9 research outputs found
Vitamin D Enhances Immune Effector Pathways of NK Cells Thus Providing a Mechanistic Explanation for the Increased Effectiveness of Therapeutic Monoclonal Antibodies
Patients with diffuse large cell lymphoma who have an adequate vitamin D supply derive
significantly more benefit from immuno-chemotherapy with rituximab than patients with vitamin
D deficiency; this is especially true for female patients. We have already been able to show that vitamin
D increases the antibody-dependent cytotoxicity (ADCC) of NK cells in a sex-dependent manner,
but it is unclear how vitamin D makes NK cells more efficient. Methods: Healthy individuals with
vitamin D deficiency were supplemented with vitamin D to sufficient levels. NK cells were isolated
from blood samples before and after vitamin D saturation. For transcriptome analysis, we used
the Affymetrix Gene-Chip 2.0âą. Gene expression analysis as well as supervised and unsupervised
pathway analysis were performed. Results: Among others the âNK cell-associated cytotoxicity
pathwayâ increased after vitamin D substitution. Five IFN-α subtypes (2, 4, 6, 7 and 10) and IFN-Îș
were more highly expressed and are mainly responsible in these pathways. In contrast, the pathway
âinterferon-gamma responseâ, as well as other sets in cytokine production and chemotaxis showed a
reduction. Toll-like receptor genes (TLR-8, TLR-7, TLR-2) were downregulated and, therefore, are
responsible for the decline of these pathways. The same could be shown for the âubiquitin-ligaseâ
pathway. Conclusions: Increased expression of several IFN-α subtypes may explain the increased
ADCC of NK cells in vitamin D-replenished and otherwise healthy subjects. Other regulators of
interferon production and ADCC are compensatory upregulated in compensation, such as Toll-like
receptors and those of the ubiquitin ligase, and normalize after vitamin D substitution
Liver stiffness as surrogate parameter in emergency assessment for inpatient health care utilization
Background
Transient elastography (TE) allows non-invasive quantification of liver stiffness (LSM) and
steatosis (controlled attenuation parameter, CAP). Here we test the feasibility and utility of
TE in the emergency department (ED) and investigate whether LSM predicts longer hospitalization and reimbursement for non-elective patients.
Methods
LSM and CAP were determined in prospectively recruited consecutive adult patients admitted to the ED of a tertiary referral center. Patients were stratified according to the 9.1 kPa
and 13.0 kPa LSM cut-offs. Elastography measurements were correlated with clinical and
outcome parameters, including duration of hospital stay and hospitalization costs.
Results
In 200 ED patients (133 men, age 18 â 97 years), median LSM was 5.5 kPa (2.4 â 69.1
kPa), and median CAP was 252 dB/m (100 â 400 dB/m). In total, 39 patients (19.5%) presented with LSM 9.1 kPa, and 24 patients (12.0%) presented with LSM 13.0 kPa. Heart
failure (n = 19) was associated with higher LSM (p = 0.045). Patients with LSM 9.1 kPa
were significantly (p < 0.01) more likely to require longer hospitalization than those with
lower LSM. Patients with LSM 13.0 kPa generated significantly (p = 0.001) higher costs
as compared to patients with low LSM.
Conclusions
Transient elastography represents an easily accessible screening tool in ED that might help
identify patients in need of increased health care resources
IgG seroprevalence of COVID-19 among people living with HIV or at high risk of HIV in south-west Germany: A seroprevalence study
Objectives: Seroprevalence studies of SARS-CoV-2 have shown that there is a
high number of undiagnosed missing cases. Seroprevalence of SARS-CoV-2 in
people living with HIV (PLWH) is lacking. Therefore, we conducted a prospective cross-sectional study to estimate the seroprevalence of SARS-CoV-2 among
PLWH without known diagnosis of COVID-19 in the south-west of Germany.
Methods: Serological testing for SARS-CoV-2 immunoglobulin G (IgG) antibodies based on two assays was performed in PLWH who visited the outpatient HIV
centre of two hospitals from April to June 2020. Additionally, patients had to answer questionnaires about possible COVID-19-related symptoms and predefined
risk factors. Moreover, we tested 50 non-HIV-infected patients receiving post- or
pre-exposure (PEP/PrEP) HIV prophylaxis.
Results: In all, 594 (488 male, 106 female) PLWH (median age 51 years) and
50 PEP/PrEP-users were included in the study. The estimated seroprevalence of
the PLWH cohort was 1.85% (11/594), with 11 positive tested cases in the cohort. Among all patients, only five had COVID-19-related symptoms. One PCRpositive patient did not show any antibody response in repeatedly carried out
tests. None of the patients was hospitalized due to COVID-19. Three PrEP users
were tested positive. Three patients had been previously diagnosed with SARSCOV-2 infection before inclusion. The used questionnaire did not help to detect
SARS-CoV-2 positive patients.
Conclusions: Despite the limitation of being only a snapshot in time because
of the ongoing pandemic, to our knowledge this is the largest study so far on
seroprevalence of SARS-CoV-2 in PLWH in Germany. Our study suggests that
the seroprevalence of SARS-CoV-2 in PLWH is comparable to those previously reported for parts of the general German population and that the questionnaire
used here might not be the best tool to predict COVID-19 diagnosis
Killer immunoglobulin-like receptor 2DS5 is associated with recovery from coronavirus disease 2019
Background
Despite numerous advances in the identification of risk factors for the development of severe coronavirus disease 2019 (COVID-19), factors that promote recovery from COVID-19 remain unknown. Natural killer (NK) cells provide innate immune defense against viral infections and are known to be activated during moderate and severe COVID-19. Killer immunoglobulin-like receptors (KIR) mediate NK cell cytotoxicity through recognition of an altered MHC-I expression on infected target cells. However, the influence of KIR genotype on outcome of patients with COVID-19 has not been investigated so far. We retrospectively analyzed the outcome associations of NK cell count and KIR genotype of patients with COVID-19 related severe ARDS treated on our tertiary intensive care unit (ICU) between February and June 2020 and validated our findings in an independent validation cohort of patients with moderate COVID-19 admitted to our tertiary medical center.
Results
Median age of all patients in the discovery cohort (nâ=â16) was 61 years (range 50â71 years). All patients received invasive mechanical ventilation; 11 patients (68%) required extracorporeal membrane oxygenation (ECMO). Patients who recovered from COVID-19 had significantly higher median NK cell counts during the whole observational period compared to patients who died (121 cells/”L, range 16â602 cells/”L vs 81 cells/”L, range 6â227 cells/”L, p-valueâ=â0.01). KIR2DS5 positivity was significantly associated with shorter time to recovery (21.6â±â2.8 days vs. 44.6â±â2.2 days, p-valueâ=â0.01). KIR2DS5 positivity was significantly associated with freedom from transfer to ICU (0% vs 9%, p-valueâ=â0.04) in the validation cohort which consisted of 65 patients with moderate COVID-19.
Conclusion
NK cells and KIR genotype might have an impact on recovery from COVID-19
Increased B-cell activity with consumption of activated monocytes in severe COVID-19 patients
The pathogenesis of autoimmune complications triggered by SARS-CoV2 has not been completely elucidated. Here, we performed an analysis of the cellular immune status, cell ratios, and monocyte populations of patients with COVID-19 treated in the intensive care unit (ICU) (cohort 1, N = 23) and normal care unit (NCU) (cohort 2, n = 10) compared with control groups: patients treated in ICU for noninfectious reasons (cohort 3, n = 30) and patients treated in NCU for infections other than COVID-19 (cohort 4, n = 21). Patients in cohort 1 presented significant differences in comparison with the other cohorts, including reduced frequencies of lymphocytes, reduced CD8+T-cell count, reduced percentage of activated and intermediate monocytes and an increased B/T8 cell ratio. Over time, patients in cohort 1 who died presented with lower counts of B, T, CD4+T, CD8+T-lymphocytes, NK cells, and activated monocytes. The B/T8 ratio was significantly lower in the group of survivors. In cohort 1, significantly higher levels of IgG1 and IgG3 were found, whereas cohort 3 presented higher levels of IgG3 compared to controls. Among many immune changes, an elevated B/T8-cell ratio and a reduced rate of activated monocytes were mainly observed in patients with severe COVID-19. Both parameters were associated with death in cohort 1
Indeterminate Dendritic Cell Tumor With Persistent Complete Metabolic Response to BRAF/MEK Inhibition
IgG seroprevalence of COVID-19 among people living with HIV or at high risk of HIV in south-west Germany: A seroprevalence study.
Objectives: Seroprevalence studies of SARS-CoV-2 have shown that there is a high number of undiagnosed missing cases. Seroprevalence of SARS-CoV-2 in people living with HIV (PLWH) is lacking. Therefore, we conducted a prospective cross-sectional study to estimate the seroprevalence of SARS-CoV-2 among PLWH without known diagnosis of COVID-19 in the south-west of Germany.
Methods: Serological testing for SARS-CoV-2 immunoglobulin G (IgG) antibodies based on two assays was performed in PLWH who visited the outpatient HIV centre of two hospitals from April to June 2020. Additionally, patients had to answer questionnaires about possible COVID-19-related symptoms and predefined risk factors. Moreover, we tested 50 non-HIV-infected patients receiving post- or pre-exposure (PEP/PrEP) HIV prophylaxis.
Results: In all, 594 (488 male, 106 female) PLWH (median age 51 years) and 50 PEP/PrEP-users were included in the study. The estimated seroprevalence of the PLWH cohort was 1.85% (11/594), with 11 positive tested cases in the cohort. Among all patients, only five had COVID-19-related symptoms. One PCR-positive patient did not show any antibody response in repeatedly carried out tests. None of the patients was hospitalized due to COVID-19. Three PrEP users were tested positive. Three patients had been previously diagnosed with SARS-COV-2 infection before inclusion. The used questionnaire did not help to detect SARS-CoV-2 positive patients
Ars2âcontaining bispecific, Fabâ and IgG1âformat BARâbodies to target DLBCL cells
Abstract Despite recent advances in the therapy of diffuse large Bâcell lymphoma, not otherwise specified (DLBCL), around 30% of patients develop refractory disease or relapse after firstâline treatment. Recently, Ars2 was reported as the autoâantigenic target of the Bâcell receptor (BCR) in approximately 25% of activated Bâcell DLBCL cases. Ars2 could be used to specifically target B cells expressing Ars2âreactive BCRs. However, the optimal therapeutic format to integrate Ars2 into has yet to be determined. To mimic therapeutic antibody formats, Ars2âcontaining bispecific and IgG1âlike constructs (BCR antigens for reverse [BAR]âbodies) were developed. Two bispecific BARâbodies connecting singleâchain antibodies against CD16 or CD3 to the BCRâbinding epitope of Ars2 were constructed. Both constructs showed strong binding to U2932 cells and induced effector cellâdependent and selective cytotoxicity against U2932 cells of up to 44% at concentrations of 20Â ÎŒg/ml. Additionally, IgG1âformat Ars2 BARâbodies were constructed by replacing the variable heavyâ and lightâchain regions of a fullâlength antibody with the Ars2 epitope. IgG1âformat Ars2 BARâbodies also bound selectively to U2932 and OCIâLy3 cells and induced selective cytotoxicity of up to 60% at 10Â ÎŒg/ml. In conclusion, Ars2âcontaining bispecific and IgG1âformat BARâbodies both are new therapeutic formats to target DLBCL cells
KIR2DS1-HLA-C status as a predictive marker for benefit from rituximab: a post-hoc analysis of the RICOVER-60 and CLL8 trials
Background The addition of rituximab to chemotherapy has substantially improved outcomes for patients with B-cell malignancies. The mechanisms of action of rituximab include activation of natural killer cells. Killer-cell immunoglobulin-like receptors (KIRs) mediate natural killer cell function through interaction with HLA. We evaluated the clinical impact of KIR-HLA genotypes on rituximab-containing therapy. Methods For this post-hoc analysis, we used data from the RICOVER-60 trial (NCT00052936) as the discovery cohort and the CLL8 trial (NCT00281918) as the validation cohort. RICOVER-60 included patients aged 61-80 years with aggressive B-cell lymphoma treated with CHOP (cyclophosphamide, doxorubicin, vincristine, and prednisone) with or without rituximab. CLL8 included patients aged 30-81 years with chronic lymphocytic leukaemia treated with chemotherapy (fludarabine and cyclophosphamide; FC) with or without rituximab. We evaluated the KIR and HLA-C status of 519 patients with available blood samples in the RICOVER-60 trial and the KIR2DS1 and HLA-C status of 549 patients with available blood samples in the CLL8 trial, and evaluated their associations with event-free survival (RICOVER-60), progression-free survival, and overall survival (RICOVER-60 and CLL8). Findings In the RICOVER-60 trial, 201 (39%) patients were positive for KIR2DS1, 79 (15%) were homozygous for HLA-C2, and 36 (7%) were positive for KIR2DS1 and homozygous for HLA-C2. In the CLL8 trial, 206 (38%) patients were positive for KIR2DS1, 75 (14%) were homozygous for HLA-C2, and 26 (5%) were positive for KIR2DS1 and homozygous for HLA-C2. In the RICOVER-60 trial, both KIR2DS1 and HLA-C status were identified as independent risk factors for survival. KIR2DS1 positivity, homozygosity for HLA-C2, and subsequent KIR2DS1-HLA-C status were associated with adverse clinical outcome in patients receiving rituximab-containing therapy (event-free survival for patients with KIR2DS1-HLA-C2/C2 vs all other patients, HR 2.6 [95% CI 1.4-4.7], p=0.0015; progression-free survival, 2.7 [1.5-5.1], p=0.0013; overall survival, 2.8 [1.5-5.4], p=0.0016) but not in patients receiving CHOP chemotherapy only (event-free survival, 0.9 [0.5-1.7], p=0.85; progression-free survival, 1.1 [0.6-2.0], p=0.81; overall survival, 1.2 [0.6-2.4], p=0.53). A significant interaction between KIR2DS1-HLA-C status and rituximab was observed (p=0.018 for event-free survival and p=0.034 for progression-free survival). In contrast to all other patients, those positive for KIR2DS1 and homozygous for HLA-C2 did not benefit from adding rituximab to CHOP chemotherapy (event-free survival, 1.9 [0.8-4.6], p=0.16; progression-free survival, 1.4 [0.6-3.4], p=0.48; overall survival, 1.6 [0.6-4.3], p=0.33). In the CLL8 trial, KIR2DS1-HLA-C status was confirmed as a predictive marker for benefit from rituximab therapy (p=0.024 for the interaction of KIR2DS1-HLA-C status and rituximab regarding progression-free survival). In contrast to all other patients, those positive for KIR2DS1 and homozygous for HLA-C2 did not benefit from adding rituximab to FC chemotherapy (progression-free survival, 2.1 [0.9-4.9], p=0.094; overall survival, 2.6 [0.5-12.7], p=0.21). Interpretation Assessment of KIR2DS1 and HLA-C genotype might identify patients who would not benefit from rituximab, thereby allowing alternative therapies to be given. Further validation of these findings in prospective clinical trials is needed