14 research outputs found
Monitoring von T-zellulären Immunantworten nach Organtransplantation am Beispiel der HBV-spezifischen Immunantwort und der endogenen Immunsuppression durch regulatorische T Zellen
Monitoring von T-zellulären Immunantworten nach Organtransplantation am Beispiel der HBV-spezifischen Immunantwort und der endogenen Immunsuppression durch regulatorische T Zellen
A Polyclonal Immune Function Assay Allows Dose-Dependent Characterization of Immunosuppressive Drug Effects but Has Limited Clinical Utility for Predicting Infection on an Individual Basis
Dosage of immunosuppressive drugs after transplantation critically determines rejection and infection episodes. In this study, a global immune function assay was characterized among controls, dialysis-patients, and transplant-recipients to evaluate its utility for pharmacodynamic monitoring of immunosuppressive drugs and for predicting infections. Whole-blood samples were stimulated with anti-CD3/toll-like-receptor (TLR7/8)-agonist in the presence or absence of drugs and IFN-γ secretion was measured by ELISA. Additional stimulation-induced cytokines were characterized among T-, B-, and NK-cells using flow-cytometry. Cytokine-secretion was dominated by IFN-γ, and mainly observed in CD4, CD8, and NK-cells. Intra-assay variability was low (CV = 10.4 ± 6.2%), whereas variability over time was high, even in the absence of clinical events (CV = 65.0 ± 35.7%). Cyclosporine A, tacrolimus and steroids dose-dependently inhibited IFN-γ secretion, and reactivity was further reduced when calcineurin inhibitors were combined with steroids. Moreover, IFN-γ levels significantly differed between controls, dialysis-patients, and transplant-recipients, with lowest IFN-γ levels early after transplantation (p < 0.001). However, a single test had limited ability to predict infectious episodes. In conclusion, the assay may have potential for basic pharmacodynamic characterization of immunosuppressive drugs and their combinations, and for assessing loss of global immunocompetence after transplantation, but its application to guide drug-dosing and to predict infectious on an individual basis is limited
Cellular immunity predominates over humoral immunity after homologous and heterologous mRNA and vector-based COVID-19 vaccine regimens in solid organ transplant recipients
Knowledge on the immunogenicity of vector-based and mRNA-vaccines in solid organ
transplant recipients is limited. Therefore, SARS-CoV-2–specific T cells and antibodies were analyzed in 40 transplant recipients and 70 controls after homologous or
heterologous vaccine-regimens. Plasmablasts and SARS-CoV-2–specific CD4 and
CD8 T cells were quantified using flow cytometry. Specific antibodies were analyzed
by ELISA and neutralization assay. The two vaccine types differed after the first vaccination, as IgG and neutralizing activity were more pronounced after mRNA priming
(p = .0001 each), whereas CD4 and CD8 T cell levels were higher after vector priming
(p = .009; p = .0001). All regimens were well tolerated, and SARS-CoV-2–specific antibodies and/or T cells after second vaccination were induced in 100% of controls and
70.6% of transplant recipients. Although antibody and T cell levels were lower in patients, heterologous vaccination led to the most pronounced induction of antibodies
and CD4 T cells. Plasmablast numbers were significantly higher in controls and correlated with SARS-CoV-2–specific IgG- and T cell levels. While antibodies were only
detected in 35.3% of patients, cellular immunity was more frequently found (64.7%)
indicating that assessment of antibodies is insufficient to identify COVID-19-vaccine
responders. In conclusion, heterologous vaccination seems promising in transplant recipients, and combined analysis of humoral and cellular immunity improves the identification of responders among immunocompromised individuals
Immunogenicity and reactogenicity of a heterologous COVID-19 prime-boost vaccination compared with homologous vaccine regimens
Heterologous priming with the ChAdOx1-nCoV-19 vector-vaccine followed by boosting with an mRNA-vaccine is currently recommended in Germany, although data on immunogenicity and reactogenicity are not available. Here we show that the heterologous regimen induced spike-specific IgG, neutralizing antibodies, and spike-specific CD4 T-cells, which were significantly more pronounced than after homologous vector boost, and higher or comparable in magnitude to the homologous mRNA regimens. Moreover, spike-specific CD8 T-cell levels after heterologous vaccination were significantly higher than after both homologous regimens. Cytokine expression profiling showed a predominance of polyfunctional T-cells expressing IFNγ, TNFα and IL-2 with subtle differences between regimens. Both recipients of the homologous vector-regimen and the heterologous vector/mRNA-combination were most affected by the priming vector-vaccination, whereas heterologous boosting was well tolerated and comparable to homologous mRNA-boosting. Taken together, heterologous vector-mRNA boosting induces strong humoral and cellular immune responses with acceptable reactogenicity profile. This knowledge will have implications for future vaccine strategies
Should We Perform Old-For-Old Kidney Transplantation during the COVID-19 Pandemic? The Risk for Post-Operative Intensive Stay
Health care systems worldwide have been facing major challenges since the outbreak of
the SARS-CoV-2 pandemic. Kidney transplantation (KT) has been tremendously affected due to
limited personal protective equipment (PPE) and intensive care unit (ICU) capacities. To provide
valid information on risk factors for ICU admission in a high-risk cohort of old kidney recipients from
old donors in the Eurotransplant Senior Program (ESP), we retrospectively conducted a bi-centric
analysis. Overall, 17 (16.2%) patients out of 105 KTs were admitted to the ICU. They had a lower
BMI, and both coronary artery disease (CAD) and hypertensive nephropathy were more frequent.
A risk model combining BMI, CAD and hypertensive nephropathy gained a sensitivity of 94.1% and a
negative predictive value of 97.8%, rendering it a valuable search test, but with low specificity (51.1%).
ICU admission also proved to be an excellent parameter identifying patients at risk for short patient
and graft survivals. Patients admitted to the ICU had shorter patient (1-year 57% vs. 90%) and graft
(5-year 49% vs. 77%) survival. To conclude, potential kidney recipients with a low BMI, CAD and
hypertensive nephropathy should only be transplanted in the ESP in times of SARS-CoV-2 pandemic
if the local health situation can provide sufficient ICU capacities
High levels of SARS-CoV-2 specific T-cells with restricted functionality in patients with severe course of COVID-19
Patients infected with SARS-CoV-2 differ in the severity of disease. In this study, SARS-CoV-2 specific T-cells and antibodies were characterized in patients with different COVID-19 related disease severity. Despite severe lymphopenia affecting all major lymphocyte subpopulations, patients with severe disease mounted significantly higher levels of SARS-CoV-2 specific T-cells as compared to convalescent individuals. SARS-CoV-2 specific CD4 T-cells dominated over CD8 T-cells and closely correlated with the number of plasmablasts and SARS-CoV-2 specific IgA- and IgG-levels. Unlike in convalescents, SARS-CoV-2 specific T-cells in patients with severe disease showed marked alterations in phenotypical and functional properties, which also extended to CD4 and CD8 T-cells in general. Given the strong induction of specific immunity to control viral replication in patients with severe disease, the functionally altered phenotype may result from the need for contraction of specific and general immunity to counteract excessive immunopathology in the lung
High levels of SARS-CoV-2-specific T cells with restricted functionality in severe courses of COVID-19
BACKGROUND. Patients infected with severe acute respiratory syndrome coronavirus 2 (SARSCoV-2) differ in the severity of disease. We hypothesized that characteristics of SARS-CoV-2–
specific immunity correlate with disease severity.
METHODS. In this study, SARS-CoV-2–specific T cells and antibodies were characterized in
uninfected controls and patients with different coronavirus disease 2019 (COVID-19) disease
severity. SARS-CoV-2–specific T cells were flow cytometrically quantified after stimulation with
SARS-CoV-2 peptide pools and analyzed for expression of cytokines (IFN-γ, IL-2, and TNF-α)
and markers for activation, proliferation, and functional anergy. SARS-CoV-2–specific IgG and
IgA antibodies were quantified using ELISA. Moreover, global characteristics of lymphocyte
subpopulations were compared between patient groups and uninfected controls.
RESULTS. Despite severe lymphopenia affecting all major lymphocyte subpopulations, patients
with severe disease mounted significantly higher levels of SARS-CoV-2–specific T cells as compared
with convalescent individuals. SARS-CoV-2–specific CD4+
T cells dominated over CD8+
T cells and
closely correlated with the number of plasmablasts and SARS-CoV-2–specific IgA and IgG levels.
Unlike in convalescent patients, SARS-CoV-2–specific T cells in patients with severe disease showed
marked alterations in phenotypical and functional properties, which also extended to CD4+
and CD8+
T cells in general.
CONCLUSION. Given the strong induction of specific immunity to control viral replication in
patients with severe disease, the functionally altered characteristics may result from the need for
contraction of specific and general immunity to counteract excessive immunopathology in the lung.
FUNDING. The study was supported by institutional funds to MS and in part by grants of Saarland
University, the State of Saarland, and the Rolf M. Schwiete Stiftung
Potent induction of humoral and cellular immunity after bivalent BA.4/5 mRNA vaccination in dialysis patients
Knowledge on immunogenicity of the bivalent Omicron BA.4/5 vaccine in dialysis patients and the effect of a previous infection is
limited. Therefore, vaccine-induced humoral and cellular immunity was analyzed in dialysis patients and immunocompetent
controls with and without prior infection. In an observational study, 33 dialysis patients and 58 controls matched for age, sex and
prior infection status were recruited. Specific IgG, neutralizing antibody activity and cellular immunity towards the spike-antigen
from parental SARS-CoV-2 and Omicron-subvariants BA.1, BA.2 and BA.4/5 were analyzed before and 13-18 days after vaccination.
The bivalent vaccine led to a significant induction of IgG, neutralizing titers, and specific CD4+ and CD8+ T-cell levels. Neutralizing
activity towards the parental strain was higher than towards the Omicron-subvariants, whereas specific T-cell levels towards
parental spike and Omicron-subvariants did not differ indicating substantial cross-reactivity. Dialysis patients with prior infection
had significantly higher spike-specific CD4+ T-cell levels with lower CTLA-4 expression compared to infection-naive patients. When
compared to controls, no differences were observed between infection-naive individuals. Among convalescent individuals, CD4+
T-cell levels were higher in patients and neutralizing antibodies were higher in controls. Vaccination was overall well tolerated in
both dialysis patients and controls with significantly less adverse events among patients. In conclusion, our study did not provide
any evidence for impaired immunogenicity of the bivalent Omicron BA.4/5 vaccine in dialysis patients. Unlike in controls, previous
infection of patients was even associated with higher levels of spike-specific CD4+ T cells, which may reflect prolonged encounter
with antigen during infection
High levels of SARS-CoV-2–specific T cells with restricted functionality in severe courses of COVID-19
BACKGROUND Patients infected with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) differ in the severity of disease. We hypothesized that characteristics of SARS-CoV-2–specific immunity correlate with disease severity.METHODS In this study, SARS-CoV-2–specific T cells and antibodies were characterized in uninfected controls and patients with different coronavirus disease 2019 (COVID-19) disease severity. SARS-CoV-2–specific T cells were flow cytometrically quantified after stimulation with SARS-CoV-2 peptide pools and analyzed for expression of cytokines (IFN-γ, IL-2, and TNF-α) and markers for activation, proliferation, and functional anergy. SARS-CoV-2–specific IgG and IgA antibodies were quantified using ELISA. Moreover, global characteristics of lymphocyte subpopulations were compared between patient groups and uninfected controls.RESULTS Despite severe lymphopenia affecting all major lymphocyte subpopulations, patients with severe disease mounted significantly higher levels of SARS-CoV-2–specific T cells as compared with convalescent individuals. SARS-CoV-2–specific CD4+ T cells dominated over CD8+ T cells and closely correlated with the number of plasmablasts and SARS-CoV-2–specific IgA and IgG levels. Unlike in convalescent patients, SARS-CoV-2–specific T cells in patients with severe disease showed marked alterations in phenotypical and functional properties, which also extended to CD4+ and CD8+ T cells in general.CONCLUSION Given the strong induction of specific immunity to control viral replication in patients with severe disease, the functionally altered characteristics may result from the need for contraction of specific and general immunity to counteract excessive immunopathology in the lung.FUNDING The study was supported by institutional funds to MS and in part by grants of Saarland University, the State of Saarland, and the Rolf M. Schwiete Stiftung