The severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) has a major impact on transplant recipients, with mortality rates up to 20%. Therefore, the effect of established messenger RNA ...(mRNA)-based SARS-CoV-2 vaccines have to be evaluated for solid organ transplant patients (SOT) since they are known to have poor responses after vaccination. We investigated the SARS-CoV-2 immune response via SARS-CoV-2 IgG detection in 23 renal transplant recipients after two doses of the mRNA-based SARS-CoV-2 vaccine BNT162b2 following the standard protocol. The antibody response was evaluated once with an anti-SARS-CoV-2 IgG CLIA 15.8 +/- 3.0 days after the second dose. As a control, SARS-CoV-2 IgG was determined in 23 healthcare workers (HCW) and compared to the patient cohort. Only 5 of 23 (22%) renal transplant recipients were tested positive for SARS-CoV-2 IgG antibodies after the second dose of vaccine. In contrast, all 23 (100%) HCWs were tested positive for antibodies after the second dose. Thus, the humoral response of renal transplant recipients after two doses of the mRNA-based vaccine BNT162b2 (Pfizer-BioNTech, Kronach, Germany) is impaired and significantly lower compared to healthy controls (22% vs. 100%;
= 0.0001). Individual vaccination strategies might be beneficial in these vulnerable patients.
An imbalanced T-cell homeostasis plays an important role in the pathogenesis of systemic lupus erythematosus (SLE). Co-stimulatory and co-inhibitory molecules regulate T-cell differentiation, ...survival, and cytokine production. B- and T-lymphocyte attenuator (BTLA) is a co-inhibitory molecule which negatively regulates T-cell activation. The aim of this study was to investigate BTLA expression on regulatory and effector CD4
T-cells in SLE patients with and without lupus nephritis (LN) during active and inactive disease. Therefore, peripheral blood of forty-one SLE patients and twenty-one healthy controls (HC) was phenotypically analyzed. Next, ex vivo stimulated T-cells were analyzed for the expression of BTLA on Th1-, Th2-, and Th17-effector cells by flow cytometry. Renal involvement was defined as biopsy-proven LN. Disease activity was assessed by SLE disease activity index (SLEDAI). Percentages of peripheral unstimulated BTLA
CD4
T-cells were significantly decreased in SLE patients with active disease. However, ex vivo stimulated Th1, Th2, and Th17 effector T-cells, expressed increased percentages of BTLA expression in active disease. In contrast, the BTLA expression on CD4
CD25
CD127
regulatory T-cells was not significantly different. BTLA seems to be an important co-inhibitory molecule in the T-cell homeostasis of patients with systemic lupus erythematosus and crucial for disease activity.
Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection induces a T cell response that most likely contributes to virus control in COVID-19 patients but may also induce ...immunopathology. Until now, the cytotoxic T cell response has not been very well characterized in COVID-19 patients. Here, we analyzed the differentiation and cytotoxic profile of T cells in 30 cases of mild COVID-19 during acute infection. SARS-CoV-2 infection induced a cytotoxic response of CD8
T cells, but not CD4
T cells, characterized by the simultaneous production of granzyme A and B as well as perforin within different effector CD8
T cell subsets. PD-1-expressing CD8
T cells also produced cytotoxic molecules during acute infection, indicating that they were not functionally exhausted. However, in COVID-19 patients over the age of 80 years, the cytotoxic T cell potential was diminished, especially in effector memory and terminally differentiated effector CD8
cells, showing that elderly patients have impaired cellular immunity against SARS-CoV-2. Our data provide valuable information about T cell responses in COVID-19 patients that may also have important implications for vaccine development.
Cytotoxic T cells are responsible for the elimination of infected cells and are key players in the control of viruses. CD8
T cells with an effector phenotype express cytotoxic molecules and are able to perform target cell killing. COVID-19 patients with a mild disease course were analyzed for the differentiation status and cytotoxic profile of CD8
T cells. SARS-CoV-2 infection induced a vigorous cytotoxic CD8
T cell response. However, this cytotoxic profile of T cells was not detected in COVID-19 patients over the age of 80 years. Thus, the absence of a cytotoxic response in elderly patients might be a possible reason for the more frequent severity of COVID-19 in this age group than in younger patients.
Purpose
The relationship between proteinuria and thyroid function remains controversial in patients with chronic kidney disease (CKD). We prospectively investigated the association between kidney and ...thyroid function in thyroid antibody-negative patients through all CKD stages.
Methods
We enrolled 184 nondialysis patients (mean age: 63.1 ± 16.9 years) without previous thyroid disease or thyroid-specific antibodies. Kidney function was assessed by estimating the glomerular filtration rate (eGFR) classified according KDIGO (CKD G1–5). Kidney damage was assessed by albuminuria (albumin-to-creatinine ratio, ACR) and classified as mild, moderate, or severe (ACR1: <300, ACR2: 300–3000, and ACR3: 3000 mg/g). To evaluate thyroid function, TSH, T4, fT4, T3, fT3, reverse T3 (rT3), and thyroxine-binding globulin (TBG) were measured.
Results
rT3 concentrations correlated negatively with albuminuria (
r
= −0.286,
p
< 0.001) and were significantly lower in patients with severe albuminuria than in those with mild or moderate albuminuria (ACR3: 0.28 vs. ACR2: 0.32 vs. ACR1: 0.36 nmol/l,
p
< 0.001). The severity of albuminuria revealed no impact on TSH, fT4, T3, fT3, and TBG. EGFR correlated with increasing T4, fT4, T3, fT3, and TBG (T4:
r
= 0.289,
p
< 0.01; fT4:
r
= 0.196,
p
< 0.01; T3:
r
= 0.408,
p
< 0.01; fT3:
r
= 0.390,
p
< 0.01) but not with rT3.
Conclusions
In thyroid antibody-negative patients presenting advanced CKD (stages 4 and 5), even severe kidney protein loss failed to influence thyroid hormone status. However, albuminuria severity correlated negatively with rT3, which was significantly lower in patients with albuminuria in the nephrotic range.
Allograft-specific regulatory T cells (T
cells) are crucial for long-term graft acceptance after transplantation. Although adoptive T
cell transfer has been proposed, major challenges include ...graft-specificity and stability. Thus, there is an unmet need for the direct induction of graft-specific T
cells. We hypothesized a synergism of the immunotolerogenic effects of rapamycin (mTOR inhibition) and plerixafor (CXCR4 antagonist) for T
cell induction. Thus, we performed fully-mismatched heart transplantations and found combination treatment to result in prolonged allograft survival. Moreover, fibrosis and myocyte lesions were reduced. Although less CD3
T cell infiltrated, higher T
cell numbers were observed. Noteworthy, this was accompanied by a plerixafor-dependent plasmacytoid dendritic cells-(pDCs)-mobilization. Furthermore, in vivo pDC-depletion abrogated the plerixafor-mediated T
cell number increase and reduced allograft survival. Our pharmacological approach allowed to increase T
cell numbers due to pDC-mediated immune regulation. Therefore pDCs can be an attractive immunotherapeutic target in addition to plerixafor treatment.
T cell immunity toward SARS-CoV-2 spike (S-), membrane (M-), and nucleocapsid (N-) proteins may define COVID-19 severity. Therefore, we compare the SARS-CoV-2-reactive T cell responses in moderate, ...severe, and critical COVID-19 patients and unexposed donors. Overlapping peptide pools of all three proteins induce SARS-CoV-2-reactive T cell response with dominance of CD4+ over CD8+ T cells and demonstrate interindividual immunity against the three proteins. M-protein induces the highest frequencies of CD4+ T cells, suggesting its relevance for diagnosis and vaccination. The T cell response of critical COVID-19 patients is robust and comparable or even superior to non-critical patients. Virus clearance and COVID-19 survival are not associated with either SARS-CoV-2 T cell kinetics or magnitude of T cell responses, respectively. Thus, our data do not support the hypothesis of insufficient SARS-CoV-2-reactive immunity in critical COVID-19. Conversely, it indicates that activation of differentiated memory effector T cells could cause hyperreactivity and immunopathogenesis in critical patients.
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M-, N-, and S-proteins induce T cell reactivity with differing immune dominanceM-protein triggers a strong CD4+ T cell responseICU and non-ICU COVID-19 patients have comparable SARS-CoV-2 T cell responsesViral clearance and COVID-19 survival are not associated with SARS-CoV-2 immunity
Thieme et al. demonstrate the T cell response against M-, N-, and S-proteins of SARS-CoV-2, with M-protein triggering a stronger CD4+ T cell response. ICU COVID-19 patients are capable of generating functional SARS-CoV-2 immunity non-inferior to non-ICU COVID-19 patients. SARS-CoV-2 clearance and COVID-19 survival are not associated with the magnitude of T cell response.
mRNA-based SARS-CoV-2 vaccines offer a preventive strategy against severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) infections that is of interest in the care of patients on hemodialysis ...(HDP). We measured humoral immune responses in 72 HDP after standard vaccination with two doses of the mRNA-based SARS-CoV-2 vaccine BNT162b2 (Pfizer-BioNTech). Antibody responses were evaluated with an anti-SARS-CoV-2 IgG ChemiLuminescent ImmunoAssay (CLIA) two weeks after the second dose. In addition, SARS-CoV-2 IgG was determined in a control of 16 healthy healthcare workers (HCW). The control group of HCW has shown a strong antibody response with a median (MD (Q1; Q3)) antibody titer of 800.0 AU/mL (520.5; 800.0). In comparison to HCW, HDP under 60 years of age responded equally (597.0 AU/mL (410.5; 800.0),
= 0.051). However, the antibody responses of the HDP negatively correlated with age (r
= 0.2954
< 0.0001), leading to significantly lower antibody titers in HDP over 60 years (280.0 AU/mL (45.7; 477.0),
< 0.0001). To thoroughly understand the immunogenicity of the new mRNA-based vaccines in HDP, longitudinal data on the effectiveness and durability of antibody responses are needed. Modifications of immunization schedules should be considered in HDP with low or without antibody responsiveness after standard vaccination to boost immune reactivity and prolong protective effects in these vulnerable patients.
The gut microbiota contributes to maintaining human health and regulating immune responses. Severe COVID-19 illness is associated with a dysregulated pro-inflammatory immune response. The effect of ...SARS-CoV-2 on altering the gut microbiome and the relevance of the gut microbiome on COVID-19 severity needs to be clarified. In this prospective study, we analyzed the gut microbiome of 212 patients of a tertiary care hospital (117 patients infected with SARS-CoV-2 and 95 SARS-CoV-2 negative patients) using
16S rRNA
gene sequencing of the V3-V4 region. Inflammatory markers and immune cells were quantified from blood. The gut microbiome in SARS-CoV-2 infected patients was characterized by a lower bacterial richness and distinct differences in the gut microbiome composition, including an enrichment of the phyla Proteobacteria and Bacteroidetes and a decrease of Actinobacteria compared to SARS-CoV-2 negative patients. The relative abundance of several genera including
Bifidobacterium
,
Streptococcus
and
Collinsella
was lower in SARS-CoV-2 positive patients while the abundance of
Bacteroides
and
Enterobacteriaceae
was increased. Higher pro-inflammatory blood markers and a lower CD8
+
T cell number characterized patients with severe COVID-19 illness. The gut microbiome of patients with severe/critical COVID-19 exhibited a lower abundance of butyrate-producing genera
Faecalibacterium
and
Roseburia
and a reduction in the connectivity of a distinct network of anti-inflammatory genera that was observed in patients with mild COVID-19 illness and in SARS-CoV-2 negative patients. Dysbiosis of the gut microbiome associated with a pro-inflammatory signature may contribute to the hyperinflammatory immune response characterizing severe COVID-19 illness.
The ability of transplant (Tx) patients to generate a protective antiviral response under immunosuppression is pivotal in COVID-19 infection. However, analysis of immunity against SARS-CoV-2 is ...currently lacking.
Here, we analyzed T cell immunity directed against SARS-CoV-2 spike-, membrane-, and nucleocapsid-protein by flow cytometry and spike-specific neutralizing antibodies in 10 Tx in comparison to 26 nonimmunosuppressed (non-Tx) COVID-19 patients.
Tx patients (7 renal, 1 lung, and 2 combined pancreas-kidney Txs) were recruited in this study during the acute phase of COVID-19 with a median time after SARS-CoV-2-positivity of 3 and 4 d for non-Tx and Tx patients, respectively. Despite immunosuppression, we detected antiviral CD4+ T cell-response in 90% of Tx patients. SARS-CoV-2-reactive CD4+ T cells produced multiple proinflammatory cytokines, indicating their potential protective capacity. Neutralizing antibody titers did not differ between groups. SARS-CoV-2-reactive CD8+ T cells targeting membrane- and spike-protein were lower in Tx patients, albeit without statistical significance. However, frequencies of anti-nucleocapsid-protein-reactive, and anti-SARS-CoV-2 polyfunctional CD8+ T cells, were similar between patient cohorts. Tx patients showed features of a prematurely aged adaptive immune system, but equal frequencies of SARS-CoV-2-reactive memory T cells.
In conclusion, a polyfunctional T cell immunity directed against SARS-CoV-2 proteins as well as neutralizing antibodies can be generated in Tx patients despite immunosuppression. In comparison to nonimmunosuppressed patients, no differences in humoral and cellular antiviral-immunity were found. Our data presenting the ability to generate SARS-CoV-2-specific immunity in immunosuppressed patients have implications for the handling of SARS-CoV-2-infected Tx patients and raise hopes for effective vaccination in this cohort.
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