Alloreactive T cells to Assess Acute Rejection Risk in Kidney Transplant Recipients.

Unlabelled: Memory T cells are important mediators of transplant rejection but are not routinely measured before or after kidney transplantation. The aims of this study were as follows: (1) validate whether pretransplant donor-reactive memory T cells are reliable predictors of acute rejection (AR) (2) determine whether donor-reactive memory T cells can distinguish AR from other causes of transplant dysfunction.

Methods: Samples from 103 consecutive kidney transplant recipients (2018-2019) were obtained pretransplantation and at time of for-cause biopsy sampling within 6 mo of transplantation.

Natural Antibodies Are Associated With Rejection and Long-term Renal Allograft Loss in a Multicenter International Cohort.

Background: Potentially harmful nonhuman leukocyte antigen antibodies have been identified in renal transplantation, including natural immunoglobulin G antibodies (Nabs) reactive to varied antigenic structures, including apoptotic cells.

Methods: In this retrospective, multicenter study, we assessed Nabs by reactivity to apoptotic cells in sera collected from 980 kidney transplant recipients across 4 centers to determine their association with graft outcomes.

Results: Elevated pretransplant Nabs were associated with graft loss (hazard ratio [HR] 2.

Boosting the VZV-Specific Memory B and T Cell Response to Prevent Herpes Zoster After Kidney Transplantation.

Background: Solid organ transplant recipients are at high risk to develop (complicated) herpes zoster (HZ). Booster vaccination could prevent HZ. However, end-stage renal disease (ESRD) patients show poor immunological responses to vaccinations.

High Tacrolimus Intrapatient Variability and Subtherapeutic Immunosuppression are Associated With Adverse Kidney Transplant Outcomes.

Background: Kidney transplant recipients with high intrapatient variability (IPV) in tacrolimus (Tac) exposure experience more rejection and reduced graft survival. To understand the underlying pathophysiology of this association, the authors investigated whether patients with high tacrolimus IPV have a more activated immune system than patients with low IPV. In addition, exposure to tacrolimus and mycophenolic acid (MPA) was studied in relation to rejection and graft survival.

Natural Antibodies and Alloreactive T Cells Long after Kidney Transplantation.

Background: The relationship between circulating effector memory T and B cells long after transplantation and their susceptibility to immunosuppression are unknown. To investigate the impact of antirejection therapy on T cell-B cell coordinated immune responses, we assessed IFN--producing memory cells and natural antibodies (nAbs) that potentially bind to autoantigens on the graft.

Methods: Plasma levels of IgG nAbs to malondialdehyde (MDA) were measured in 145 kidney transplant recipients at 5-7 years after transplantation.

Pre-transplant donor-reactive IL-21 producing T cells as a tool to identify an increased risk for acute rejection.

Pre-transplant screening focuses on the detection of anti-HLA alloantibodies. Previous studies have shown that IFN-γ and IL-21 producing T cells are associated with the development of acute rejection (AR). The aim of this study, was to assess whether pre-transplant donor-reactive T cells and/or B cells are associated with increased rejection risk.

A systematic review and meta-analysis of enzyme-linked immunosorbent spot (ELISPOT) assay for BK polyomavirus immune response monitoring after kidney transplantation.

BK virus (BKV) infection after kidney transplantation can cause BKV nephropathy (BKVAN) resulting in graft dysfunction and allograft loss. The treatment for BKVAN is reduction of the immunosuppressive load which increases the risk of kidney transplant rejection. There is no biomarker to monitor BKV activity besides BK viral load.

Donor-specific ELISPOT assay for predicting acute rejection and allograft function after kidney transplantation: A systematic review and meta-analysis.

Acute rejection remains an important problem after kidney transplantation. Enzyme-linked immunosorbent spot (ELISPOT) assay has been investigated extensively and has shown promising results as a predictor of allograft rejection. The objective of this study was to systematically review and analyze the predictive value of the donor-specific ELISPOT assay to identify recipients at risk for acute rejection.

Herpes Zoster in Solid Organ Transplantation: Incidence and Risk Factors.

Background: Studies on herpes zoster (HZ) incidence in solid organ transplant (SOT) recipients report widely varying numbers. We investigated HZ incidence, severity, and risk factors in recipients of four different SOTs, with a follow-up time of 6-14 years.

Methods: Records of 1,033 transplant recipients after first heart (HTx: n = 211), lung (LuTx: n = 121), liver (LiTx: n = 258) and kidney (KTx: n = 443) transplantation between 2000 and 2014 were analyzed for VZV-PCR, clinical signs of HZ, and complications.

Immunosuppression Has Long-Lasting Effects on Circulating Follicular Regulatory T Cells in Kidney Transplant Recipients.

FoxP3 follicular regulatory T cells (Tfr) have been identified as the cell population controlling T follicular helper (Tfh) cells and B cells which, are both involved in effector immune responses against transplanted tissue. To understand the biology of Tfr cells in kidney transplant patients treated with tacrolimus and mycophenolate mofetil (MMF) combination immunosuppression, we measured circulating (c)Tfh and cTfr cells in peripheral blood by flow cytometry in = 211 kidney transplant recipients. At the time of measurement patients were 5-7 years after transplantation.

Impact of low tacrolimus exposure and high tacrolimus intra-patient variability on the development of anti-HLA donor-specific antibodies in kidney transplant recipients.

: donor-specific antibodies (DSA) directed against HLA are a major contributing factor to the chronic deterioration of renal allograft function. Several factors, including the degree of HLA matching, younger recipient age, and past sensitization events have been shown to increase the risk for the development of DSA. The development of DSA is also strongly associated with modifications in the immunosuppressive regimen, non-adherence, and under-immunosuppression.

An overview of T follicular cells in transplantation: spotlight on their clinical significance.

: For late stage organ failure patients, transplantation is the best option to increase life expectancy with a superior quality of life. Unfortunately, after transplantation many patients are at risk of cellular and antibody-mediated rejection (ABMR). The latter is initiated by donor specific antibodies (DSA) which depend on the actions of B cells, T follicular helper (Tfh) cells and T follicular regulatory (Tfr) cells that are present in the germinal center of lymphoid organs.

The role of follicular T helper cells in the humoral alloimmune response after clinical organ transplantation.

Over the past decade, antibody-mediated or humoral rejection in combination with development of de novo donor-specific antibodies (DSA) has been recognized as a distinct and common cause of transplant dysfunction and is responsible for one-third of the failed allografts. Detailed knowledge of the mechanisms that initiate and maintain B-cell driven antidonor reactivity is required to prevent and better treat this antidonor response in organ transplant patients. Over the past few years, it became evident that this response largely depends on the actions of both T follicular helper (Tfh) cells and the controlling counterparts, the T follicular regulatory (Tfr) cells.

The Number of Donor-Specific IL-21 Producing Cells Before and After Transplantation Predicts Kidney Graft Rejection.

Interleukin (IL)-21 supports induction and expansion of CD8 T cells, and can also regulate the differentiation of B cells into antibody-producing plasma cells. We questioned whether the number of circulating donor-specific IL-21 producing cells (pc) can predict kidney transplant rejection, and evaluated this in two different patient cohorts. The first analysis was done on pre-transplantation samples of 35 kidney transplant recipients of whom 15 patients developed an early acute rejection.

Adipose Tissue-Derived Mesenchymal Stem Cells Have a Heterogenic Cytokine Secretion Profile.

Mesenchymal stem cells derived from adipose tissue (ASC) have immune regulatory function, which makes them interesting candidates for cellular therapy. ASC cultures are however heterogeneous in phenotype. It is unclear whether all ASC contribute equally to immunomodulatory processes.

Humoral and cellular response after varicella vaccination in VZV IgG seronegative kidney transplant candidates.

Background: In immunocompromised patients, primary infection with VZV may have a disastrous clinical course. Vaccination of VZV-seronegative patients on the waiting list for renal transplantation may prevent severe disease. However, the immunologic response of end-stage renal disease patients to peptide vaccines is far from optimal.

The Biological Effects of IL-21 Signaling on B-Cell-Mediated Responses in Organ Transplantation.

Antibody-mediated rejection has emerged as one of the major issues limiting the success of organ transplantation. It exerts a highly negative impact on graft function and outcome, and effective treatment is lacking. The triggers for antibody development, and the mechanisms leading to graft dysfunction and failure, are incompletely understood.

Herpes zoster after lung transplantation boosts varicella zoster virus-specific adaptive immune responses.

Background: Varicella zoster virus (VZV)-specific memory T cells are significantly lower in transplant recipients than in controls. In addition, VZV-specific immunoglobulin G titers are significantly lower after than before transplantation. Data on the incidence and timing of herpes zoster (HZ) after lung transplantation are limited.

Interleukin-17-producing CD4(+) cells home to the graft early after human heart transplantation.

Background: Interleukin-17 (IL-17) is regarded as a major effector cytokine with pro-inflammatory actions. It has pleiotropic and environment-specific functions by promoting adaptive cytotoxic T-lymphocyte responses during inflammation. Therefore, it is tempting to speculate that IL-17 plays a major role in inflammatory responses in transplant recipients.

Rotterdam: main port for organ transplantation research in the Netherlands.

This overview describes the full spectrum of current pre-clinical and clinical kidney-, liver-, heart- and lung transplantation research performed in Erasmus MC - University Medical Centre in Rotterdam, The Netherlands. An update is provided on the development of a large living donor kidney transplantation program and on optimization of kidney allocation, including the implementation of a domino kidney-donation program. Our current research efforts to optimize immunosuppressive regimens and find novel targets for immunosuppressive therapy, our recent studies on prevention of ischemia-reperfusion-induced graft injury, our newest findings on stimulation of tissue regeneration, our novel approaches to prevent rejection and viral infection, and our latest insights in the regulation of allograft rejection, are summarized.

An immunological basis for chronic histiocytic intervillositis in recurrent fetal loss.

Problem: Chronic histiocytic intervillositis (CHIV) is a rare type of placental pathology that is associated with reproductive loss at all gestational ages. The aim of the study was to investigate the relationship between the severity of CHIV and the outcome of pregnancy and to compare the immune response between CHIV patients and controls to explore an immunological origin of CHIV.

Method Of Study: Microscopic slides were reviewed and scored according to a previously published grading system in 30 pregnancies of 22 CHIV patients.

Systemic varicella zoster virus reactive effector memory T-cells impaired in the elderly and in kidney transplant recipients.

Varicella zoster virus (VZV) infections cause varicella and subsequently herpes zoster upon reactivation. Immune-compromised individuals and the elderly are at high risk of developing herpes zoster due to waning of VZV-specific T-cell immunity. In the present study, a novel functional T-cell assay was developed to test the correlation between age and VZV-specific T-cell responses in peripheral blood from healthy individuals.

Human mesenchymal stem cells are susceptible to lysis by CD8(+) T cells and NK cells.

There is growing interest in the use of mesenchymal stem cells (MSCs) to improve the outcome of organ transplantation. The immunogenicity of MSCs is, however, unclear and is important for the efficacy of MSC therapy and for potential sensitization against donor antigens. We investigated the susceptibility of autologous and allogeneic MSCs for lysis by CD8(+) T-lymphocytes and NK cells in a kidney transplant setting.

Vaccine-induced allo-HLA-reactive memory T cells in a kidney transplantation candidate.

Background: Allo-human leukocyte antigen (HLA) reactivity by naturally acquired viral-specific memory T cells is common. However, the effect of successful vaccination on the alloreactive memory T-cell repertoire is unclear. We hypothesized that vaccination could specifically induce allo-HLA-reactive memory T cells.

Preeclampsia is associated with increased cytotoxic T-cell capacity to paternal antigens.

Objective: During an uncomplicated pregnancy the conceptus is a semiallogeneic entity in which rejection is prevented by suppression of the maternal immune system. We hypothesized that this suppression is disturbed in patients with preeclampsia and that a maternal immune response to fetal (foreign/paternal) antigens in the fetal-maternal interface may be responsible for local inflammation, with subsequent endothelial dysfunction and systemic disease.

Study Design: Blood samples were obtained from 14 women with preeclampsia (cases), 14 gestational-age and parity-matched women with uncomplicated pregnancies (controls), and their partners.