Advances In Immunosuppressive Therapy Research Articles

Liraglutide, a Glucagon-like Peptide-1 Receptor Agonist, Attenuates Development of Cardiac Allograft Vasculopathy in a Murine Heart Transplant Model

Advances in immunosuppressive therapy have significantly improved short-term but not long-term survival of cardiac transplant recipients; this is largely due to severe cardiac allograft vasculopathy (CAV). Glucagon-like peptide-1 receptor (GLP-1R)-based therapy exerts physiological effects on the cardiovascular system in addition to its traditional role in controlling glucose. We have investigated the effects of liraglutide, a GLP-1R agonist, on the development of CAV in a murine heart transplant model. Heterotopic murine cardiac transplantation was performed with a major histocompatibility complex class II-mismatched model. Recipient mice were subcutaneously administered vehicle (0.9% saline solution) or liraglutide (300 μg·kg every 12 hours) from the day of transplantation. Allografts were harvested at 2 or 8 weeks and histologically analyzed. Inflammatory infiltrates were measured by immunohistochemistry, and immunofluorescence and western blotting analyzes were used to evaluate GLP-1R expression and markers of endothelial-to-mesenchymal transition (EndMT) in cardiac allografts and human coronary artery endothelial cells challenged with transforming growth factor-beta 1. Glucagon-like peptide-1 receptor was predominantly localized to vascular endothelial cells and was upregulated in cardiac allografts after liraglutide treatment. Liraglutide ameliorated CAV and cardiac fibrosis with reduced inflammatory cell infiltration and downregulated expression of adhesion molecules. Liraglutide inhibited EndMT in allografts and attenuated EndMT by inhibiting Smad3 activation in transforming growth factor-beta 1-treated human coronary artery endothelial cells. Administration of liraglutide from the time of transplantation upregulated GLP-1R in the transplanted heart and reduced cardiac fibrosis, inflammation, and CAV development. Therefore, liraglutide may be a novel therapy for CAV.

Management of Post-transplant Hyperparathyroidism and Bone Disease.

Significant advances in immunosuppressive therapies have been made in renal transplantation, leading to increased allograft and patient survival. Despite improvement in overall patient survival, patients continue to require management of persistent post-transplant hyperparathyroidism. Medications that treat persistent hyperparathyroidism include vitamin D, vitamin D analogues, and calcimimetics. Medication side effects such as hypocalcemia or hypercalcemia, and adynamic bone disease, may lead to a decrease in the drugs. When medical management fails to control persistent post-transplant hyperparathyroidism, treatment is a parathyroidectomy. Surgical techniques are not uniform between centers and surgeons. Undergoing the surgery may include a subtotal technique or a technique including total parathyroid gland resection with partial heterotopic gland reimplantation. In addition, there are possible post-surgical complications. The ideal treatment for persistent post-transplant hyperparathyroidism is the treatment and prevention of the condition while patients are being managed for their late-stage chronic kidney disease and end-stage renal disease.

EPURE Transplant (Eplerenone in Patients Undergoing Renal Transplant) study: study protocol for a randomized controlled trial

BackgroundDespite advances in immunosuppressive therapy, kidney graft survival has failed to improve during the last decades. Ischemia/reperfusion injury (IRI) is one of the main pathophysiological mechanisms underlying delayed graft function, which is associated with poor long-term graft survival. Due to organ shortage, the proportion of grafts from expanded criteria donors (ECDs) is ever growing. These grafts may particularly benefit from IRI prevention. In preclinical models, mineralocorticoid receptor antagonists (MRAs) have been shown to efficiently prevent IRI. This study aims to assess the effect of MRA administration in the early phase of kidney transplantation (KT) among recipients of ECD grafts on mid-term graft function.Methods/designThis is a multicenter, double-blind, placebo-controlled, randomized clinical trial. Patients on hemodialysis and undergoing a single or a dual KT from an ECD will be eligible for inclusion. We plan to randomize 132 patients. Included patients will be randomized (1:1) to receive either eplerenone 25 mg every 12 h during 4 days (the first dose being administered just prior to KT) or placebo. The primary outcome is graft function at 3 months, assessed by glomerular filtration rate (GFR, in mL/min/1.73m2) measured using iohexol clearance. Secondary outcomes include (1) proportion of patients with either dialysis dependency or a GFR < 30 mL/min/1.73m2 at 3 months, (2) proportion of patients with immediate, slow, or delayed graft function, (3) proteinuria at 3 months, (4) occurrence of hyperkalemia during the first week following KT, (5) length of hospital stay for the KT, and (6) occurrence of biopsy-proven acute rejection in the first 3 months following KT. Estimated GFR, graft, and patient survival will also be collected at 1, 3, and 10 years via the national database of organ recipients.DiscussionImprovement of ECD grafts is a public health priority, since better ECD outcomes could eventually limit organ shortage. MRA administration in the early phase of KT may prevent IRI and subsequently improve mid-term graft function. The trial will also assess the safety of MRA administration in this population, primarily the absence of threatening hyperkalemia.Trial registrationClinicalTrials.gov, NCT02490904. Registered on 1 July 2015.

Causes of Ineligibility for Recipients in Living Kidney Transplantation

BackgroundEven if a living donor candidate exists, there are some cases that do not result in kidney transplantation (KTx) due to problems on the recipient side. The aim of this study was to clarify causes of ineligibility for KTx in these cases, so as to make RTx more applicable for patients. MethodsWe targeted 470 patients with end-stage renal disease who applied for the primary kidney KTx from 2010 to 2012. Then we selected those who were not applicable for KTx and investigated recipient causes of ineligibility for KTx or not receiving KTx. ResultsThe average age of recipients was 47.6 ± 12.9 (7–82) years. A majority of the 470 patients were male (n = 305, 64.9%). Two hundred ninety-seven patients intended to receive a living donor KTx and the others hoped for a deceased donor KTx. Of the 297 patients, 207 (70.0%) underwent KTx and 9 (1.9%) were being prepared for KTx at the time of the survey. Eighty-three patients (27.9%) did not receive a living KTx, with 59 of these due to recipient-related problems and 30 due to donor-related problems. We further classified the reasons for these 59 recipients not undergoing KTx as follows: (1) unclear reasons (35.6%); (2) insufficient intention to receive transplant (13.6%); (3) heart disease (10.2%); (4) malignancy (8.5%); (5) immunologic risks (5.1%); (6) death during the waiting period (5.1%); (7) cerebrovascular events (5.1%); (8) cardiovascular problems (5.1%); (9) psychiatric disorders (3.4%); and (10) infections (3.4%). ConclusionNearly 50% of the reasons for ineligibility as a recipient were related to their intention to receive KTx, with 94.9% of the nontransplanted cases due to nonimmunologic reasons. Thanks to the recent advances in immunosuppressive therapy, there were only 3 patients who could not undergo KTx due to immunologic risks. Based on these results, transplant surgeons should not only emphasize physical evaluation but should also pay careful attention to the recipient's intention to receive KTx.

High Body Mass Index is a Risk Factor for Acute Cellular Rejection in Lung Transplant Recipients

High body mass index (BMI) is associated with increased risk of acute cellular rejection (ACR) in renal and cardiac transplant recipients. Despite advances in immunosuppressive therapies, ACR continues to occur in more than a third of recipients in the first year post lung transplant (LTx). Although there is data on the association between primary graft dysfunction and obesity in LTx, the effect of BMI on the incidence of ACR has not been examined.

Pregnancy After Liver Transplantation: Risks and Outcomes

ObjectiveThe aim of this study was to evaluate the outcomes of liver transplant recipients who became pregnant after transplantation. MethodsThe clinical data of all patients who underwent liver transplantation between January 2007 and December 2016 in our liver transplantation institute were reviewed. The following data were analyzed: indications for transplantation, recipient age at the beginning of pregnancy, the interval between transplantation and pregnancy, maternal and fetal complications, type of delivery, the health condition of neonates, and modifications in immunosuppressive therapy. ResultsDuring the study period, 1890 patients underwent liver transplantation. There were 185 women (9.8%) in childbearing age (15–45 years old), and 18 (9.7%) of them became pregnant during the study period. There were a total of 26 pregnancies. The mean age of patients at the time of operation was 25.3 ± 5.2 years, and the mean interval between operation and conception was 32.7 ± 15.3 months. Seventeen pregnancies (65.4%) ended in a live birth in the study. Six pregnancies (23%) resulted with no maternal or fetal complications. The most frequent maternal complication during pregnancy was pregnancy-induced hypertension (n = 3; 16.6%). ConclusionsDespite advances in immunosuppressive therapy and increasing experience in the management of these patients, pregnancies in liver transplant recipients are still more risky than in the general population for both the mother and the fetus. Thus, the issues related to fertility should be comprehensively discussed with the patients and their partners, preferably before transplantation, and pregnancies in liver transplant recipients should be followed up more carefully by a multidisciplinary team.

Necroptosis Is Involved in CD4+ T Cell-Mediated Microvascular Endothelial Cell Death and Chronic Cardiac Allograft Rejection.

Despite advances in immunosuppressive therapies, the rate of chronic transplant loss remains substantial. Organ injury involves various forms of cell death including apoptosis and necrosis. We now recognize that early injury of cardiac transplants involves a newly described form of programmed necrotic cell death, termed necroptosis. Because this involves receptor-interacting protein (RIP) kinase 1/3, this study aimed to establish the role of RIP3 in chronic cardiac allograft rejection. We used major histocompatibility complex class II mismatched C57BL/6N (H-2; B6) or B6.RIP3 (H-2; RIP3) mice to B6.C-H-2 (H2-Ab1; bm12) mouse cardiac transplantation. Microvascular endothelial cells (MVEC) were developed from B6 and RIP3 cardiac grafts. CD4 T cell-mediated cardiac graft rejection is inhibited using RIP3 deficient donor grafts, with reduced cellular infiltration and vasculopathy compared with wild type cardiac grafts. Alloreactive CD4 T cell-mediated MVEC death involves TNFα, Fas ligand (FasL) and granzyme B. Although necroptosis and release of danger molecule high-mobility group box 1 are eliminated by the absence of RIP3, CD4 T cells had attenuated MVEC death through granzyme B and FasL. CD4 T cell-mediated MVEC death involves in TNFα, FasL and granzyme B. Necroptotic cell death and release of the danger molecule may promote inflammatory responses and transplant rejection. Although loss of RIP3 does not eliminate alloimmune responses, chronic graft injury is reduced. RIP3 is an important therapeutic target but additional granzyme and caspases inhibition is required for sufficiently improving long-term graft survival.

Molecular Imaging of Acute Cardiac Transplant Rejection: Animal Experiments and Prospects.

Acute rejection (AR) remains the biggest challenge during the first year after heart transplantation despite advances in immunosuppressive therapy. The early detection and curbing of AR are crucial to the survival of transplant recipients. However, as the criterion standard for AR, endomyocardial biopsy has several limitations because of its inherent invasiveness and morbidity. Traditional imaging techniques, such as echocardiography and cardiac magnetic resonance imaging, are of certain value for AR, but their diagnostic criteria and accuracy remain in question. Molecular imaging sheds new light on AR diagnosis because it can provide information about gene expression and the location of molecules and cells. This article reviews the latest research and applications of several typical modalities of molecular imaging used in AR and discusses their advantages and disadvantages.

Update on Immunosuppression in Liver Transplantation.

ABSTRACTThe standard therapy for decompensated end-stage chronic liver disease of any etiology and acute fulminant hepatic failure is liver transplantation (LT). Advances in immunosuppressive therapy decreased the rates of acute and chronic rejections. Thus, graft and patient survivals have significantly improved. However, long-term adverse effects of prolonged use of immunosuppressive agents such as malignancies, opportunistic infections, metabolic disorders, and other organ toxicities have now become a major concern. Consequently, alternative approaches are needed to deescalate the customary drugs and their side effects. Therapy must be individualized and additional preventive measures should be taken by patients with particular risk factors or predisposed to certain adverse effects. Current opinion favors a combination of agents with different mechanism of actions and toxicity profiles. Corticosteroids are employed in immediate and early postoperative period. Although they have a pronounced side effect profile, calcineurin inhibitors (CNIs) are still the backbone of early and late phase immunosuppressive regimens because of their proved efficacy. Antimetabolites are frequent choices for steroid and/or CNI-sparing strategies. Studies also have established a role for mammalian target of rapamycin (mTOR) inhibitors in specific groups of recipients. Biologic agents are a hot topic of interest and made their way into current strategies for induction. Agents extrapolated from other transplantation or immunologic experience are being evaluated.How to cite this articleTasdogan BE, Ma M, Simsek C, et al. Update on Immunosuppression in Liver Transplantation. Euroasian J Hepato-Gastroenterol 2019;9(2):96–101.

Removal of focal segmental glomerulosclerosis (FSGS) factor suPAR using CytoSorb.

Treatment of primary focal segmental glomerulosclerosis (FSGS) and its recurrence after kidney transplantation associated with rapid deterioration of kidney function remains to be challenging despite advances in immunosuppressive therapy. The presence of circulating factors has been postulated to be a pivotal player in the pathogenesis of FSGS, although suPAR and CLCF-1 have been identified as the most promising causative factors. The potential therapeutic effect of suPAR elimination in an FSGS patient using CytoSorb, a hemoadsorption device that gained attention in the cytokine elimination in septic patients, was studied. Efficiency of total plasma exchange to remove suPAR was determined. CytoSorb hemoadsorption caused a 27.33% reduction of the suPAR level in a single treatment, whereas total plasma exchange showed a suPAR level reduction of 25.12% (n = 3; 95% confidence interval, 0.2777-0.8090; P < 0.01), which may indicate therapeutic potential in the treatment of primary FSGS and its recurrence in a kidney transplant.

Long-term-management of organ transplant recipients

Due to advances in immunosuppressive therapy and surgical techniques, survival rates after solid organ transplantation have constantly improved over the last decades. In long-term care after transplantation, physicians need to focus as much on diagnosis and treatment of allograft-related complications as they should consider comorbidities and evaluate risk-factors and adverse events of immunosuppressive agents to prevent secondary diseases. In particular, cardiovascular and metabolic diseases, malignancy and infection play a major role in long-term survival. Therefore, screening of organ transplant recipients in regard to these complications and adverse events is a crucial part of follow up in these patients.

Knockout of microRNA-155 ameliorates the Th1/Th17 immune response and tissue injury in chronic rejection

MicroRNAs (miRNAs) are integral for maintaining immune homeostasis and self-tolerance. The influence of miRNAs on T-cell differentiation and plasticity are critical in the development of chronic rejection of transplanted hearts. In this study, we sought to determine whether the knockout of miR-155 affects the development of cardiac allograft vasculopathy (CAV) in a murine model. miRNA microarray and quantitative polymerase chain reaction (qPCR) analyses were performed for allograft neointimal lesion samples in chronic rejection. A model of heterotopic murine heart transplantation (bm12 to miR-155+/+ or miR-155-/- mice) was then used to analyze allograft survival, histology, mRNA expression and T-cell sub-populations in spleens. The accelerated experiments were performed by intraperitoneal injection of either recombinant interleukin-17A or phosphate-buffered saline (PBS) after heart transplantation. For the competitive transfer experiments, CD4+ splenocytes from wild-type (WT) or miR-155-/- mice were mixed and injected into Rag1-/- mice, and cardiac transplantation was performed after 24 hours. The differentiation of T-helper subsets (Th1/Th17/iTreg) was investigated in vitro. miR-155-/- mice showed resistance to cardiac rejection along with weakened T-cell-mediated inflammation, especially for Th17 cells. Recombinant IL-17A could restore this relieved injury. The competitive experiments implied that miR-155 plays a vital role in the stability of the Th17 phenotype. In vitro, we also demonstrated that miR-155-/- mice exhibit a defect in Th17 differentiation. miR-155 regulates Th1/Th17-related inflammation in chronic cardiac rejection and may be a potential therapeutic target to attenuate cardiac allograft rejection. Despite advancements in immunosuppressive therapy, the immunologic mechanisms responsible for allograft rejection remain an important issue for both clinicians and researchers. Allograft rejection is a T-cell-dependent phenomenon and is critically dependent on inflammation mediated by CD4+ Th subsets, including Th1, Th2, Th17, Th9 and regulatory T (Treg) cells.

Added effects of dexamethasone and mesenchymal stem cells on early Natural Killer cell activation

Graft rejection and graft-versus-host disease are leading causes of transplant related mortality despite advancements in immunosuppressive therapy. Mesenchymal stem cells (MSCs) offer a promising addition to immunosuppressive drugs (ISD), while NK-cells are increasingly used as effector cells in graft-versus-leukemia. Combined therapy of ISD, NK-cells and/or MSCs is used in clinical practice. Here, we examined the effects of MSCs and selected ISD (tacrolimus, cyclosporin A, mycophenolic acid, dexamethasone) treatment on early NK-cell activation. We assessed STAT4 and STAT5 phosphorylation triggered by IL-12 and IL-2, respectively. Furthermore, we determined IFNγ, perforin production and the expression pattern of selected NK-cell receptors. Of all drugs tested, only dexamethasone inhibited NK-cell STAT4 and STAT5 phosphorylation. All ISD, with the exception of MPA, significantly inhibited IFNγ, and only dexamethasone inhibited upregulation of early activation markers CD69 and CD25 (IL-2 condition only). MSCs inhibited IL-2 induced NK cell STAT5 phosphorylation, IFNγ production and CD69 upregulation, and IL-12 induced IFNγ and perforin production. While MSCs mediated inhibition of CD69 expression was cell contact dependent, inhibition of IFNγ and perforin production, as well as STAT5 phosphorylation was cell-contact independent. Importantly, dexamethasone augmented MSCs mediated inhibition of both IL-12 and IL-2 induced CD69 expression and IFNγ production, as well as IL-2 induced STAT5 phosphorylation. Taken together, these novel insights may help the design of future NK-cell and MSCs based immunotherapy.

Malignancy After Heart Transplantation Under Everolimus Versus Mycophenolate Mofetil Immunosuppression

BackgroundWith advances in immunosuppressive therapy, heart transplantation is currently recommended as the only established surgical treatment for refractory heart failure. However, chronic immunosuppression increases the risk for malignancy. Everolimus (EVR) is a potent mammalian target of rapamycin inhibitor that is used after transplantation and to treat advanced malignancies, as we have done in Taiwan after heart transplantation since 2004. Mycophenolate mofetil (MMF) and EVR are frequently used as cell-cycle inhibitors to optimize post-transplantation outcomes. MethodsWe retrospectively analyzed the characteristics and outcomes of 454 patients who received either MMF (n = 232) or EVR (n = 222) after heart transplantation at the National Taiwan University Hospital from March 1, 1990, to March 1, 2015. Patient characteristics and Kaplan-Meier survival curves were compared between groups. ResultsDuring a median follow-up of 69.2 months, malignancy was diagnosed in 27 patients receiving MMF (n = 23) or EVR (n = 4). There was a significant difference in malignancy risk between groups (9.91% vs 1.80%, P = .001). The most common malignancies were non-Hodgkin lymphoma, skin cancers, and lung squamous cell carcinoma. The 2-year overall survival after malignancy was 50% in the EVR group and 47% in the MMF group (P = .745). ConclusionsEVR treatment after heart transplant is associated with a lower risk of malignancy than is MMF treatment. The 2-year survival rate after malignancy was similar between EVR and MMF groups.

Aplastic Anemia in Egypt: Current Situation and Future Prospective

Aplastic anemia (AA) is a hypoproliferative anemia that led to a significant morbidity and mortality. Recently, dramatic improvement in prognosis of AA was achieved; this was in part due to advances in immunosuppressive therapy and HSCT. Nevertheless, AA is still one of the most challenging hematological disorders that could face a hematologist. This study was conducted at Assiut University Hospital (AUH), Assiut, Egypt to evaluate current situation and future prospective of AA. 63 patients with AA were prospectively enrolled in the study; they were admitted at the Hematology unit, AUH in the period 1stJan2011 to Feb2012, a 38 patients with iron deficiency anemia (IDA) were included for comparison. Patients' demographic and clinical data were collected through medical history and clinical examination. Both direct and indirect health care costs of anemia were assessed Direct parameters included doctors' and hospital fees, costs of laboratory investigations, medication fees and costs of HSCT or any procedure. Indirect costs included travelling expenses and earning losses. Social burden of anemia was estimated by anemia related morbidity and mortality. Data were analyzed with SPSSV.17, results showed that AA affected young age group with mean age 30.89±13.39 years, without sex predilection, acquired AA was more common than idiopathic (55.6% vs. 44.4%), however mortality was higher in idiopathic AA (46.2%). Causes of aplasia were exposure to chemicals, drugs and hepatitis in order. Only 63.5% of AA were admitted once and 47.6% in general ward, the mean hospital days for patients with AA was 17.73±11.10, compared to 8.32±6.69 in IDA, P=0.000, also higher socio-economic burden of AA was found compared with IDA. These results denoted that management of AA is still ineffective, and that there is a definite need for a strict plan to prevent incidence of AA, particularly in developing countries where effective management of AA is too expensive and relatively unavailable.

Introduction of a Framework for Dynamic Knowledge Representation of the Control Structure of Transplant Immunology: Employing the Power of Abstraction with a Solid Organ Transplant Agent-Based Model.

Agent-based modeling has been used to characterize the nested control loops and non-linear dynamics associated with inflammatory and immune responses, particularly as a means of visualizing putative mechanistic hypotheses. This process is termed dynamic knowledge representation and serves a critical role in facilitating the ability to test and potentially falsify hypotheses in the current data- and hypothesis-rich biomedical research environment. Importantly, dynamic computational modeling aids in identifying useful abstractions, a fundamental scientific principle that pervades the physical sciences. Recognizing the critical scientific role of abstraction provides an intellectual and methodological counterweight to the tendency in biology to emphasize comprehensive description as the primary manifestation of biological knowledge. Transplant immunology represents yet another example of the challenge of identifying sufficient understanding of the inflammatory/immune response in order to develop and refine clinically effective interventions. Advances in immunosuppressive therapies have greatly improved solid organ transplant (SOT) outcomes, most notably by reducing and treating acute rejection. The end goal of these transplant immune strategies is to facilitate effective control of the balance between regulatory T cells and the effector/cytotoxic T-cell populations in order to generate, and ideally maintain, a tolerant phenotype. Characterizing the dynamics of immune cell populations and the interactive feedback loops that lead to graft rejection or tolerance is extremely challenging, but is necessary if rational modulation to induce transplant tolerance is to be accomplished. Herein is presented the solid organ agent-based model (SOTABM) as an initial example of an agent-based model (ABM) that abstractly reproduces the cellular and molecular components of the immune response to SOT. Despite its abstract nature, the SOTABM is able to qualitatively reproduce acute rejection and the suppression of acute rejection by immunosuppression to generate transplant tolerance. The SOTABM is intended as an initial example of how ABMs can be used to dynamically represent mechanistic knowledge concerning transplant immunology in a scalable and expandable form and can thus potentially serve as useful adjuncts to the investigation and development of control strategies to induce transplant tolerance.

Decade in review--renal transplantation: A spectrum of advances in renal transplantation.

Although the first 50 years of renal transplantation were marked by great advances in immunosuppressive therapies, the past decade has been marked by an unprecedented increase in technology. This progress has spurred investigators to challenge old paradigms and investigate how best to utilize these technologies to further improve patient care.

Single nucleotide polymorphisms for genes encoding cytokines in the context of cardiac surgery. Part I: Heart transplantation.

Cardiovascular diseases remain the leading cause of death in Poland and other countries of the European Union. Patients with end-stage heart failure constitute a patient subgroup for whom the treatment of choice is heart transplantation. Despite advances in immunosuppressive therapy, acute or chronic graft rejection occurs in 20-30% of cases in the first six months after transplantation. The significance of the immune response and inflammation in graft rejection implies the important role of cytokines. Molecular markers are sought to facilitate risk assessment and improve patient care. At present, genetic tests are not used for this purpose, but studies aiming to rectify that have been conducted for years, including studies on single nucleotide polymorphisms of cytokine genes. This paper presents the results of research on the single nucleotide polymorphisms (SNPs) of the IL-2, IL-4, IL-6, IL-10, TGF-β1, PDGF, VEGF, and TNF-α genes in conjunction with heart transplantation. The analyzed data do not allow for reliable application of these genetic tests in clinical practice, but suggest that it is a promising direction which may improve the options of treatment individualization in the future.

Natural killer cells play a critical role in cardiac allograft vasculopathy in an interleukin-6--dependent manner.

Approximately 50% of cardiac transplants fail in the long term, and currently, there are no specific treatments to prevent chronic rejection. In the clinic, donor cardiac graft ischemia time is limited to within a few hours and correlates with delayed graft function and organ failure. It is still unknown how ischemic injury negatively influences allograft function over the long term despite advances in immunosuppression therapy. Allogeneic cardiac grafts were stored at 4 °C for 4 hr before being transplanted into T/B cell-deficient Rag(-/-) mice or T/B/natural killer (NK) cell-deficient γc(-/-)Rag(-/-) mice. Grafts were harvested 60 days after transplantation and indicators of chronic allograft vasculopathy (CAV) were quantified. We have found that cold ischemia of cardiac grafts induces CAV after transplantation into Rag1(-/-) mice. Interestingly, cold ischemia-induced CAV posttransplantation was not seen in T/B/NK cell-deficient γc(-/-)Rag(-/-) mice. However, cardiac grafts in γc(-/-)Rag(-/-) mice that received an adoptive transfer of NK cells developed CAV, supporting the role of NK cells in CAV development. Analysis of various cytokines that contribute to NK cell function revealed high interleukin (IL)-6 expression in cardiac grafts with CAV. In addition, IL-6-deficient cardiac grafts did not develop CAV after transplantation into allogeneic Rag(-/-) mice. These data demonstrate that cold ischemia and NK cells play critical roles in the development CAV. Natural killer cells and injured grafts may play a reciprocal role for CAV development in an IL-6-independent manner. Specific therapeutic strategies may be required to attenuate NK cell contribution to chronic cardiac rejection.

Recent immunomodulatory strategies in transplantation

Despite preservation methods, surgical procedures, current immunosuppressive therapy regimens advances, organ transplantation is accompanied with a poor long-term survival and significant mortality. This has led to an increased interest to optimize outcomes while minimizing associated toxicity by using alternative methods for maintenance immunosuppression, organ rejection treatment, and monitoring of immunosuppression. Advance in long-standing allograft outcomes may depend on new drugs with novel mechanisms of action with minimal toxicity. Newer treatment techniques have been developed, including using novel stem cell-based therapies such as mesenchymal stem cells, phagosomes and exosomes. Immunoisolation techniques and salvage therapies, including photopheresis and total lymphoid irradiation have emerged as alternate therapeutic choices. The present review evaluates the recent clinical advances in immunosuppressive therapies for organ transplantation.