subset of T cells with potent immunoregulatory properties and the potential to promote immunosuppression-free allograft survival. In this review, we consider the evidence for Treg therapy in VCA transplantation.

In transplantation, the contribution of B cells to the rejection or acceptance of the allograft is a topic of major interest. The presence of donor-specific antibodies in transplant recipients is often associated with decreased graft function and rejection, clearly indicating a pathogenetic role of B cells in transplantation. However, data from studies in humans and rodents suggest that under certain conditions, B cells have the capacity to control or regulate the immune response to a transplanted organ. Although a great deal of attention has been focused on B cells in human and murine models of autoimmunity, our understanding of the role of these cells in transplantation is limited at present. Indeed, results in this setting are controversial and seem to depend on the model system used or the clinical situation studied. Here, we review the current understanding of the various phenotypes and roles that have been associated with immune-regulating B cells. We also discuss the mechanisms employed by subsets of these regulatory B cells to control the immune response in transplant recipients and in animal models of transplantation.

Recently, The Transplantation Society convened a workshop to address the question, “What do we need to have in place to make tolerance induction protocols a ‘standard of care’ for organ transplant recipients over the next decade” In a productive 2-day meeting, there was wide-ranging discussion on a broad series of topics, resulting in five consensus recommendations as follows: (1) establish a registry of results for patients enrolled in tolerance trials; (2) establish standardized protocols for sample collection and storage; (3) establish standardized biomarkers and assays; (4) include children 12 years and older in protocols that have been validated in adults; and (5) establish a task force to engage third-party payers in discussions of how to fund tolerance trials. Future planned workshops will focus on progress in implementing these recommendations and identifying other steps that the community needs to take.

Malignancy is increasingly the leading cause of mortality in solid-organ recipients. Cancer incidence among the transplant population is overall threefold to fivefold higher than the general population with poorer outcomes for late-stage disease. Insights into the identification of patients at particular risk of developing a posttransplantation malignancy are imperative to ensure appropriate measures are instigated to reduce associated morbidity and mortality. This review focuses on potential clinical, immunologic, and genetic translational markers aimed at identifying long-term solid-organ transplant patients at high risk of developing cancer.

Human regulatory T cells (Treg) offer an attractive adjunctive therapy to reduce current reliance on lifelong, nonspecific immunosuppression after transplantation. Here, we evaluated the ability of ex vivo expanded human Treg to prevent the rejection of islets of Langerhans in a humanized mouse model and examined the mechanisms involved.

The pathogenesis of transplant vasculopathy (TV) is a multifactorial process. We hypothesized that ischemia-reperfusion injury and antibody-mediated damage contribute to the development of TV.

T cells must be activated before they can elicit damage to allografts, through interaction of their T cell receptor (TCR) with peptide-MHC complex and through accessory molecules. Signaling through accessory molecules or costimulatory molecules is a critical way for the immune system to fine tune T cell activation. An emerging therapeutic strategy is to target selective molecules involved in the process of T cell activation using biologic agents, which do not impact TCR signaling, thus only manipulating the T cells, which recognize alloantigen. Costimulatory receptors and their ligands are attractive targets for this strategy and could be used both to prevent acute graft rejection as well as for maintenance immunosuppression. Therapeutic agents targeting costimulatory molecules, notably belatacept, have made the progression from the bench, through nonhuman primate studies and into the clinic. This overview describes some of the most common costimulatory molecules, their role in T cell activation, and the development of reagents, which target these pathways and their efficacy in transplantation.

Regulatory T cells (Treg) are potentially a useful therapeutic option for the treatment of immunopathological conditions including graft-versus-host disease. Umbilical cord blood (UCB) offers certain advantages over adult peripheral blood (APB) as a source of Treg for cellular therapy but yields far fewer Treg per unit. Pooling of Treg from multiple donors may overcome this challenge.

Deciphering the mechanisms of tolerance represents a crucial aim of research in transplantation. We previously identified by DNA chip interleukin (IL)-27 p28 and transforming growth factor (TGF)–1 as overexpressed in a model of rat cardiac allograft tolerance mediated by regulatory CD4CD25T cells. The role of these two molecules on the control of the inflammatory response remains controversial. However, both are involved in the regulation of the T helper 17Treg axis, suggesting their involvement in tolerance.

Introduction:Long-term immunosuppressive therapy represents a huge burden on transplant recipients, but currently cannot be omitted. Improving long-term transplant outcome by immunosuppressive drug withdrawal may be achieved in patients who have developed (partial) immunological unresponsiveness towards their graft, either spontaneously or through tolerance induction. Reliable biomarkers are essential to define such immunological unresponsiveness and will facilitate controlled immunosuppressive drug weaning as well as provide surrogate end-points for tolerance induction trials.Areas covered:Tolerance biomarkers have been defined for both liver and kidney transplantation and can accurately identify operationally tolerant transplant recipients retrospectively. These two tolerance fingerprints are remarkably different, indicating the involvement of distinct mechanisms. Limited data suggest that tolerance biomarkers can be detected in immunosuppressed transplant recipients. Whether these patients can safely have their immunosuppressive drugs withdrawn needs to be established.Expert opinion:Mechanistic interpretation of the kidney transplant tolerance biomarker profile dominated by B-cell markers remains a challenge in light of experimental evidence suggesting the pivotal involvement of regulatory T cells. Therefore, defining animal models that resemble human transplant tolerance is crucial in understanding the underlying mechanisms. Additionally, to ensure patient safety while monitoring for tolerance, it is essential to develop biomarkers to non-invasively detect early signs of rejection as well.

Rejection is the major barrier to successful transplantation. The immune response to an allograft is an ongoing dialogue between the innate and adaptive immune system that if left unchecked will lead to the rejection of transplanted cells, tissues, or organs. Activation of elements of the innate immune system, triggered as a consequence of tissue injury sustained during cell isolation or organ retrieval and ischemia reperfusion, will initiate and amplify the adaptive response. T cells require a minimum of two signals for activation, antigen recognition, and costimulation. The activation requirements of naive T cells are more stringent than those of memory T cells. Memory T cells are present in the majority of transplant recipients as a result of heterologous immunity. The majority of B cells require help from T cells to initiate antibody production. Antibodies reactive to donor human leukocyte antigen molecules, minor histocompatibility antigens, endothelial cells, RBCs, or autoantigens can trigger or contribute to rejection early and late after transplantation. Antibody-mediated rejection triggered by alloantibody binding and complement activation is recognized increasingly as a significant contribution to graft loss. Even though one component of the immune system may dominate and lead to rejection being described in short hand as T cell or antibody mediated, it is usually multifactorial resulting from the integration of multiple mechanisms. Identifying the molecular pathways that trigger tissue injury, signal transduction and rejection facilitates the identification of targets for the development of immunosuppressive drugs.

Currently, acute allograft rejection can only be detected reliably by deterioration of graft function confirmed by allograft biopsy. A huge drawback of this method of diagnosis is that substantial organ damage has already taken place at the time that rejection is diagnosed. Discovering and validating noninvasive biomarkers that predict acute rejection, and chronic allograft dysfunction, is of great importance. Many studies have investigated changes in the peripheral blood in an attempt to find biomarkers that reflect changes in the graft directly or indirectly. Herein, we will review the promises and limitations of the peripheral blood biomarkers that have been described in the literature so far.

This overview traces the history of regenerative medicine pertinent to organ transplantation, illustrates potential clinical applications reported to date, and highlights progress achieved in the field of complex modular organ engineering. Regenerative medicine can now produce relatively simple tissues such as skin, bladders, vessels, urethras, and upper airways, whereas engineering or generation of complex modular organs remains a major challenge. Ex vivo organ engineering may benefit from complementary investigations in the fields of developmental biology and stem cells and transplantation before its full potential can be realized.

T helper (Th) type 17 cells are a recently described CD4T-cell subset that may contribute to allograft rejection and act as a barrier to the induction of transplant tolerance. This review examines the involvement of Th17 cells in transplant rejection, how immunosuppressive medication may affect their induction and maintenance and the potential plasticity of developing Th17 cells. It also addresses the complex interplay between the Th17 and regulatory T-cell developmental pathways and the susceptibility of Th17 cells to regulation. Despite accumulating evidence, the precise impact of Th17 cells on transplant rejection and the induction of tolerance require further clarification.

Leukocyte depletion at the time of transplantation with alemtuzumab (Campath-1H) has been demonstrated to be a potential strategy for reducing long-term exposure to immunosuppressive drugs. Although the impact of alemtuzumab treatment on the immune system has been explored, the effects of long-term immunosuppressive therapy in alemtuzumab-treated patients still need to be elucidated.

This review focuses on the immunogenicity of embryonic stem cell (ESC)-derived progenitors and the impact of the immune response on applications of cell replacement therapy (CRT). Possible strategies to induce immunological tolerance to ESC-derived progenitor cells will also be discussed.

Solid organ transplantation is the most effective treatment for end-stage organ failure, but the long-term outcomes remain suboptimal. CD4regulatory T cells (Tregs) are emerging as a potential therapy to facilitate long-term allograft survival. This review provides a general overview of the biology of CD4Tregs and then goes on to discuss the most relevant and recent experimental and clinical evidence for their therapeutic use in solid organ transplantation.

OX40 is a member of the tumor necrosis factor receptor superfamily and is a potent T-cell costimulatory molecule. Although the impact of blockade of the OX40-OX40L pathway has been documented in models of autoimmune disease, the effect on allograft rejection is less well defined.

This review aims to provide an overview of the latest evidence for the involvement of Th17 cells in the rejection of solid organ allografts. It will also consider the implications of the relationship between the differentiation pathways of Th17 and regulatory T cells (Tregs), as well as their plasticity in the context of transplantation tolerance.

We have developed a method to generate alloreactive regulatory T cells in vitroin the presence of interferon (IFN)-γ and donor antigen presenting cells (APCs). We hypothesized that these IFN-γ–conditioned T cells (Tcon) would reduce transplantation-associated arteriosclerosis. Tcon were generated from mouse (CBA.Ca, H-2k) CD4+T cells cultured in the presence of IFN-γ for 14 days. These cultures were pulsed with bone marrow–derived B6 (H-2b) APC. 1 × 105CD25−CD4+effector T cells from naive H-2kmice were then cotransferred with 4 × 105Tcon into CBA-rag−/−mice. One day later, these mice received a fully allogenic B6 CD31−/−abdominal aorta transplant. Transfer of CD25−CD4+effectors resulted in 29.7 ± 14.5% luminal occlusion of allogeneic aortic grafts after 30 days. Cotransfer of Tcon reduced this occlusion to 11.7 ± 13.1%; P< 0.05. In addition, the CD31−donor endothelium was fully repopulated by CD31+recipient endothelial cells in the absence of Tcon, but not in the presence of Tcon. In some experiments, we cotransplanted B6 skin with aortic grafts to ensure enhanced reactivation of the regulatory cells, which led to an additional reduction in vasculopathy (1.9 ± 3.0% luminal occlusion). In the presence of Tcon, CD4+T cell infiltration into grafts was markedly reduced by a regulatory mechanism that included reduced priming and proliferation of CD25−CD4+effectors. These data illustrate the potential of ex vivogenerated regulatory T cells for the inhibition of transplant-associated vasculopathy.

Intravenous immunoglobulins (IVIg) therapy is effective as a treatment for T-cell-mediated immune diseases, but whether and how IVIg suppress allogeneic T-cell responses is largely unknown.

Mesenchymal stem cells (MSCs) are known to be capable of suppressing immune responses and offer therapeutic potential for achieving transplantation tolerance. This review will discuss the impacts of MSCs on transplant immunity and focus on the potential role of MSCs in protecting islet grafts from both rejection and autoimmune attack.

Switching the balance from rejection of major histocompatibility-mismatched grafts toward long-term tolerance of donor grafts, with the need for minimal immunosuppressive drugs, is a major transplantation goal. Regulatory T cells (Treg) can induce and maintain antigen-specific immune tolerance and facilitate allogeneic graft survival successfully in animals. This review will focus on the valuable insights experimental mouse models have given us into the effects of currently used immunosuppressive reagents on Treg, the Treg transcription factor forkhead box P3, and strategies to expand or induce alloantigen-reactive Treg in vivo and in vitro. These have facilitated the translation of strategies for promoting transplantation tolerance towards a new clinical era.

Donor reactive regulatory T cells (Treg) play an important role in tolerance induction and maintenance in experimental transplant models. In this review we focus on the formation of the donor reactive Treg pool and explore the potential of these cells for therapeutic application in clinical transplantation.

The progeny of embryonic stem (ES) cells may eventually be used to replace damaged tissues in transplantation, yet their immunogenicity remains ill-defined. The major histocompatibility complex (MHC) is a determinant of immunogenicity in transplantation.

Blockade of the CD40-CD154 costimulatory pathway can prolong allograft survival, but does not prevent the development of transplant arteriosclerosis in several models. In this study, we investigated the mechanisms of CD40-CD154-independent transplant arteriosclerosis in major histocompatibility complex (MHC)-class I-mismatched aortic allografts.

In recent years there has been increased interest in understanding the physiology and function of regulatory T cells. In this review we focus on the characterization of regulatory T-cell subsets and their potential therapeutic use in organ transplantation.

The chemokine receptor CCR7 plays a pivotal role in the homing of naïve T cells and regulatory T cells to secondary lymphoid organs and the migration of dendritic cells into afferent lymphatic vessels. Antigen presentation, T cell recruitment, and expansion of regulatory cells are crucial events in establishing and controlling chronic allograft dysfunction. In this study, we report an important role for chemokine receptor CCR7 in the development of transplant arteriosclerosis.

Regulatory T cells (Treg) play important roles in preventing autoimmunity, graft-versus host disease and transplant rejection. In rodent transplant models, tolerance induction strategies can induce graft protective CD25CD4Treg in vivo but therapeutic exploitation of active regulation will more likely depend on protocols that allow generation or selection of regulatory cells ex vivo for use as a cellular therapy. We have used adoptive transfer skin and islet allograft models to identify, develop and evaluate ex vivo protocols that generate donor-reactive, adaptive Treg.

The precise role that CD8T cells play in the rejection and acceptance of different types of allograft is unclear and has been shown to vary between donor–recipient combinations.

Interleukin-23 (IL-23) and the recently discovered Th17 cells have been implicated in the pathogenesis of autoimmune diseases. This review will discuss current understanding of T-cell subsets in transplantation immunity and will explore the role of IL-23 and Th17 cells in allograft rejection, tolerance, and ischemia reperfusion injury.