Advances In Immunosuppressive Therapy Research Articles

Efficacy of ursodeoxycholic acid as an adjuvant treatment to prevent acute cellular rejection after liver transplantation: a meta-analysis of randomized controlled trials

Acute cellular rejection (ACR) after liver transplantation (LT) is one of the most common problems faced by transplant recipients in spite of advances in immunosuppressive therapy. Recently, clinical trials reported that ursodeoxycholic acid (UDCA) reduced the incidence of ACR significantly. However, others have shown contradictory conclusion. Therefore, we performed a meta-analysis of rigorous randomized controlled trials (RCTs) to determine the efficacy of UDCA in reducing ACR after LT. All RCTs that evaluated efficacy of UDCA as an adjuvant treatment to prevent ACR after LT were searched from PubMed/MEDLINE, EMBASE, Cochrane Central Register of Controlled Trials, ScienceDirect databases and Web of Science (from January 1981 to March 2012). There was no language limitation in these searches. Relevant abstracts of international meetings were also searched. References of each included study were searched manually. A total of 234 patients from four high-quality RCTs (Jadad score 4 to 5) were included in this meta-analysis. Prophylactic use of UDCA did not decrease the incidence of ACR (RR: 0.94, 95% CI: 0.77-1.16, P>0.05), steroid-resistant rejection (RR: 0.77, 95% CI: 0.47-1.27, P>0.05) and the number of patients with the multiple episodes of ACR (RR: 0.60, 95% CI: 0.28-1.30, P>0.05). Different intervention programs (high-dose vs low-dose UDCA; early vs delayed UDCA treatment) also did not alter the outcomes. UDCA, as an adjuvant treatment, was not able to prevent ACR and steroid-resistant rejection after LT. Further trials should be done to determine whether higher dose of UDCA will be beneficial.

Cytomegaloviral Infection in Solid Organ Transplant Recipients: Preliminary Report of One Transplant Center Experience

BackgroundDespite advances in immunosuppressive therapy and post-transplantation care, antiviral prevention, and therapy, cytomegalovirus (CMV) infection remains the most common viral infection after solid organ transplantation (SOT). MethodsThis study included 2,375 patients under the care of our transplant center during the 1-year period from June 2012 to June 2013. There were 351 patients (14.78%) suspected and tested for CMV infection with the use of viral DNA amplification test. ResultsSymptoms that triggered diagnostics were graft dysfunction in 24 (55.8%), diarrhea in 18 (41.9%), fever in 15 (34.9%), leukopenia in 14 (32.6%), abdominal pain in 13 (30.2%), nausea in 7 (16.3%), cough in 6 (14%), and shivers in 2 (4.7%). Positive test results were obtained in 43 patients (12.3% of patients tested and 1.8% of the entire cohort). The group consisted of 17 women (39.5%) and 26 men (60.5%), 26 kidney (60.5%) and 17 liver (39.5%) transplant recipients, aged 49.3 years (SD 14.9). The initial viral load was median 8,093 (range: 4,232–219,180) copies/mL. The mean ganciclovir (GCV) treatment duration was 19.05 (SD 8.1) days. GCV doses ranged from 100 to 1,000 mg/d, mean 370.6 (SD 254.2) mg/d. Clinical resistance to treatment was diagnosed in 5 patients (11.6%). We found a positive correlation of GCV treatment duration with natural logarithm of initial CMV viremia (r = 0.56; P = .0002) and of time in months to CMV infection with mean cyclosporine level (r = −0.74; P = .04) and GCV dose (r = −0.34; P = .03). The duration of GCV therapy was positively influenced by CMV load and tacrolimus administration and negatively by patient's age and male sex. ConclusionsAppearance of any symptoms occurring after transplantation, even nonspecific, should lead to diagnostics for CMV infection. The duration of treatment depends on the severity of the infection expressed by CMV viremia. Clinical resistance to GCV is not frequent, but it is an important transplantologic problem.

Impact of CYP3A4 and MDR1 gene (G2677T) polymorphisms on dose requirement of the cyclosporine in renal transplant Egyptian recipients.

Advances in immunosuppressive therapy allowed renal transplantation to become the treatment of choice for suitable candidates with (end stage renal disease) ESRD. The post-transplant therapeutic strategy is difficult due to narrow therapeutic indices for the currently used immunosuppressive drugs. Inter-individual differences in drug bioavailability are related to genetic and non genetic factors. The idea of targeted and personalized therapy is to achieve therapeutic success. The empirical dose has lost its value in the post-transplant therapy and an individualized dosage regimen must be established. Interindividual heterogeneity in expression of ABCB1 and CYP3A4 has been suspected to be one of the factors resulting in cyclosporine (CsA) pharmacokinetic variation. This study aimed to investigate the impact of inter-individual CYP3A4 rs4646437C>T and MDR1 G2677T/A polymorphisms on cyclosporine dose requirements among a sample of renal transplant Egyptian recipients. Fifty adult Egyptian patients on CsA were genotyped for CYP3A4 rs4646437C>T and MDR1 G2677T/A and correlated with CsA dose requirement and dose-adjusted CsA (C0) blood levels at 3, 6, and 9months post transplantation. CYP3A4 rs4646437C>T influenced significantly cyclosporine kinetics, the T carriers requiring higher cyclosporine dose. Daily dose requirements were also significantly higher in T allele MDR1 2677G>T GG genotype as compared to GT/TT genotypes at 3, 6, and 9months post transplantation. Genotyping of both CYP3A4 and MDR1 SNPs may be helpful in providing pre-transplant pharmacogenetic information to individualize CsA dosing. Heterozygous CT genotype is the most frequent CYP3A4 rs4646437C>T genotype in the studied group of Egyptian population (48%) followed by CC genotype and TT genotype. Daily dose requirements were significantly higher in T allele MDR1 2677G>T GG genotype as compared to GT/TT genotypes at 3, 6, and 9months post transplantation.

Allogeneic hematopoietic cell transplantation for acute myeloid leukemia during first complete remission: a clinical perspective.

Allogeneic hematopoietic cell transplantation (HCT) is the most potent therapy for preventing relapse of acute myeloid leukemia (AML). Although its efficacy is compromised by a high risk of treatment-related morbidity and mortality, an accumulating body of evidence has led to the general recommendation favoring allogeneic HCT from a matched sibling donor during first complete remission (CR1) for younger patients with cytogenetically intermediate- or high-risk AML. Over the past few decades, this field has seen a great many advancements. The indications for allogeneic HCT have been refined by taking into account the molecular profiles of leukemic cells and the degree of comorbidities. The introduction of high-resolution human leukocyte antigen-typing technology and advances in immunosuppressive therapy and supportive care measures have improved outcomes in alternative donor transplantation, while the parallel growth of unrelated donor registries and greater use of umbilical cord blood and haploidentical donors have considerably improved the chance of finding an alternative donor. The development of reduced-intensity and non-myeloablative conditioning has made it possible to receive allogeneic HCT for patients who might once have been considered ineligible due to advanced age or comorbidities. Thanks to these advances, the role of allogeneic HCT during CR1 has become progressively more important in the treatment of AML.

Transplantation in highly HLA-sensitized patients: challenges and solutions

Transplantation in highly HLA-sensitized patients: challenges and solutions Irene K Kim, Ashley Vo, Stanley C Jordan Transplant Immunotherapy Program, Comprehensive Transplant Center, Cedars-Sinai Medical Center, Los Angeles, CA, USA Abstract: Despite better understanding of the impact of development of the human leukocyte antigen (HLA) antibody and numerous advancements in immunosuppressive therapy, the ability to successfully transplant highly sensitized patients remains a significant challenge. As the percentage of the waiting list becomes increasingly populated with highly sensitized patients, there is a growing demand for effective strategies to manage these patients. Over the past 20 years, desensitization therapies have been modified and developed, and are mainly utilized at transplant centers that have developed expertise. In addition, recognition that the highly sensitized patient population is disadvantaged on the transplant waiting list has led to recent changes in national kidney allocation policy. Furthermore, creative strategies, such as enrollment of sensitized patients into paired kidney exchange programs, have been developed to find compatible matches for these patients. The goal of this article is to address some of the specific challenges related to transplanting the highly sensitized patient at a high-volume transplant center with experience in desensitization and to review established and emerging solutions to help this patient population. Keywords: human leukocyte antigen, antibodies, desensitization, high-dose intravenous immunoglobulin, rituximab

Biomarkers of acute rejection following cardiac transplantation.

Cardiac transplantation can be a life-saving treatment for selected patients with heart failure. However, despite advances in immunosuppressive therapy, acute allograft rejection remains a significant cause of morbidity and mortality. The current 'gold standard' for rejection surveillance is endomyocardial biopsy, which aims to identify episodes of rejection prior to development of clinical manifestations. This is an invasive technique with a risk of false-positive and false-negative results. Consequently, a wide variety of noninvasive alternatives have been investigated for their potential role as biomarkers of rejection. This article reviews the evidence behind proposed alternatives such as imaging techniques, electrophysiological parameters and peripheral blood markers, and highlights the potential future role for biomarkers in cardiac transplantation as an adjunct to biopsy.

Renal transplant vascular complications: the role of Doppler ultrasound.

Improvements in the care of kidney transplant recipients and advances in immunosuppressive therapy have reduced the incidence of graft rejection. As a result, other types of kidney transplant complications, such as surgical, urologic, parenchymal, and vascular complications, have become more common. Although vascular complications account for only 5-10% of all post-transplant complications, they are a frequent cause of graft loss. Ultrasonography, both in B-mode and with Doppler ultrasound, is a fundamental tool in the differential diagnosis of renal allograft dysfunction. Doppler ultrasound is highly specific in cases of transplanted renal artery stenosis, pseudoaneurysms, arteriovenous fistulas, and thrombosis with complete or partial artery or vein occlusion. A single measurements of color Doppler indexes display high diagnostic accuracy and in particular cases are more useful during the post-transplantation follow-up period. More recent techniques, such as contrast-enhanced ultrasound, undoubtedly increase the accuracy of ultrasonography in the diagnosis of vascular complications involving the transplanted kidney.

A Case of Infective Endocarditis with Cytomegalovirus Infection after Kidney Transplantation

Advances in immunosuppressive therapy have increased the survival of kidney transplant recipients, yet suppression of the immune system after transplantation can promote infectious complications. Cytomegalovirus (CMV) infection remains one of the most important complications following kidney transplantation and it is a risk factor for developing superinfections with other organisms. Aspergillus endocarditis is a rare life‐threatening complication in kidney transplantation. Coinfection of CMV and Aspergillus endocarditis is rare worldwide and has not been reported in Korea. We report a case of Aspergillus endocarditis that developed in a patient with CMV infection after kidney transplantation. His clinical condition did not improve despite mitral valve replacement and empirical antibiotic treatment, but he was eventually treated successfully with antifungal agents for 6 weeks. (Korean J Med 2014;86:627-631)

Immunosuppressive therapy in allograft transplantation: from novel insights and strategies to tolerance and challenges.

Immunosuppression therapy is the key to successful post-transplantation outcomes. The need for ideal immunosuppression became durable maintenance of long-term graft survival. In spite of current immunosuppressive therapy regimens advances, surgical procedures, and preservation methods, organ transplantation is associated with a long-term poor 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. T regulatory (Treg) cells, which have immunosuppressive functions and cytokine profiles, have been studied during the last decades. Treg cells are able to inhibit the development of allergen-specific cell responses and consequently play a key role in a healthy immune response to allergens. Mature dendritic cells (DCs) play a crucial role in the differentiation of Tregs, which are known to regulate allergic inflammatory responses. 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 alternative therapeutic choices. The present review evaluates the recent clinical advances in immunosuppressive therapies for organ transplantation.

Invited Commentary

Lung transplantation has evolved into a life-saving therapy for patients with advanced lung diseases. Success rates after lung transplantation are largely due to advances in immunosuppressive therapies that have enabled transplant recipients to maintain lung allograft function with decreased acute and chronic rejection. However, it is unclear if any particular immunosuppressive therapy is better for decreasing rejection and improving survival after lung transplant.

Human Leukocyte Antigen Mismatch in Heart Transplants Continues To Predict Outcomes in Modern Era of Immunosuppression

Purpose HLA mismatches (HLA-MM) have been shown to affect survival after heart transplantation (HTX). However, it is generally felt that current immunosuppressive therapies (IS) minimize the effects of HLA-MM. This study wishes to test the hypothesis that despite advances in IS, HLA-MM still plays a predictive role in determining outcomes. Methods and Materials We retrospectively analyzed survival and freedom from immunologic adverse events on all patients undergoing HTX at our institution between 2005 and 2012 (n=129). Groups were stratified by number of HLA-MM at HLA-A, B, DQ and DR (Group 1, 3-4 MM) (Group 2, 5-6 MM) (Group 3, 7-8 MM). Events considered as adverse were biopsy-proven rejection (BPR) (ISHLT grade > 2R), allograft dysfunction (EF Results 100% of patients had > 3 MM. Group 1-15/129, (12%), Group 2-59/129 (46%), Group 3-55/129 (43%). Freedom from adverse events and survival were significantly worse in patients with >4 MM (Group 2 and 3) (Figure 1). Conclusions Despite the use of triple-drug immunosuppression including tacrolimus in our patients, HLA-MM remains a significant predictor of adverse events and survival. Given this, novel immunologic strategies to abrogate the effect of HLA-MM are urgently needed.

Heterotopic heart transplantation: where do we stand?

Orthotopic heart transplantation (OHT) is a well established and commonly utilized procedure for end-stage heart failure patients. Heterotopic heart transplantation (HHT) is a surgical procedure that allows the graft to be connected to the native heart in a parallel fashion. The main advantage of HHT is to assist the patient's native heart and to maintain circulation in the cases of severe acute rejection. HHT has also been proposed to overcome pulmonary hypertension, to increase the size of the donor pool and to decrease waiting times without increasing morbidity caused by the procedure. However, only a few papers have reported the short- or long-term results of HHT, and most of these studies have included <30 cases. OHT remains the standard technique and is preferable whenever the patient meets the current criteria and a suitable organ is available. HHT is far less useful than in the past because of the major advances in immunosuppression therapy and the development of long-term mechanical circulatory support. This study reviews the origin of HHT and discusses clinical developments, including their advantages and disadvantages.

History and ethics of hand transplants

Hand transplantation is a form of composite tissue allotransplantation, whereby the hand of a cadaveric donor is transferred to the forearm of an amputee. The aim of such a procedure is to achieve better outcomes in terms of functionality and appearance when compared with prosthetics. The microsurgical techniques required have been well established for many years. In addition, advances in immunosuppressive therapy have meant that hand transplantation is a feasible therapeutic option. However this is not a life-saving procedure, requiring lifelong antirejection treatment with potentially serious side-effects. Hand transplantation is therefore a controversial concept with ethical, financial and psychological implications that need careful consideration. Before this treatment can be fully accepted, further research is still required; this should be directed towards achieving immunological tolerance, while minimizing costs and potential side-effects of post-transplant therapy.

Damage Assessment in ANCA-Associated Vasculitis

Antineutrophil cytoplasm antibody associated vasculitis has been transformed from life-threatening conditions to chronic relapsing long-term diseases as a result of significant advances in immunosuppressive therapy. Although mortality still occurs, it is much less frequent, with an average 5-year survival of over 70 %. In the setting of chronic conditions, it becomes increasingly important to monitor the burden of disease in terms of both active inflammation requiring immunosuppression and chronic damage (scarring) from vasculitis and its treatment and associated comorbidity. The damage that accumulates in patients with vasculitis does not respond to immunosuppressive treatment. It is important to distinguish disease activity from disease damage to prevent unnecessary immunosuppression, but it is equally important to recognize damage for what it is, so that it can be addressed appropriately. Damage is an inevitable consequence of long-term vasculitis for over 80 % of patients, which should not surprise us given the severity of the original illness. There is potential value in measuring damage as a means of providing prognostic information. Using a quantified score such as the Vasculitis Damage Index (VDI) allows us to predict mortality. Patients with at least five items of damage on the VDI score have substantially worse mortality (7- to 11-fold worse risk), as compared with those with lesser amounts of damage. These findings should be taken into context when planning the management of patients with vasculitis, as well as in clinical trials of vasculitis. Disease damage is an important surrogate for long-term outcome in vasculitis, and studies should be designed to limit the amount of damage accumulating as a result of therapeutic intervention, rather than simply controlling disease activity, as is currently the aim in recent randomized controlled trials in vasculitis. Furthermore, careful cataloguing of damage, as well as disease activity items, provides much greater detail in describing and observing the long-term natural history of primary systemic vasculitis in patients treated with immunosuppressive agents who survive their initial disease process.

Remission of refractory Crohn's disease by high‐dose cyclophosphamide and autologous peripheral blood stem cell transplantation

Despite advances in immunosuppressive therapy, up to 10% of patients with severe Crohn's disease (CD) remain refractory to conventional treatment. Limited evidence from pilot trials suggests that high-dose immunosuppression and autologous peripheral blood stem cell transplantation (autoPBSCT) may induce remission in these patients, but there is substantial controversy regarding the safety and efficacy of this approach. To address this issue, a monocentre phase I/II trial of autoPBSCT was performed in patients with refractory CD in our hospital. Here, we report on the outcome of 12 patients with refractory CD treated with autoPBSCT. Briefly, CD34(+) -selected PBSCs were harvested after mobilisation therapy with cyclophosphamide and granulocyte-colony stimulating factor. Later, immunoablative conditioning therapy with high-dose cyclophosphamide followed by autoPBSCT was applied and clinical and endoscopic responses were analysed after a mean follow-up of 3.1years (range 0.5-10.3years). PBSC harvest following mobilisation chemotherapy was successful in 11/12 patients and resulted in a clinical and endoscopic improvement in 7/12 patients. Subsequent conditioning and autoPBSCT were performed in nine patients and were relatively well tolerated. Among those, five patients achieved a clinical and endoscopic remission within 6months after autoPBSCT. However, relapses occurred in 7/9 patients during follow-up, but disease activity could be controlled by low-dose corticosteroids and conventional immunosuppressive therapy. Immunoablation by cyclophosphamide and autologous peripheral blood stem cell transplantation is safe and effective to induce remission of refractory Crohn's disease, and should be further evaluated in randomised controlled trials.

Intestinal Transplantation Outcomes

Intestinal transplantation has evolved from being considered an experimental procedure into a clinically accepted therapy for patients with intestinal failure and parenteral nutrition life-threatening complications. Early referral, advances in immunosuppression therapy, standardization of surgical techniques, prophylactic therapy of infections, early diagnosis of rejection, and better posttransplant patient management are some of the changes that have allowed more patients to receive transplants, thus recovering intestinal sufficiency, and at the same time allowing the procedure to spread worldwide. Over the last 2 decades, transplant centers have focused on improving short-term patient survival, which has consequently increased by >20%. It is now clear that even though isolated intestinal-transplant recipients have lower mortality risk on the waiting list, they are at higher risk for long-term graft loss. Mortality is higher on the waiting list and early posttransplant in recipients whose intestinal transplants are associated with liver grafts; however, they have better long-term patient and graft survival. Nevertheless, 3-year actuarial patient survival has not changed over the same period of time, and therefore this is our challenge for the next decade.

Trends in Immunologic Risk Among Kidney Transplant Recipients in the United States

Introduction: Despite advances in immunosuppressive therapy, immune factors remain important predictors of graft failure following renal transplantation. However, development of a composite measure of immunologic risk is necessary to better inform clinician decision making and organ allocation policy reform. Methods: We retrospectively examined 208,560 recipients of kidney transplants from the United Network for Organ Sharing (UNOS) database preformed between 1995 and 2010. Graft survival according to a composite (re-transplantation, panel reactive antibody >40%, human leukocyte antigen mismatch, recipient hepatitis C virus seropositive, and African American race) Immunologic Risk Index (IRI) was analyzed using Kaplan-Meier and log-rank methodology. Cox proportional hazards regression was utilized to examine both the performance of individual immune risk factors and the IRI as predictors of graft failure. Stratified analysis and calculation of the Rothman Synergy Index were used to characterize the interaction between immune risk factors. Results: A decline in unadjusted graft survival was observed with escalating Immunologic Risk Index score (Figure 1). After risk adjustment for donor and recipient covariates, the Immunologic Risk Index remains a significant predictor of graft failure (HR 1.21 per point, 95% CI 1.19-1.22, p<0.0001). Recipient Hepatitis C virus (HR 1.36, 95% CI 1.31-1.41, p<0.0001) was the strongest and panel reactive antibody >40% (HR 1.12, 95% CI 1.09-1.16, p<0.0001) the weakest predictor of graft failure. in contrast, the transplant era 2005-2010 (HR 0.90, 95% CI 0.86-0.95, p=0.0001) and high (>1000 cases) transplant center volume (HR 0.82, 95% CI 0.78-0.88, p<0.0001) protected against graft failure. Interestingly, the mean Immunologic Risk Index score increased from 1.47 in 1995 to a peak of 1.52 in 2003, but abruptly declined thereafter reaching a nadir of 1.40 in 2005. Conclusions: the Immunologic Risk Index is a superior risk predictor compared to individual immune risk factors. A decline in the Immunologic Risk Index after 2003 might explain the improvement in graft survival observed in the 2005-2010 transplant era. Immunologic risk aversion and/or the unintended consequences of changes made to kidney allocation policy in 2003 are implicated. Policy reform may be necessary to preserve equal access to renal transplantation among high immunologic risk patients.

Recent advances in biomarker discovery in solid organ transplant by proteomics

The identification and clinical use of more sensitive and specific biomarkers in the field of solid organ transplantation is an urgent need in medicine. Solid organ transplantation has seen improvements in the short-term survival of transplanted organs due to recent advancements in immunosuppressive therapy. However, the currently available methods of allograft monitoring are not optimal. Recent advancements in assaying methods for biomolecules such as genes, mRNA and proteins have helped to identify surrogate biomarkers that can be used to monitor the transplanted organ. These high-throughput ‘omic’ methods can help researchers to significantly speed up the identification and the validation steps, which are crucial factors for biomarker discovery efforts. Still, the progress towards identifying more sensitive and specific biomarkers remains a great deal slower than expected. In this article, we have evaluated the current status of biomarker discovery using proteomics tools in different solid organ transplants in recent years. This article summarizes recent reports and current status, along with the hurdles in efficient biomarker discovery of protein biomarkers using proteomics approaches. Finally, we will touch upon personalized medicine as a future direction for better management of transplanted organs, and provide what we think could be a recipe for success in this field.

Recent advances in immunosuppressive therapy for prevention of renal allograft rejection

Current immunosuppressive therapies are highly successful at regulating acute allograft rejection and inducing long-term transplanted kidney survival; however, currently available medications are associated with generalized immune suppression and drug toxicities, including nephrotoxicity. In recent years, advances in immunosuppression that target specific pathways involved in immune activation have been developed. In particular, promising medications are currently under evaluation that target ischemia-reperfusion injury as well as the cellular and humoral branches of the adaptive immune response. Targets of T-cell-mediated activation include antibodies and fusion proteins interfering with LFA-1/ICAM-1, CD2/LFA-3, CD40/CD154, and CD28/B7.1 and B7.2 interactions. Intracellular targets involved in T- and B-cell activation pathways are being evaluated, including protein kinase C inhibitors, Janus-associated kinase (JAK) inhibitors, and proteasome inhibitors. Several new medications demonstrate promise in inhibiting donor-directed humoral immunity by targeting B-cell-activating factor (BAFF) and complement activation pathways. The present review evaluates the recent clinical advances in immunosuppressive therapies for kidney transplantation. Publications regarding advances in immunosuppressive therapies over the past year were evaluated in the context of the specific immune pathways involved in allograft rejection.

High-dose cyclophosphamide and autologous hematopoieitic cell transplantation for inflammatory bowel disease – a single center experience

Background: Despite recent advances in immunosuppressive therapy, up to 10% of patients with severe inflammatory bowel disease remain refractory to conventional treatment. Recent studies show that immune ablation by high-dose immunsuppression and autologous peripheral blood hematopoietic cell transplantation (aPBHCT) may efficiently induce long-lasting clinical remission in autoimmune disease.