Publications by authors named "Monika Lindemann"

68 Publications

Comparison of Cytomegalovirus-Specific Immune Cell Response to Proteins versus Peptides Using an IFN-γ ELISpot Assay after Hematopoietic Stem Cell Transplantation.

Diagnostics (Basel) 2021 Feb 15;11(2). Epub 2021 Feb 15.

Department of Internal Medicine III, Hematology and Oncology, University Medical Center Regensburg, 93053 Regensburg, Germany.

Cytomegalovirus (CMV) infection is a major cause of morbidity and mortality following hematopoietic stem cell transplantation (HSCT). Measuring CMV-specific cellular immunity may improve the risk stratification and management of patients. IFN-γ ELISpot assays, based on the stimulation of peripheral blood mononuclear cells with CMV pp65 and IE-1 proteins or peptides, have been validated in clinical settings. However, it remains unclear to which extend the T-cell response to synthetic peptides reflect that mediated by full-length proteins processed by antigen-presenting cells. We compared the stimulating ability of pp65 and IE-1 proteins and corresponding overlapping peptides in 16 HSCT recipients using a standardized IFN-γ ELISpot assay. Paired qualitative test results showed an overall 74.4% concordance. Discordant results were mainly due to low-response tests, with one exception. One patient with early CMV reactivation and graft-versus-host disease, sustained CMV DNAemia and high CD8 counts showed successive negative protein-based ELISpot results but a high and sustained response to IE-1 peptides. Our results suggest that the response to exogenous proteins, which involves their uptake and processing by antigen-presenting cells, more closely reflects the physiological response to CMV infection, while the response to exogenous peptides may lead to artificial in vitro T-cell responses, especially in strongly immunosuppressed patients.
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http://dx.doi.org/10.3390/diagnostics11020312DOI Listing
February 2021

Characterization of follicular T helper cells and donor-specific T helper cells in renal transplant patients with de novo donor-specific HLA-antibodies.

Clin Immunol 2021 Feb 24;226:108698. Epub 2021 Feb 24.

Department of Nephrology, University Hospital Essen, University of Duisburg-Essen, Essen 45147, Germany. Electronic address:

T follicular helper (T) cells are a heterogeneous subset of immunocompetent T helper (T) cells capable of augmenting B cell responses in lymphoid tissues. In transplantation, exposure to allogeneic tissue activates T cells increasing the risk of the emergence of de novo donor-specific HLA-antibodies (dnDSA). These can cause antibody-mediated rejection (AMR) and allograft loss. Follicular regulatory T (T) cells counteract T cell activity. Here, we investigated the implications of T and T cells on dnDSA formation after renal transplantation (RTX). Considering T cells to be CXCR5 and IL-21, we found by flow cytometry that patients with dnDSA produced IL-21 more abundantly compared to healthy volunteers. In in vitro alloreactivity assays, patients with dnDSA featured an enhanced alloreactive T cell pool in response to donor-specific HLA antigens. Besides, longitudinal investigations suggested enhanced alloreactivity shortly after transplantation increasing the risk of dnDSA development. Taken together, in spite of continuous immunosuppression we report a strong IL-21 response in T cells and an expanded reservoir of donor-specific memory T cells in patients with dnDSA. This warrants further investigations if aberrant T cell activation may precede the formation of dnDSA promoting AMR.
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http://dx.doi.org/10.1016/j.clim.2021.108698DOI Listing
February 2021

Systematic memory B cell archiving and random display shape the human splenic marginal zone throughout life.

J Exp Med 2021 Apr;218(4)

Institute of Cell Biology (Cancer Research), University of Duisburg-Essen, Essen, Germany.

Human memory B cells (MBCs) are generated and diversified in secondary lymphoid tissues throughout the organism. A paired immunoglobulin (Ig)-gene repertoire analysis of peripheral blood (PB) and splenic MBCs from infant, adult, and elderly humans revealed that throughout life, circulating MBCs are comprehensively archived in the spleen. Archive MBC clones are systematically preserved and uncoupled from class-switching. Clonality in the spleen increases steadily, but boosts at midlife, thereby outcompeting small clones. The splenic marginal zone (sMZ) represents a primed MBC compartment, generated from a stochastic exchange within the archive memory pool. This is supported by functional assays, showing that PB and splenic CD21+ MBCs acquire transient CD21high expression upon NOTCH2-stimulation. Our study provides insight that the human MBC system in PB and spleen is composed of three interwoven compartments: the dynamic relationship of circulating, archive, and its subset of primed (sMZ) memory changes with age, thereby contributing to immune aging.
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http://dx.doi.org/10.1084/jem.20201952DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7868796PMC
April 2021

SARS-CoV-2-specific humoral and cellular immunity in two renal transplants and two hemodialysis patients treated with convalescent plasma.

J Med Virol 2021 Feb 2. Epub 2021 Feb 2.

Department of Infectious Diseases, West German Centre of Infectious Diseases, Universitätsmedizin Essen, University of Duisburg-Essen, Essen, Germany.

When patients with chronic kidney disease are infected with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) they can face two specific problems: virus-specific immune responses may be impaired and remdesivir, an antiviral drug described to shorten recovery, is contraindicated. Antiviral treatment with convalescent plasma (CP) could be an alternative treatment option. In this case report, we present two kidney transplant recipients and two hemodialysis patients who were infected with SARS-CoV-2 and received CP. Antibodies against the receptor-binding domain in the S1 subunit of the SARS-CoV-2 spike protein were determined sequentially by immunoglobulin G (IgG) enzyme-linked immunosorbent assay (ELISA) and neutralization assay and specific cellular responses by interferon-gamma ELISpot. Before treatment, in both kidney transplant recipients and one hemodialysis patient antibodies were undetectable by ELISA (ratio < 1.1), corresponding to low neutralizing antibody titers (≤1:40). ELISpot responses in the four patients were either weak or absent. After CP treatment, we observed an increase of SARS-CoV-2-specific antibodies (IgG ratio and neutralization titer) and of specific cellular responses. After intermittent clinical improvement, one kidney transplant recipient again developed typical symptoms on Day 12 after treatment and received a second cycle of CP treatment. Altogether, three patients clinically improved and could be discharged from the hospital. However, one 83-year-old multimorbid patient deceased. Our data suggest that the success of CP therapy may only be temporary in patients with chronic kidney disease; which requires close monitoring of viral load and antiviral immunity and possibly an adaptation of the treatment regimen.
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http://dx.doi.org/10.1002/jmv.26840DOI Listing
February 2021

Comparison of Three Cellular Assays to Predict the Course of CMV Infection in Liver Transplant Recipients.

Vaccines (Basel) 2021 Jan 25;9(2). Epub 2021 Jan 25.

Institute for Transfusion Medicine, University Hospital Essen, Virchowstraße 179, 45147 Essen, Germany.

To estimate protection from (CMV) replication after solid organ transplantation, CMV serology has been considered insufficient and thus CMV immunity is increasingly assessed by cellular in vitro methods. We compared two commercially available IFN-γ ELISpot assays (T-Track CMV and T-SPOT) and an IFN-γ ELISA (QuantiFERON-CMV). Currently, there is no study comparing these three assays. The assays were performed in 56 liver transplant recipients at the end of antiviral prophylaxis and one month thereafter. In CMV high- or intermediate-risk patients the two ELISpot assays showed significant correlation ( < 0.0001, > 0.6) but the correlation of the ELISpot assays with QuantiFERON-CMV was weaker. Results of both ELISpot assays were similarly predictive of protection from CMV-DNAemia ≥500 copies/mL [CMV pp65 T-SPOT. at the end of prophylaxis: area under curve (AUC) = 0.744, cut-off 142 spot forming units (SFU), sensitivity set to 100%, specificity 46%; CMV IE-1 T-Track CMV at month 1: AUC = 0.762, cut-off 3.5 SFU, sensitivity set to 100%, specificity 59%]. The QuantiFERON-CMV assay was inferior, reaching a specificity of 23% when setting the sensitivity to 100%. In conclusion, both CMV-specific ELISpot assays appear suitable to assess protection from CMV infection/reactivation in liver transplant recipients.
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http://dx.doi.org/10.3390/vaccines9020088DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7911226PMC
January 2021

Cellular Immunity in COVID-19 Convalescents with PCR-Confirmed Infection but with Undetectable SARS-CoV-2-Specific IgG.

Emerg Infect Dis 2021 01 15;27(1). Epub 2020 Oct 15.

We investigated immune responses against severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) among a group of convalescent, potential blood donors in Germany who had PCR-confirmed SARS-CoV-2 infection. Sixty days after onset of symptoms, 13/78 (17%) study participants had borderline or negative results to an ELISA detecting IgG against the S1 protein of SARS-CoV-2. We analyzed participants with PCR-confirmed infection who had strong antibody responses (ratio >3) as positive controls and participants without symptoms of SARS-CoV-2 infection and without household contact with infected patients as negative controls. Using interferon-γ ELISpot, we observed that 78% of PCR-positive volunteers with undetectable antibodies showed T cell immunity against SARS-CoV-2. We observed a similar frequency (80%) of T-cell immunity in convalescent donors with strong antibody responses but did not detect immunity in negative controls. We concluded that, in convalescent patients with undetectable SARS-CoV-2 IgG, immunity may be mediated through T cells.
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http://dx.doi.org/10.3201/2701.203772DOI Listing
January 2021

SARS-CoV-2-specific antibody detection in healthcare workers in Germany with direct contact to COVID-19 patients.

J Clin Virol 2020 07 13;128:104437. Epub 2020 May 13.

Institute for Virology, University Hospital Essen, University of Duisburg-Essen, Virchowstr. 179, 45147 Essen, Germany.

Background: The novel coronavirus SARS-CoV-2 is associated with a severe respiratory manifestation, COVID-19, and presents a challenge for healthcare systems worldwide. Healthcare workers are a vulnerable cohort for SARS-CoV-2 infection due to frequent and close contact to patients with COVID-19.

Study Design: Serum samples from 316 healthcare workers of the University Hospital Essen, Germany were tested for SARS-CoV-2-IgG antibodies. A questionnaire was used to collect demographic and clinical data. Healthcare workers were grouped depending on the frequency of contact to COVID-19 patients in high-risk-group (n = 244) with daily contact to known or suspected SARS-CoV-2 positive patients, intermediated-risk-group (n = 37) with daily contact to patients without known or suspected SARS-CoV-2 infection at admission and low-risk-group (n = 35) without patient contact.

Results: In 5 of 316 (1.6 %) healthcare workers SARS-CoV-2-IgG antibodies could be detected. The seroprevalence was higher in the intermediate-risk-group vs. high-risk-group (2/37 (5.4 %) vs. 3/244 (1.2 %), p = 0.13). Four of the five subject were tested negative for SARS-CoV-2 via PCR. One (20 %) subject was not tested via PCR since he was asymptomatic.

Conclusion: The overall seroprevalence of SARS-CoV-2 in healthcare workers of a tertiary hospital in Germany is low (1.6 %). The data indicate that the local hygiene standard might be effective.
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http://dx.doi.org/10.1016/j.jcv.2020.104437DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7219425PMC
July 2020

NKG2C NK Cells Regulate the Expansion of Cytomegalovirus-Specific CD8 T Cells.

J Immunol 2020 06 13;204(11):2910-2917. Epub 2020 Apr 13.

Institute of Virology, University Hospital Düsseldorf, Heinrich Heine University, Medical Faculty, 40225 Düsseldorf, Germany;

Infection with the human CMV associates with phenotypic alterations in lymphocyte subsets. A highly reproducible finding in CMV-seropositive individuals is an expansion of NKG2C NK cells. In this study, we analyzed if the altered NK cell compartment in CMV-seropositive human donors may affect CMV-specific CD8 T cells. Resting CMV-specific CD8 T cells were terminally differentiated and expressed high levels of the NKG2C ligand HLA-E. Activation of CMV-specific CD8 T cells with the cognate Ag further increased HLA-E expression. In line with a negative regulatory effect of NKG2C NK cells on HLA-E CD8 T cells, depletion of NKG2C NK cells enhanced Ag-specific expansion of CMV-specific CD8 T cells in vitro. In turn, the activation of NK cells in coculture with CMV-specific CD8 T cells promoted a selective loss of HLA-E CD8 T cells. To test if NKG2C NK cells can target HLA-E CD8 T cells, Jurkat T cells with and without stabilized HLA-E on the surface were used. NKG2C NK cells stimulated with HLA-E Jurkat cells released higher levels of Granzyme B compared with NKG2C NK cells and NKG2C NK cells stimulated with HLA-E Jurkat cells. Moreover, intracellular levels of caspase 3/7 were increased in HLA-E Jurkat cells compared with HLA-E Jurkat cells, consistent with higher rates of apoptosis in HLA-E T cells in the presence of NKG2C NK cells. Our data show that NKG2C NK cells interact with HLA-E CD8 T cells, which may negatively regulate the expansion of CMV-specific CD8 T cells upon activation.
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http://dx.doi.org/10.4049/jimmunol.1901281DOI Listing
June 2020

Humoral response to a 13-valent pneumococcal conjugate vaccine in kidney transplant recipients.

Vaccine 2020 04 13;38(17):3339-3350. Epub 2020 Mar 13.

Department of Infectious Diseases, University Hospital Essen, University Duisburg-Essen, Essen, Germany.

Background: Vaccination against S. pneumoniae is recommended by national guidelines. Moderate immunogenicity of the 13-valent pneumococcal conjugate vaccine (PCV13) has been reported in adult kidney transplant recipients (KTR). This study further defines the immunogenicity of PCV13 in this cohort.

Methods: 49 KTR were immunized with PCV13. A validated opsonophagocytic killing assay (OPA), a global anti-pneumococcal capsular polysaccharide (anti-PCP) IgG, IgG2, IgM and IgA ELISA, and - for selected patients - a serotype specific anti-PCP WHO reference ELISA were performed pre-vaccination and at month 1 and 12 post-vaccination.

Results: Geometric mean OPA titers increased significantly for 13/13 serotypes at month 1 and for 10/13 serotypes at month 12 post-vaccination. Vaccine response defined as an OPA titer ≥1:8 was reached in 9/13 serotypes (median). 53% reached the vaccine response criteria at month 1 and 45% at month 12. At month 1 after vaccination, the median OPA titer in an age-group matched healthy reference population was 5- to 10-fold higher than in KTR. OPA titers correlated strongly with results to the global and serotype specific anti-PCP IgG ELISA. Lower OPA titers significantly (p < 0.05) correlated with albuminuria, an interval between vaccination and transplantation <12 months, age and treatment with mycophenolate mofetil. Global IgG, IgG2, IgM and IgA, as well as serotype specific anti-PCP antibody concentrations (12/13 serotypes) increased significantly at month 1 and 12 post-vaccination.

Conclusions: Kidney transplant recipients show a significant humoral response after vaccination with PCV13. Functional antibody response exists, but is not as vigorous as in healthy adults.
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http://dx.doi.org/10.1016/j.vaccine.2020.02.088DOI Listing
April 2020

Decreased Soluble Human Leukocyte Antigen E Levels in Patients After Allogeneic Hematopoietic Stem Cell Transplantation Are Associated With Severe Acute and Extended Chronic Graft-versus-Host Disease and Inferior Overall Survival.

Front Immunol 2019 10;10:3027. Epub 2020 Jan 10.

Institute for Transfusion Medicine, University Hospital Essen, Essen, Germany.

HLA-E is a member of the non-classical HLA molecules and by interaction with activating or inhibitory receptors of NK and T cells, HLA-E can lead to immune activation or suppression context-dependently. Recently, the non-classical HLA molecules gain more attention in the setting of allogeneic hematopoietic stem cell transplantation (HSCT). Most studies so far have focused on the two most frequent genotypes (HLA-E*01:01 and HLA-E*01:03) and investigated their potential association with clinical endpoints of HSCT, like graft-versus-host disease (GvHD), relapse, and overall survival (OS). However, these studies have produced inconsistent results regarding the role of HLA-E and the clinical endpoints after HSCT. We therefore here investigate the amount of soluble HLA-E (sHLA-E) in patients following HSCT and relate this to the clinical endpoints after HSCT. In univariate analysis, we observe a significant association of reduced levels of sHLA-E with severe acute GvHD, extended chronic GvHD and with inferior OS. Using receiver operating characteristic analyses specific thresholds obtained 1, 2, or 3 month(s) after HSCT were identified being indicative for severe acute GvHD, extended chronic GvHD, or inferior OS. In sub-group analyses, this effect can be confirmed in patients not treated with ATG, but is derogated in ATG-treated patients. Notably, we could not detect any association of the course of sHLA-E levels post-HSCT with the three most frequent HLA-E genotypes (HLA-E*01:03/*01:03, HLA-E*01:01/*01:01, HLA-E*01:01/*01:03). However, with regard to 5-year-OS there was an association of HLA-E*01:03 homozygosity with inferior OS. Taking ATG-treatment, recipient and donor HLA-E genotypes into consideration among other well-known risk factors, the sHLA-E status was found as an independent predictor for the development of extended cGvHD and inferior OS following HSCT irrespective of the sHLA-E thresholds. These findings shed some light on the possible impact of reduced sHLA-E levels after HSCT on GvHD and OS. Thus, sHLA-E appears to be a novel promising candidate for the prediction of clinical HSCT outcome with regards to extended cGvHD and OS.
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http://dx.doi.org/10.3389/fimmu.2019.03027DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6966962PMC
November 2020

Standardized monitoring of cytomegalovirus-specific immunity can improve risk stratification of recurrent cytomegalovirus reactivation after hematopoietic stem cell transplantation.

Haematologica 2021 Feb 1;106(2):363-374. Epub 2021 Feb 1.

Dpt of Internal Medicine III, Hematology and Oncology, University Medical Center Regensburg, Germany.

Recurrence of cytomegalovirus reactivation remains a major cause of morbidity and mortality following allogeneic hematopoietic stem cell transplantation. Monitoring cytomegalovirus-specific cellular immunity using a standardized assay might improve the risk stratification of patients. A prospective multicenter study was conducted in 175 intermediate- and high-risk allogeneic hematopoietic stem cell transplant recipients under preemptive antiviral therapy. Cytomegalovirus-specific cellular immunity was measured using a standardized IFN-γ ELISpot assay (T-Track® CMV). Primary aim was to evaluate the suitability of measuring cytomegalovirus-specific immunity after end of treatment for a first cytomegalovirus reactivation to predict recurrent reactivation. 40/101 (39.6%) patients with a first cytomegalovirus reactivation experienced recurrent reactivations, mainly in the high-risk group (cytomegalovirus-seronegative donor/cytomegalovirus-seropositive recipient). The positive predictive value of T-Track® CMV (patients with a negative test after the first reactivation experienced at least one recurrent reactivation) was 84.2% in high-risk patients. Kaplan-Meier analysis revealed a higher probability of recurrent cytomegalovirus reactivation in high-risk patients with a negative test after the first reactivation (hazard ratio 2.73; p=0.007). Interestingly, a post-hoc analysis considering T-Track® CMV measurements at day 100 post-transplantation, a time point highly relevant for outpatient care, showed a positive predictive value of 90.0% in high-risk patients. Our results indicate that standardized cytomegalovirus-specific cellular immunity monitoring may allow improved risk stratification and management of recurrent cytomegalovirus reactivation after hematopoietic stem cell transplantation. This study was registered at www.clinicaltrials.gov as #NCT02156479.
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http://dx.doi.org/10.3324/haematol.2019.229252DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7849569PMC
February 2021

Expression pattern of co-inhibitory molecules on CMV-specific T-cells in lung transplant patients.

Clin Immunol 2019 11 6;208:108258. Epub 2019 Sep 6.

Department of Nephrology, University Hospital Essen, University Duisburg-Essen, Hufelandstr. 55, 45147 Essen, Germany. Electronic address:

Objectives: Cytomegalovirus infection (CMVi) occurs frequently in transplant patients. Co-inhibitory molecules on CMV-specific T-cells (TCMV) in patients after lung transplantation were investigated.

Methods: 59 lung transplant patients were stratified according to anti-CMV serostatus at time of transplantation. The co-inhibitors Programmed-Death-Receptor-1 (PD1) and B-and-T-Lymphocyte-Attenuator (BTLA) were detected on TCMV by flow cytometry (FACS).

Results: TCMV were detectable in CMV sero-positive patients (R+) and in CMV sero-negative patients with a lung graft of a CMV sero-positive donor (D+/R-); in both cases, the frequency of TCMV was higher than in healthy controls (HC). PD-1 on TCMV was increased in D+/R+ and D+/R- patients as compared to HC. BTLA was significantly enhanced on TCMV of D+/R- patients vs. HC. R+ patients with CMV reactivation in the past had an increased fraction of BTLA+ TCMV.

Conclusion: In conclusion, the expression pattern of co-inhibitory molecules on TCMV is altered in patients after lung transplantation.
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http://dx.doi.org/10.1016/j.clim.2019.108258DOI Listing
November 2019

Sex-Specific Differences in HLA Antibodies after Pneumococcal Vaccination in Kidney Transplant Recipients.

Vaccines (Basel) 2019 Aug 6;7(3). Epub 2019 Aug 6.

Department of Infectious Disease, University Hospital Essen, University Duisburg-Essen, 45147 Essen, Germany.

In transplant recipients vaccination against is recommended to reduce mortality from invasive pneumococcal disease. It is still debated if vaccination in transplant recipients triggers alloresponses. Therefore, it was our aim to define if vaccination with Prevenar 13, a 13-valent, conjugated pneumococcal vaccine (Pfizer, New York, NY, USA) that acts T cell dependently, induces human leukocyte antigen (HLA) antibodies in clinically stable kidney transplant recipients. Forty-seven patients were vaccinated once with Prevenar 13 and HLA antibodies were determined prior to vaccination and at month 1 and 12 thereafter. In parallel, pneumococcal IgG antibodies were measured. Using Luminex™ Mixed Beads technology (One Lambda/Thermo Fisher, Canoga Park, CA, USA) we observed overall no change in HLA antibodies after vaccination. Pneumococcal antibodies increased significantly at month 1 ( < 0.0001) and remained elevated at month 12 ( < 0.005). A more detailed analysis of HLA antibodies showed that in 18 females HLA class I and II antibodies increased significantly at month 1 and 12 ( < 0.05); whereas in 29 males HLA class I and II antibodies tended to decrease. Using Luminex™ Single Antigen Beads assay, no de novo donor-specific HLA antibodies were detected after vaccination. In conclusion, the current data indicate that females may be more susceptible to the induction of (non-specific) HLA antibodies after vaccination.
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http://dx.doi.org/10.3390/vaccines7030084DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6789899PMC
August 2019

Enhancement of Cytomegalovirus-Specific Cytokine Production after Modulation of the Costimulation in Kidney Transplant Patients.

J Immunol Res 2019 25;2019:3926175. Epub 2019 Feb 25.

Institute for Transfusion Medicine, University Hospital Essen, University of Duisburg-Essen, 45147 Essen, Germany.

Kidney transplantation is the therapy of choice for patients with end stage renal disease. Due to immunosuppressive treatment, patients are at risk for opportunistic infections. Cytomegalovirus (CMV) reactivation is highly relevant in kidney transplant recipients because it occurs-depending on the serological constellation of the donor and recipient-in more than half of the patients and influences patient outcome. Patients with CMV reactivation show decreased allograft and overall survival. Previous studies could demonstrate that transplant patients often show weak CMV-specific immunity. Besides immunosuppressive treatment, additional mechanisms may reduce CMV-specific immunocompetence such as enhanced negative costimulation. Hence, the aim of this study was to investigate if the function of CMV-specific cells of kidney transplant recipients could be restored by a modulation of costimulatory molecules. To address this question, lymphocytes of kidney transplant patients were stimulated with CMV-specific antigens and incubated with programmed death-ligand 1 (PD-L1), programmed cell death protein 1 (PD-1), or B- and T-lymphocyte attenuator (BTLA) antibodies. Afterwards, the IFN-, IL-21, and IL-17A production was measured by the ELISpot assay. It could be shown that a blockade of the ligand PD-L1 resulted in an increased CMV-specific IFN-, IL-21, and IL-17A secretion. The blockade of the receptor PD-1 distinctly enhanced the production of IL-21. BTLA antibodies, however, led only to a marginal increase of CMV-specific IFN- and of IL-21 production. Experiments in healthy controls could confirm the results of the kidney transplant recipients. Furthermore, they could demonstrate that treatment with the immunosuppressive drug tacrolimus resulted in decreased CMV-specific IFN- and of IL-21 production. Thus, our study could show for the first time that the blockade of the PD-L1/PD-1 pathway also modulates CMV-specific Th21 and Th17 cell function in kidney transplant recipients. Further studies are mandatory to clarify the role of Th21 and Th17 cells in CMV control of these patients.
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http://dx.doi.org/10.1155/2019/3926175DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6410444PMC
July 2019

DNA lesions correlate with lymphocyte function after selective internal radiotherapy.

Cancer Immunol Immunother 2019 Jun 15;68(6):907-915. Epub 2019 Mar 15.

Institute for Transfusion Medicine, University Hospital Essen, Virchowstraße 179, 45147, Essen, Germany.

In patients with non-resectable hepatic malignancies selective internal radiotherapy (SIRT) with yttrium-90 is an effective therapy. However, previous data indicate that SIRT leads to impaired immune function. The aim of the current study was to determine the extent of DNA lesions in peripheral blood mononuclear cells of SIRT patients and to correlate these lesions with cellular immune responses. In ten patients γH2AX and 53BP1 foci were determined. These foci are markers of DNA double-strand breaks (DSBs) and occur consecutively. In parallel, lymphocyte proliferation was assessed after stimulation with the T cell mitogen phytohemagglutinin. Analyses of vital cells were performed prior to and 1 h and 1 week after SIRT. 1 h and 1 week after SIRT numbers of γH2AX and of 53BP1 foci were more than threefold larger than before (p < 0.01). Already at baseline, foci were more abundant than published in healthy controls. Lymphocyte proliferation at baseline was below the normal range and further decreased after SIRT. Prior to therapy, there was an inverse correlation between lymphocyte proliferation and the quotient 53BP1/γH2AX; which could be considered as a measure of the course of DNA DSB repair (r = - 0.94, p < 0.0001). Proliferative responses were inversely correlated with 53BP1 foci prior to therapy and γH2AX and 53BP1 foci 1 h after therapy (r < - 0.65, p < 0.05). In conclusion, DNA foci in SIRT patients were correlated with impaired in vitro immune function. Unrepaired DNA DSBs or cell cycle arrest due to repair may cause this impairment.
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http://dx.doi.org/10.1007/s00262-019-02323-xDOI Listing
June 2019

The Cytomegalovirus-Specific IL-21 ELISpot Correlates with Allograft Function of Kidney Transplant Recipients.

Int J Mol Sci 2018 Dec 8;19(12). Epub 2018 Dec 8.

Department of Nephrology, University Hospital Essen, Hufelandstraße 55, 45147 Essen, Germany.

In kidney transplant recipients, the cytomegalovirus (CMV) is frequently causing infection/reactivation and can trigger allograft rejection. To assess the risk of reactivation, the cellular immune response against CMV is increasingly assessed by cellular in vitro methods, such as the interferon (IFN)-γ ELISpot. In the current study we compared the IFN-γ ELISpot with our newly established CMV-specific ELISpot assays determining IL-17A, IL-21, IL-22, granzyme B, and perforin and correlated the results with flow cytometric data and clinical parameters. In 77 kidney transplant recipients, the highest frequency was observed for CMV pp65-specific cells secreting IFN-γ, followed by cells secreting IL-21 (62.9 and 23.2 Δ spot forming cells/10⁵ cells). We observed a positive correlation between the percentage of CMV-specific CD3+ CD4+ CD154+ cells and results of the CMV-specific IL-21 ELISpot ( = 0.002). Results of the CMV pp65-specific IL-21 ELISpot correlated negatively with kidney function (estimated glomerular filtration rate, = 0.006) and were significantly higher in women ( = 0.005). IL-21, a cytokine involved in aging that is secreted by activated CD4+ T cells, may also impact on allograft function. Thus, the CMV-specific IL-21 ELISpot could become a new tool to assess if CMV seropositivity represents a hazard for the graft.
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http://dx.doi.org/10.3390/ijms19123945DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6320857PMC
December 2018

A Single-Nucleotide Polymorphism Upstream of the HLA-C Locus Is Associated With an Anti-Hepatitis C Virus-Seronegative State in a High-Risk Exposed Cohort.

J Infect Dis 2018 11;218(12):2016-2019

Institute for Transfusion Medicine, University Hospital Essen, Germany.

In this study, we examined the impact of the rs9264942 single-nucleotide polymorphism, previously shown to be associated with human immunodeficiency virus infection status and HLA-C expression, on the hepatitis C virus status in 359 people who inject drugs (PWID). The linkage of rs9264942 alleles to HLA-C antigens assigned to different expression levels was confirmed. Multivariate analysis revealed the age (P = .003) and the rs9264942 genotype (P = .006) to be independent factors for the classification to the PWID groups. Our study showed that the presence of the rs9264942 C/C genotype was associated with persistent seronegativity.
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http://dx.doi.org/10.1093/infdis/jiy492DOI Listing
November 2018

T-Track-CMV and QuantiFERON-CMV assays for prediction of protection from CMV reactivation in kidney transplant recipients.

J Clin Virol 2018 08 12;105:91-96. Epub 2018 Jun 12.

Institute for Virology, University Hospital Essen, University of Duisburg-Essen, Essen, Germany.

Background: Assays detecting CMV-specific cell-mediated immunity (CMI) may support the current management of CMV infection in solid-organ transplant (SOT) recipients, by allowing a better risk assessment and adjusting antiviral treatment.

Objectives: The primary endpoint was the performance of two tests measuring CMV-specific interferon-gamma production, both approved for commercial use in clinical settings. Secondarily, we determined a cut-off for the cellular immune response, which protects against CMV reactivation/infection.

Study Design: Thirty kidney transplant (KTx) patients were stratified according to their CMV-IgG status pre-transplantation (Tx) and were divided into two groups: pre-emptive (donor-/recipient+, donor+/recipient+) and prophylaxis (donor+/recipient-). An ELISpot (T-Track-CMV) was performed at month 1 post-Tx (pre-emptive group) and end of prophylaxis and one month thereafter (prophylaxis group). An ELISA (QuantiFERON-CMV) was performed every 2-4 weeks (pre-emptive) or monthly (prophylaxis), in parallel to the CMV viral load (PCR).

Results: A good positive agreement was obtained between the QuantiFERON-CMV or T-Track-CMV and the CMV-IgG (kappa = 0.839 and 0.824, respectively). A cut-off of 19.5 spot forming units (SFU)/200,000 lymphocytes for the T-Track-CMV IE-1 (AUC = 0.802, sensitivity 45%, specificity 100%) and 495 SFU/200,000 lymphocytes for the T-Track-CMV pp65 (AUC = 0.617, sensitivity 11%, specificity 100%) was defined to assess protection against reactivation. The QuantiFERON-CMV performed modestly (AUC = 0.477, cut-off 85.1 IU/ml).

Conclusions: The QuantiFERON-CMV and T-Track-CMV enable the functional assessment of CMV-specific CMI in KTx recipients. In combination with CMV viral load monitoring, T-Track-CMV results could stratify patients at risk of CMV reactivation/infection.
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http://dx.doi.org/10.1016/j.jcv.2018.06.009DOI Listing
August 2018

Potential triggering factors of acute liver failure as a first manifestation of autoimmune hepatitis-a single center experience of 52 adult patients.

World J Gastroenterol 2018 Apr;24(13):1410-1418

Department of Gastroenterology and Hepatology, University Clinic of Essen, Essen 45147, Germany.

Aim: To investigate potential triggering factors leading to acute liver failure (ALF) as the initial presentation of autoimmune hepatitis (AIH).

Methods: A total of 565 patients treated at our Department between 2005 and 2017 for histologically-proven AIH were retrospectively analyzed. However, 52 patients (9.2%) fulfilled the criteria for ALF defined by the "American Association for the Study of the Liver (AASLD)". According to this definition, patients with "acute-on-chronic" or "acute-on-cirrhosis" liver failure were excluded. Following parameters with focus on potential triggering factors were evaluated: Patients' demographics, causation of liver failure, laboratory data (liver enzymes, MELD-score, autoimmune markers, virus serology), liver histology, immunosuppressive regime, and finally, outcome of our patients.

Results: The majority of patients with ALF were female (84.6%) and mean age was 43.6 ± 14.9 years. Interestingly, none of the patients with ALF was positive for anti-liver kidney microsomal antibody (LKM). We could identify potential triggering factors in 26/52 (50.0%) of previously healthy patients presenting ALF as their first manifestation of AIH. These were drug-induced ALF (57.7%), virus-induced ALF (30.8%), and preceding surgery in general anesthesia (11.5%), respectively. Unfortunately, 6 out of 52 patients (11.5%) did not survive ALF and 3 patients (5.7%) underwent liver transplantation (LT). Comparing data of survivors and patients with non-recovery following treatment, MELD-score ( < 0.001), age ( < 0.05), creatinine ( < 0.01), and finally, ALT-values ( < 0.05) reached statistical significance.

Conclusion: Drugs, viral infections, and previous surgery may trigger ALF as the initial presentation of AIH. Advanced age and high MELD-score were associated with lethal outcome.
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http://dx.doi.org/10.3748/wjg.v24.i13.1410DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5889821PMC
April 2018

Elevated soluble human leukocyte antigen G levels in patients after allogeneic stem cell transplantation are associated with less severe acute and chronic graft-versus-host disease.

Bone Marrow Transplant 2018 09 14;53(9):1149-1156. Epub 2018 Mar 14.

Institute for Transfusion Medicine, University Hospital Essen, Essen, 45147, Germany.

HLA-G is a non-classical class I molecule which induces tolerance in allogeneic situations by inhibition of cytotoxic NK and CD8 + T cells and by induction of regulatory T cells. Concordantly, in solid organ transplantation HLA-G is associated with a lower risk for acute and chronic rejection, whereas its role in allogeneic stem cell transplantation (allo-SCT) is less established. We here present detailed analyses of HLA-G-levels in patients after allo-SCT showing a correlation of elevated soluble HLA-G (sHLA-G) levels with less severe acute (p = 0.06) and chronic GvHD (p = 0.0025) and with a superior overall survival (p = 0.03). Soluble HLA-G levels are also positively correlated with the frequency of regulatory T cells in vivo. These clinical data are corroborated by in vitro analyses showing that patients-derived sHLA-G inhibit allogeneic immune responses. ATG-treatment of patients dominantly affects the sHLA-G levels post allo-SCT. Thus, this study highlights the association of elevated sHLA-G levels with less severe acute and chronic GvHD and provides additional functional analyses elucidating possible tolerance-inducing mechanisms of sHLA-G in the context of allo-SCT.
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http://dx.doi.org/10.1038/s41409-018-0145-1DOI Listing
September 2018

Impaired lymphocyte function in patients with hepatic malignancies after selective internal radiotherapy.

Cancer Immunol Immunother 2018 May 2;67(5):843-853. Epub 2018 Mar 2.

Institute for Transfusion Medicine, University Hospital Essen, Virchowstraße 179, 45147, Essen, Germany.

The purpose of our study was to assess the immune function of patients with inoperable hepatic malignancies after treatment with selective internal radiotherapy (SIRT) and to identify possible correlations with clinical parameters. In 25 patients receiving SIRT lymphocyte proliferation and the production of pro- and anti-inflammatory cytokines (interferon-γ and interleukin-10) after stimulation with mitogens and microbial antigens were tested prior to therapy, directly after therapy (day 1) and at day 2, 7 and 28 post therapy using the lymphocyte transformation test and enzyme-linked immunospot assays. Absolute counts and percentages of leukocyte and lymphocyte subsets were determined by flow cytometry. The most prominent finding was an immediate and significant (p < 0.05) decrease of lymphocyte proliferation and interferon-γ production directly after therapy which lasted until day 28 and was stronger upon stimulation with microbial antigens than with mitogens. Moreover, lymphopenia was revealed, affecting all lymphocyte subsets (CD3+, CD4+, CD8+ T cells, CD4+ CD8+ T cells, B cells and NK cells). SIRT led to a reduction in the percentage of activated HLA-DR+ monocytes and of CD45R0+ memory T cells. Higher radiation activity, the presence of liver cirrhosis, chronic kidney disease, diabetes mellitus and metastases were unfavorable factors for immunocompetence, while a better Eastern Cooperative Oncology Group performance status was associated with stronger immunological reactions. In conclusion, SIRT leads to severe impairment of cellular in vitro immune responses. Further studies are needed to assess a potential clinical impact.
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http://dx.doi.org/10.1007/s00262-018-2141-0DOI Listing
May 2018

Cytomegalovirus induces HLA-class-II-restricted alloreactivity in an acute myeloid leukemia cell line.

PLoS One 2018 29;13(1):e0191482. Epub 2018 Jan 29.

Department of Bone Marrow Transplantation, West German Cancer Center, University Hospital of Essen, Essen, Germany.

Cytomegalovirus (HCMV) reactivation is found frequently after allogeneic hematopoietic stem cell transplantation (alloSCT) and is associated with an increased treatment-related mortality. Recent reports suggest a link between HCMV and a reduced risk of cancer progression in patients with acute leukemia or lymphoma after alloSCT. Here we show that HCMV can inhibit the proliferation of the acute myeloid leukemia cell line Kasumi-1 and the promyeloid leukemia cell line NB4. HCMV induced a significant up-regulation of HLA-class-II-molecules, especially HLA-DR expression and an increase of apoptosis, granzyme B, perforin and IFN-γ secretion in Kasumi-1 cells cocultured with peripheral blood mononuclear cells (PBMCs). Indolamin-2,3-dioxygenase on the other hand led only to a significant dose-dependent effect on IFN-γ secretion without effects on proliferation. The addition of CpG-rich oligonucleotides and ganciclovir reversed those antiproliferative effects. We conclude that HCMV can enhance alloreactivity of PBMCs against Kasumi-1 and NB4 cells in vitro. To determine if this phenomenon may be clinically relevant further investigations will be required.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0191482PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5788343PMC
March 2018

Clinical validation of a novel enzyme-linked immunosorbent spot assay-based in vitro diagnostic assay to monitor cytomegalovirus-specific cell-mediated immunity in kidney transplant recipients: a multicenter, longitudinal, prospective, observational study.

Transpl Int 2018 04 16;31(4):436-450. Epub 2018 Jan 16.

Vth Department of Medicine, University Medical Center Mannheim, Mannheim, Germany.

Impaired cytomegalovirus (CMV)-specific cell-mediated immunity (CMV-CMI) is a major cause of CMV reactivation and associated complications in solid-organ transplantation. Reliably assessing CMV-CMI is desirable to individually adjust antiviral and immunosuppressive therapy. This study aimed to evaluate the suitability of T-Track CMV, a novel IFN-γ ELISpot assay based on the stimulation of peripheral blood mononuclear cells with pp65 and IE-I CMV proteins, to monitor CMV-CMI following kidney transplantation. A prospective longitudinal multicenter study was conducted in 86 intermediate-risk renal transplant recipients. CMV-CMI, CMV viral load, and clinical complications were monitored over 6 months post-transplantation. Ninety-five percent and 88-92% ELISpot assays were positive pre- and post-transplantation, respectively. CMV-specific response was reduced following immunosuppressive treatment and increased in patients with graft rejection, indicating the ability of the ELISpot assay to monitor patients' immunosuppressive state. Interestingly, median pp65-specific response was ninefold higher in patients with self-clearing viral load compared to antivirally treated patients prior to first viral load detection (P < 0.001), suggesting that reactivity to pp65 represents a potential immunocompetence marker. Altogether, T-Track CMV is a highly sensitive IFN-γ ELISpot assay, suitable for the immunomonitoring of CMV-seropositive renal transplant recipients, and with a potential use for the risk assessment of CMV-related clinical complications (ClinicalTrials.gov Identifier: NCT02083042).
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http://dx.doi.org/10.1111/tri.13110DOI Listing
April 2018

Sensitive detection of rare antigen-specific T cells directed against Wilms' tumor 1 by FluoroSpot assay.

Leuk Lymphoma 2018 02 2;59(2):490-492. Epub 2017 Jun 2.

a Institute for Transfusion Medicine, University Hospital , Essen , Germany.

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http://dx.doi.org/10.1080/10428194.2017.1330955DOI Listing
February 2018

Granzyme B producing B-cells in renal transplant patients.

Clin Immunol 2017 11 28;184:48-53. Epub 2017 Apr 28.

Department of Nephrology, University Hospital Essen, University Duisburg-Essen, Hufelandstr. 55, 45147 Essen, Germany. Electronic address:

Objectives: A separate subset of Granzyme B (GrB) producing B-cells regulating T-cell mediated immunity has been identified. In the present study, we investigated the role of GrB B-cells in renal transplant patients (RTX).

Methods: 12 healthy controls (HC) and 26 RTX patients were enrolled. In addition, 19 healthy volunteers treated with cyclosporine A (CsA) were enrolled. GrB B-cells were determined via flow cytometry.

Results: RTX Patients showed a diminished fraction of GrB B-cells as compared to HC. CsA treatment of healthy volunteers had no impact on the development of GrB B-cells. RTX patients with a history of allograft rejection showed an increased frequency of GrB B-cells. RTX patients with at least one episode of CMV viremia tended to have lower GrB B-cells as compared to patients without viremic episodes.

Conclusion: We demonstrate that treatment with CsA does not impair the development of GrB B-cells. GrB B-cells may have a dual role in renal transplantation as regulatory cells to maintain allospecific tolerance and as effector cells enhancing viral control.
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http://dx.doi.org/10.1016/j.clim.2017.04.016DOI Listing
November 2017

Outcome and Genetic Factors in IgG4-Associated Autoimmune Pancreatitis and Cholangitis: A Single Center Experience.

Gastroenterol Res Pract 2017 2;2017:6126707. Epub 2017 Mar 2.

Department of Gastroenterology and Hepatology, University Hospital Essen, Essen, Germany.

. Most investigations on autoimmune pancreatitis (AIP) were published on Asian cohorts while those on Caucasians are limited. However, there might be differences related to the origin. . We analyzed 36 patients and compared type 1 (AIP1) with type 2 (AIP2). . The majority of patients suffered from AIP1 (55.6%). AIP1 patients were significantly older than AIP2 patients (54.4 versus 40.8 years). Moreover, 85.0% of AIP1 patients had concurrent autoimmune cholangitis (AIC) while 18.8% of AIP2 patients suffered from overlap to ulcerative colitis (UC). However, AIP1 patients revealed a cholestatic course and had significantly higher immunoglobulin G4 levels (IgG4). When compared to allele frequencies in healthy controls, in patients with AIP1 HLA-B8 reached statistical significance. Response to steroids was excellent in both groups, but we noticed high rates of relapse especially in AIP1 patients. Finally, 3 patients with AIP1 were diagnosed with cholangiocellular carcinoma (CCC). . In contrast to Asian studies, we found an almost equal distribution of AIP1 and AIP2 patients in our German cohort. AIP2 patients were younger and mostly of female gender whereas AIP1 patients revealed higher IgG4 levels and involvement of the biliary tract in sense of IgG4-associated cholangitis.
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http://dx.doi.org/10.1155/2017/6126707DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5352972PMC
March 2017

Lymphocyte function following radium-223 therapy in patients with metastasized, castration-resistant prostate cancer.

Eur J Nucl Med Mol Imaging 2017 Feb 8;44(2):242-246. Epub 2016 Oct 8.

Institute for Transfusion Medicine, University Hospital Essen, Virchowstraße 179, 45147, Essen, Germany.

Purpose: Therapy with the alpha-emitter radium-223 chloride (Ra) is an innovative therapeutic option in patients with metastasized, castration-resistant prostate cancer. However, radiotherapy can lead to hematopoietic toxicity. The aim of this study was to determine if Ra therapy induces an impairment of cellular antimicrobial immune responses.

Methods: In 11 patients receiving Ra treatment, lymphocyte proliferation and the production of pro- and anti-inflammatory cytokines (interferon-γ and interleukin-10) were determined, using lymphocyte transformation testing and ELISpot, respectively. Lymphocyte function after stimulation with mitogens and microbial antigens was assessed prior to therapy and at day 1, 7 and 28 after therapy.

Results: Lymphocyte proliferation and the production of interferon-γ and interleukin-10 towards mitogens and antigens remained unchanged after therapy. Consistent with these in vitro data, we did not observe infectious complications after treatment.

Conclusions: The results argue against an impairment of lymphocyte function after Ra therapy. Thus, immune responses against pathogens should remain unaffected.
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http://dx.doi.org/10.1007/s00259-016-3536-9DOI Listing
February 2017

Vaccination Against Human Papilloma Viruses Leads to a Favorable Cytokine Profile of Specific T Cells.

J Immunother 2016 10;39(8):316-20

*Institute for Transfusion Medicine †Department of Otorhinolaryngology, University Hospital, Essen, Germany.

Several human papilloma viruses (HPV) are known to cause malignant transformation. The high-risk type HPV 16 is associated with cervical carcinoma and head and neck squamous cell carcinoma. HPV 16-positive tumor cells exclusively carry the HPV 16 oncogenes E6 and E7. These oncogenes appear as excellent targets for an adoptive immunotherapy. We here addressed the question whether specific T cells from HPV-vaccinated healthy volunteers could be especially suitable for an HPV-specific cellular immunotherapy. Of note, vaccines contain HPV 16. To quantify HPV 16 E6-specific and E7-specific cells, enzyme-linked immunospot assays to measure interferon-γ (IFN-γ) and interleukin-10 (Th1-Th2 balance) and the secretion of the cytotoxic molecules granzyme B and perforin have been optimized. The frequency of peripheral blood mononuclear cells secreting IFN-γ and perforin was significantly (P<0.05) increased in HPV-vaccinated versus nonvaccinated volunteers. Overall, however, the median frequency of HPV 16-specific cells with a favorable secretion profile (Th1 balanced and cytotoxic) was low even in vaccinated volunteers (IFN-γ: 0.0018% and 0.0023%, perforin: 0.01% and 0.0087% for E6-specific and E7-specific cells, respectively). But some vaccinated volunteers showed up to 0.1% HPV-specific, IFN-γ or perforin-secreting cells. In conclusion, our data suggest that vaccinated volunteers are superior to nonvaccinated donors for HPV-specific cellular cancer immunotherapy.
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http://dx.doi.org/10.1097/CJI.0000000000000137DOI Listing
October 2016

IL-17 ELISpot as Predictor for Kidney Allograft Rejection?

Clin Lab 2016 ;62(5):963-5

Background: IL-17 expression in kidney biopsies had been described as predictive of allograft rejection.

Methods: We tested the hypothesis that IL-17A ELISpot responses towards a pool of third party cells could predict acute rejections of kidney allografts. This assay determines alloresponses but does not require donor cells. IL-17A ELISpot assays were performed in 50 kidney transplant recipients prior to transplantation. Seventeen of the recipients suffered from acute allograft rejection.

Results: We observed that the amount of IL-17A producing T cells did not differ between transplant recipients with and without kidney allograft rejection, rebutting our hypothesis. Further, we found that the alloreactivity before transplantation correlated with the reaction against the mitogen phythohemagglutinin (r = 0.5, p = 0.0009).

Conclusions: IL-17A ELISpot was not predictive of acute kidney allografts rejection. But ELISpots after stimulation with allogeneic cells and phythohemagglutinin could similarly detect the "general" capacity of T cells to secrete IL-17A.
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http://dx.doi.org/10.7754/clin.lab.2015.150933DOI Listing
July 2016