Role Of Transplantation Research Articles

Efficacy of Autologous and Allogeneic Hematopoietic Cell Transplantation in Waldenström Macroglobulinemia: A Systematic Review and Meta-analysis

IntroductionWaldenström macroglobulinemia (WM) is an IgM-producing lymphoproliferative disorder that remains incurable. Patients with high-risk disease have an overall survival (OS) of less than 3 years. Both autologous (AHCT) and allogeneic (allo-HCT) hematopoietic cell transplantation (HCT) are prescribed for treatment of WM despite a lack of randomized controlled studies. Materials and MethodsWe performed a comprehensive literature search using PubMed/Medline and EMBASE on September 10, 2019. Data on clinical outcomes related to benefits and harms was extracted independently by 3 authors. Fifteen studies (8 AHCT [n = 278 patients], 7 allo-HCT [n = 311 patients]) were included in this systematic review/meta-analysis. ResultsPooled OS, progression-free survival (PFS), and nonrelapse mortality (NRM) rates post AHCT were 76% (95% confidence interval [CI], 65%-86%), 55% (95% CI, 42%-68%), and 4% (95% CI, 1%-7%), respectively. Pooled OS, PFS, and NRM rates post allografting were 57% (95% CI, 50%-65%), 49% (95% CI, 42%-56%), and 29% (95% CI, 23%-34%), respectively. OS and PFS rates were reported at 3 to 5 years, and NRM was reported at 1 year in most studies. Pooled ORR (at day 100) post AHCT and allo-HCT were 85% (95% CI, 72%-94%) and 81% (95% CI, 69%-91%), respectively. Pooled complete response rates post AHCT and allo-HCT were 22% (95% CI, 17%-28%) and 26% (95% CI, 7%-50%), respectively. Relapse rates post AHCT and allo-HCT were 42% (95% CI, 30%-55%) and 23% (95% CI, 18%-28%), respectively. ConclusionsOur results show that both AHCT and allo-HCT are effective in the treatment of WM. A 2-fold lower relapse rate but a 7-fold higher NRM was noted for allo-HCT compared with AHCT. The role of transplant in WM needs to be addressed in the era of novel agents.

Contrasting effects of B cell depletion on CD4+ and CD8+ memory T cell responses generated after transplantation.

Alloreactive memory T cells play a key role in transplantation by accelerating allograft rejection and preventing tolerance induction. Some studies using µMT mice, which are constitutionally devoid of B cells, showed that B cells were required for the generation of memory T cells after allotransplantation. However, whether B cell depletion in normal adult mice has the same effect on memory responses by CD4+ and CD8+ T cells activated after transplantation has not been thoroughly investigated. In this study, we tested the effect of anti-CD20 antibody-mediated B cell depletion on CD4+ and CD8+ memory T cell alloresponses after skin transplantation in wild-type mice. We found that B cell depletion prevented the development of memory alloresponses by CD4+ T cells but enhanced that of CD8+ memory T cells. Next, we tested the influence of B cell depletion on hematopoietic chimerism. In OT-II CD4+ anti-OVA TCR transgenic mice sensitized to ovalbumin antigen, B cell depletion also impaired allospecific memory T cell responses and thereby enhanced donor hematopoietic chimerism and T cell deletion after bone marrow transplantation. This study underscores the complexity of the relationships between B and T cells in the generation and reactivation of different memory T cell subsets after transplantation.

Evaluation of Plasma Levels of Soluble HLA-G and HLA-G Genotypes in Kidney Transplant Recipients

In the field of transplantation, expression of HLA-G, a nonclassical HLA molecule with immunosuppressive functions and limited gene polymorphism, is considered beneficial for graft acceptance; various studies have aimed to demonstrate this role in transplantation. Recently, in other clinical conditions, it has been observed that insulin resistance was associated with HLA-G14bpins/del polymorphism, the most studied regulatory polymorphism of this molecule. In the present study, plasma levels of the soluble form of HLA-G (sHLA-G) were analyzed in kidney transplant recipients (n = 103) with different HLA-G14bpins/del genotypes. In a group of 26 recipients, sHLA-G was detected before and after transplantation (1 year) to evaluate early variations. In 77 recipients, sHLA-G was detected after transplantation (3-24 years) and correlated with occurrence of long-term post-transplant morbidity (diabetes mellitus, hyperlipidemia, hypertension, obesity, etc.). MethodsLevels of sHLA-G were measured in plasma with an enzyme-linked immunosorbent assay; HLA-G14bpins/del and HLA-G+3142C>G genotypes were assessed using direct polymerase chain reaction. ResultsPlasma levels of sHLA-G significantly decreased during the first year after transplantation (P = .019); no significant correlations were found with genotypes or early post-transplant events. Lower levels of sHLA-G were found in recipients with post-transplant diabetes mellitus or obesity carrying the HLA-G14bpins/ins (P = .006 and P = .003, respectively) or HLA-G+3142G/G genotypes. ConclusionsA complex modulation of HLA-G, which includes both immunologic and metabolic effects, could affect the risk for long-term post-transplant morbidity in kidney transplant recipients. Associations of HLA-G, diabetes, and obesity deserve to be investigated by deeply exploring HLA-G regulatory variants.

Effect of Rewarming on Leukocyte-Endothelial Interaction After Deep Hypothermic Preservation.

BackgroundThe preservation of harvested organs plays an essential role in transplantation. Cold hypothermia is frequently applied but may lead to graft compromise resulting from reperfusion and rewarming injury. This study investigates the effect of deep hypothermia and posterior rewarming on leukocyte-endothelial interactions and junctional adhesion molecules.Material/MethodsWe established an in vitro model to investigate the transendothelial migration of leukocytes (TEM) during deep hypothermia (4°C) as well as during the post-hypothermic rewarming process. Additionally, leukocyte-endothelial interactions were analyzed by quantifying surface expression of the junctional adhesion molecules A (JAMA-A and JAM-B).ResultsWhile deep hypothermia at 4°C was associated with reduced leukocyte infiltration, rewarming after hypothermic preservation resulted in a significant increase in TEM. This process is mainly triggered by activation of endothelial cells. Post-hypothermic rewarming caused a significant downregulation of JAM-A, whereas JAM-B was not altered through temperature modulation.ConclusionsHypothermia exerts a protective effect consisting of reduced leukocyte-endothelial interaction. Rewarming after hypothermic preservation, however, causes considerable upregulation of leukocyte infiltration. Downregulation of JAM-A may play a role in modulating TEM during hypothermia and rewarming. We conclude that the rewarming process is an essential but underestimated aspect during transplantation.

Early Posttransplant Mobilization of Monocytic Myeloid-derived Suppressor Cell Correlates With Increase in Soluble Immunosuppressive Factors and Predicts Cancer in Kidney Recipients.

Myeloid-derived suppressor cells (MDSCs) increase in patients with cancer and are associated with poor prognosis; however, their role in transplantation is not yet understood. Here we aimed to study the MDSC effects on the evolution of kidney transplant recipients (KTRs). A cohort of 229 KTRs was prospectively analyzed. Two myeloid cells subsets. CD11bCD33CD14CD15HLA-DR (monocytic MDSC [M-MDSC]) and CD11bCD33CD14CD15HLA-DR (monocytes), were defined by flow cytometry. The suppressive capacity of myeloid cells was tested in cocultures with autologous lymphocytes. Suppressive soluble factors, cytokines, anti-HLA antibodies, and total antioxidant capacity were quantified in plasma. Pretransplant, M-MDSC, and monocytes were similar in KTRs and healthy volunteers. M-MDSCs increased immediately posttransplantation and suppressed CD4 and CD8 T cells proliferation. M-MDSCs remained high for 1 y posttransplantation. Higher M-MDSC counts at day 14 posttransplant were observed in patients who subsequently developed cancer, and KTRs with higher M-MDSC at day 14 had significantly lower malignancy-free survival. Day 14 M-MDSC >179.2 per microliter conferred 6.98 times (95% confidence interval, 1.28-37.69) more risk to develop cancer, independently from age, gender, and immunosuppression. Early posttransplant M-MDSCs were lower in patients with enhanced alloimmune response as represented by anti-HLA sensitization. M-MDSC counts correlated with higher circulatory suppressive factors arginase-1 and interleukin-10, and lower total antioxidant capacity. Early posttransplant mobilization of M-MDSCs predicts cancer and adds risk as an independent factor. M-MDSC may favor an immunosuppressive environment that promotes tumoral development.

Current status of stem cell transplantation in paroxysmal nocturnal hemoglobinuria

Paroxysmal nocturnal hemoglobinuria (PNH) is a clonal, acquired hematopoietic stem cell disorder, which is caused by activation of the complement system leading to life-threatening manifestations such as hemolysis, thrombosis, and marrow failure. Eculizumab is a complement inhibitor of C5, which acts by blocking complement-mediated hemolysis. It needs to be administered lifelong to the patient; hence, there are major financial implications. This drug is easily available in the Western countries; however, in low resource countries, where its availability is limited, hematopoietic stem cell transplantation (HSCT) still remains the main modality for achieving cure in PNH. PNH being a rare disease, large prospective studies and guidelines are scarce. To choose the ideal candidate for transplant is the real challenge. This article aims to review the trends in HSCT for PNH, such as the use of reduced-intensity conditioning to attain the graft versus PNH effect or the use of haploidentical donors. In the era of complement inhibitor therapy, the role of transplantation still needs to be explored.

Regulatory B cells: Development, phenotypes, functions, and role in transplantation.

The interest in regulatory B cells (Bregs) began in the 1970s with the evidence that B cells could downregulate the immune system by the production of "inhibitory" antibodies. Subsequently, a series of results from different studies have emphasized that B cells have antibody-independent immunoregulatory functions. Since then, different subsets of B cells with regulatory functions and their development and mechanisms of action have been identified both in human and in animal models of inflammation, transplantation, and autoimmunity. The present review outlines the suggested pathways by which Bregs develop, describes the different subsets of Bregs with their phenotypes and function as well as their role in transplantation, highlighting the differences between human and animal studies throughout.

Human Leucocyte Antigens in blood transfusion

Human Leucocyte Antigen (HLA) genes and molecules have an important role in transplantation, aetiology of many autoimmune, non‐autoimmune and infection diseases. Due to the extremely high polymorphism of HLA genes and their different frequency distributions in various populations, an increasing probability of HLA non‐compatible blood products, tissues or organs usage exists. For that reason, the aim of this paper was to give a concise overview of the role of HLA antigens and antibodies in adverse reactions caused by administration of transfusion products. The HLA system can cause detrimental immune reactions in transfusion therapy (platelet immune refractoriness, febrile transfusion reaction, transfusion‐related acute lung injury and transfusion‐associated graft versus host disease). Anti‐HLA antibodies present in the patient are responsible for some of these reactions, while anti‐HLA antibodies or HLA reactive cells present in the transfused product are accountable for immune‐reactivity in other cases. In order to avoid or reduce the development of these transfusion‐related events, anti‐HLA antibody‐negative or compatible products should be used. This is increasingly facilitated by introduction of more sensitive and specific techniques to determine anti‐HLA antibodies and gene polymorphisms. In conclusion, the most common adverse reactions related to administration of incompatible HLA transfusion products are discussed. Basic information about HLA genes and antibodies as well as methods for their detection is also provided in order to give sufficient data for safe and efficient administration of transfusion products.

Improving CAR T cell immunotherapy-mediated remissions for pediatric leukemia.

Chimeric antigen receptor (CAR) T cells are an effective therapy for relapsed or refractory pediatric B cell leukemia. Analysis of the starting material, the T cells collected from the patient prior to CAR manufacture, reveals possible biomarkers of cells destined to perform poorly in patients. Long-term follow-up shows that long periods of B cell aplasia, a marker of in vivo CAR activity, are associated with longer remission but also a higher chance of antigen-negative relapse. The role of transplantation as consolidative therapy is unclear in this nonrandomized data, but clearly warrants further study.

Role of Transplant in Biliary Disease.

Orthotopic liver transplantation (OLT) has many roles in biliary disease. OLT provides excellent results for patients with unresectable hilar cholangiocarcinoma. OLT prolongs survival in primary biliary cirrhosis not responsive to therapy and improves quality of life. OLT remains the durable option for patients with primary sclerosing cholangitis and complications of end-stage liver disease or recurrent cholangitis secondary to biliary obstruction. Indications for OLT after bile duct injury are chronic liver disease secondary to biliary cirrhosis and acute liver failure from associated vascular injury. OLT is treatment of choice for Caroli disease and syndrome when fibrosis leads to portal hypertension and esophageal varices.

A Deep History of Chinese Shareholding

By the turn of the twentieth century the absence of codified law governing private economic transactions was a key target of foreign and Chinese critiques of the imperial legal system. Expectations ran high that China's first legal transplant, the 1904 Company Law, would lead to unprecedented public investment in large-scale industrial projects. Their disappointment, and the continued dominance of small business in the Chinese marketplace, has been attributed to factors ranging from Chinese cultural aversion to impersonal investment to shortcomings in the law itself. This study shifts our attention to the indigenous practices that company law was meant to supplant, examining the diverse sources of Chinese shareholding practices and the rich menu of options they provided investors. Most importantly, it argues that by the late imperial period shares were well-established as abstract income producing assets that could be bought and sold, creating the possibility of partnership relationships that could be both impersonal and long-lived despite the absence in China of a formal company law. That this tradition did not lead to the emergence of an analogue to the corporation in the West raises new questions about the demand for such entities and the role of transplantation in suppressing indigenous solutions to business problems.

The role of transplantation in Hodgkin lymphoma

Autologous stem cell transplantation is the standard salvage strategy for young and fit patients with Hodgkin lymphoma failing induction therapy, and is effective in nearly 50% of cases. The quality of response at transplantation is the most relevant prognostic aspect, as patients in complete response can obtain better outcomes. Therefore, first-line salvage treatments applied before transplantation need to produce high quality responses without excessive myelotoxicity and without affecting peripheral blood stem cell mobilisation. In this sense, the incorporation of new agents active in Hodgkin lymphoma, such as brentuximab vedotin and anti-programmeddeath 1 antibodies, in conventional regimens, may help to enhance complete remission rates. Working on conditioning regimen and applying a post-autologous consolidation treatment (for example with brentuximab vedotin) are two ways for improving transplant outcomes, particularly in patients displaying high-risk features for early relapse or progression. Allogeneic transplantation maintains its curative potential also in the era of new drugs, although its most correct timing and the most suitable sequence of post-autologoussalvage treatments still remain to be determined.

State of the Art: Role of the Dendritic Cell in Induction of Allograft Tolerance.

Despite decades of research, the induction and maintenance of long-term allograft tolerance without immunosuppression remains an elusive goal in the field of solid organ and cell transplantation. Immunosuppressive medications frequently prevent or minimize acute cellular rejection but have failed to halt antidonor antibody production and chronic organ rejection. Past efforts aimed at promoting lasting allograft tolerance have focused primarily on peripheral T-cell depletion, augmentation of regulatory T cells, or induction via simultaneous hematopoietic stem cell transplantation and facilitation of donor chimerism. So far, none of these methods have led to consistently safe, feasible and long lasting donor organ acceptance. Over the course of the past 4 decades, the study of a unique population of antigen-presenting cells known as dendritic cells has shown promise for breaking new ground in achieving indefinite allograft survival without immunosuppression and its associated adverse effects. In this review, we discuss the discovery and early investigations of dendritic cells and chronicle some of the key studies demonstrating their role in transplantation, particularly in indirect allorecognition, the immunologic pathway thought to drive chronic rejection and perhaps tolerance induction.

Effect of Stem Cells and Gene Transfected Stem Cells Therapy on the Pancreas of Experimentally Induced Type 1 Diabetes.

Background and ObjectivesInsulin secretion entirely depends on Ca2+ influx and sequestration into endoplasmic reticulum (ER) of β-cells, performed by Sarco-ER Ca2+-ATPase 2b (SERCA2b). In diabetes, SERCA2b is decreased in the β-cells leading to impaired intracellular Ca2+ homeostasis and insulin secretion. Adipose mesenchymal stem cells (AMSCs) play a potential role in transplantation in animal models. The present study aimed at investigating and comparing the therapeutic effect of non-transfected AMSCs and SERCA2b gene transfected AMSCs on the pancreas of induced diabetes type 1 in rat.Methods and Results58 adult male albino rats were divided into: Donor group: 22 rats, 2 for isolation, propagation and characterization of AMSCs and SERCA2b transfected AMSCs, in addition 20 for isolated islet calcium level assessment. Group I (Control Group): 6 rats, Group II (Diabetic Group): 10 rats, 50 mg streptozotocin (STZ) were injected intraperitoneal (IP), Group III (AMSCs Group): 10 rats, 1×106 AMSCs were injected intravenous and Group IV (SERCA2b transfected AMSCs Group): 10 rats, 1×106SERCA2b transfected AMSCs were injected as in group III. Groups I, II, III and IV were sacrified 3 weeks following confirmation of diabetes. Serological, histological, morphometric studies and quantitative polymerase chain reaction (qPCR) were performed. Nuclear, cytoplasmic degenerative and extensive fibrotic changes were detected in the islets of group II that regressed in groups III and IV. Isolated islet calcium, blood glucose, plasma insulin and qPCR were confirmative.ConclusionsAMSCs and SERCA2b gene transfected AMSCs therapy proved definite therapeutic effect, more obvious in response to SERCA2b gene transfected AMSCs.

What is the role of transplantation in the management of alcoholic liver disease?

Alcoholic liver disease is a major cause of morbidity and mortality with effective pharmacotherapy being limited at present. As such, abstinence remains the cornerstone of therapy, and requires a multidisciplinary approach to address the medical and psychosocial determinants of addiction to effectively prevent relapse. Liver transplantation has a well-established role in the treatment of chronic alcoholic cirrhosis, with outcomes comparable to other aetiologies of chronic liver disease. Transplantation has been shown to be successful in highly selected candidates with acute alcoholic hepatitis (AAH), with favorable outcomes. However, AAH has not gained universal acceptance as an indication for liver transplantation, and remains controversial at present. Designing and applying objective and reliable selection rules while ensuring fair allocation in an era of organ shortage remains a challenge.

Dynamics of CD25 Positive Myeloid Derived Suppressor Cells in Solid Organ Transplanted Patients and Relationship with Rejection

Backgound Myeloid derived suppressor cells (MDSC) are immature cells with immunosuppressive capacities. Three MDSC subsets are currently defined: monocytic, early stage, and polymorphonuclear MDSC (M-MDSC, eMDSC and PMN-MDSC respectively). While MDSC increase in cancer and chronic infections and associate with poor prognosis, their role in transplantation (Tx) is unknown. Changes in MDSC in transplant patients could provide biomarkers of graft evolution, and they could be useful as immunosuppressive therapy and/or to stimulate the allograft tolerance. Methods Peripheral blood MDSC were identified in cohorts of kidney (n=164) and liver (n=30) recipients and healthy volunteers (HV) as CD33+CD11b+HLA-DRlo/-. We characterized CD14+CD15- (M-MDSC) and CD14-CD15- (eMDSC) subsets. Suppression assays and measurement of surface CD25 expression (MFI) on MDSC were performed. Results Renal recipients MDSC were able to suppress CD4 and CD8 T cell proliferation in vitro. MDSC % were similar in pre-transplant, kidney transplant recipients (KTR), than in HV. However, MDSC and M-MDSC increased, mainly at 7 and 14 days post-transplant (3.48% and 3.85% vs 1.14%; 2.47% and 2.48% vs 0.24% p≤0,001 vs pre-transplant). The increase of MDSC in KTR with basiliximab as induction therapy was lower than in patients induced with thymoglobulin or without induction, and eMDSC were particularly decreased in basiliximab-treated patients (vs no induction, p≤0.05; vs thymoglobulin, p≤0.05). We confirmed that eMDSC expressed CD25, target of basiliximab. Pre-Tx, liver transplant recipients (LTR) had higher % of CD25+ eMDSC and higher CD25 MFI than KTR and HV. In LTR and KTR without basiliximab, % and MFI of CD25 in eMDSC increased after transplant. In KTR cohort, 7% of patients suffered acute rejection (AR). Absolute numbers of MDSC at 7 days post-transplant (measured before the rejection event) were significantly lower in AR than in non-rejectors (25.84 cells/uL vs 53.18 cells/uL respectively, p≤0,05). Conclusions MDSC and M-MDSC increase post-Tx except in patients receiving basiliximab. MDSC were lower in AR patients and low MDSC counts significantly preceded rejection. Transplant recipients eMDSC express CD25 which upregulates after Tx. Whether eMDSC express a complete and functional IL-2R is under investigation.

Surgical Management of Hilar Cholangiocarcinoma

To provide a comprehensive review of the preoperative and operative considerations for the surgical management of hilar cholangiocarcinoma. The management of hilar cholangiocarcinoma has evolved over the past 20 years, with data from large institutional series emerging, which has influenced decisions regarding the need for preoperative biliary drainage, portal-vein embolization, extent of surgical resection, role of transplantation, and efficacy of adjuvant and palliative therapies. Hepatectomy has become the standard of care for resectable hilar cholangiocarcinoma, while transplantation can offer promising results for unresectable patients with localized disease. Perioperative mortality can be minimized through careful preoperative management of the future liver remnant via appropriate use of biliary drainage and portal-vein embolization. Adjuvant therapies prolong survival after resection, while emerging data on endoluminal therapies and radiation provide palliation and improved survival for patients with advanced, unresectable disease.

Teenagers and Their Future Role in Transplantation: An Analysis of Their Attitudes Toward Solid Organ Xenotransplantation

IntroductionIt is important to determine the level of social acceptance of xenotransplantation, especially in places where there are preclinical xenotransplantation projects. In this sense, it is important to know the attitude of teenagers, given that their attitude could have an influence on this kind of donation in the future. ObjectivesThe aim of this study is to analyze the attitudes of teenagers toward xenotransplantation and to determine the variables affecting their attitudes. Material and MethodsA random simple was obtained of students who were between 12 and 16 years of age in secondary schools in the southeast of Spain (n = 3633). Their attitudes were assessed with the use of a validated psychosocial questionnaire about xenotransplantation (PCID-XenoTx Ríos). The questionnaire was completed anonymously and was self-administered. Descriptive statistical analysis, Student t, and χ2 tests were used. ResultsThe completion rate was 97% (n = 3531). With regard to animal organ donation for humans, 44% (n = 1569) would be in favor, 22% (n = 784) against, and 34% (n = 1178) undecided. Attitude was related to knowing a transplantation patient (P = .02), believing that transplant organ needs are not covered (P = .004), having received information about organ donation and transplantation (ODT) on television and from schools (P = .001), family discussion about ODT (P < .001), attitude of the respondent's parents (P < .001), and attitude toward human donation (P < .001). ConclusionsMore than half of the teenagers had unfavorable attitudes toward xenotransplantation as this was determined by factors related to knowledge of and previous information about ODT, the attitude of one's family, and attitudes toward the different types of human organ donation.

High-Throughput Contiguous Full-Length Next-Generation Sequencing of HLA Class I andII Genes from 96 Donors in aSingle MiSeq Run.

The human leukocyte antigen (HLA) genes regulate and drive the immune system, and are among the most polymorphic loci in the human genome. HLA diversity is known to play an important role in transplantation and disease association studies. There are multiple approaches to DNA-based HLA genotyping and recent advances in next-generation sequencing (NGS) technologies have facilitated the development of whole gene sequencing methods. We describe an accurate, efficient, scalable, and cost-effective approach to contiguously amplify and sequence full-length genes of six HLA class I and II loci from 96 individuals on a single Illumina MiSeq run.

Obituary: Prof Johannes Joseph van Rood (1926‐2017)

Obituary: Prof Johannes Joseph van Rood (1926‐2017)