T cells in ANCA-associated vasculitis: what can we learn from lesional versus circulating T cells?

Anti-neutrophil cytoplasmic antibody (ANCA) - associated vasculitis (AAV) is a life-threatening autoimmune disease characterized by an antibody-mediated glomerulonephritis and necrotizing vasculitis. Apart from antibodies, T cells are also involved in disease pathogenesis. This review stresses the hallmarks of T cell-mediated pathology in AAV and highlights the characteristics of lesional and circulating T cells in the immune response in AAV. Circulating effector T-cell populations are expanded and are in a persistent state of activation. Circulating regulatory T-cell subsets are less well characterized but seem to be impaired in function. Lesional effector T cells are present in granulomas, vasculitic lesions, and nephritis. Lesional T cells usually show pro-inflammatory properties and promote granuloma formation. Apart from T cells, dendritic cells are abundantly present at the sites of inflammation and locally orchestrate the immune response. Targeting the above-mentioned T cell-mediated disease mechanisms will potentially provide powerful therapeutic tools for AAV

CD107a(+) (LAMP-1) Cytotoxic CD8(+) T-Cells in Lupus Nephritis Patients

Cytotoxic CD8(+) T-cells play a pivotal role in the pathogenesis of systemic lupus erythematosus (SLE). The aim of this study was to investigate the role of CD107a (LAMP-1) on cytotoxic CD8(+) T-cells in SLE-patients in particular with lupus nephritis. Peripheral blood of SLE-patients (n = 31) and healthy controls (n = 21) was analyzed for the expression of CD314 and CD107a by flow cytometry. Kidney biopsies of lupus nephritis patients were investigated for the presence of CD8(+) and C107a(+) cells by immunohistochemistry and immunofluorescence staining. The percentages of CD107a(+) on CD8(+) T-cells were significantly decreased in SLE-patients as compared to healthy controls (40.2 +/- 18.5% vs. 47.9 +/- 15.0%, p = 0.02). This was even more significant in SLE-patients with inactive disease. There was a significant correlation between the percentages of CD107a(+)CD8(+) T-cells and SLEDAI. The evaluation of lupus nephritis biopsies showed a significant number of CD107a(+)CD8(+) T-cells mainly located in the peritubular infiltrates. The intrarenal expression of CD107a(+) was significantly correlated with proteinuria. These results demonstrate that CD8(+) T-cells of patients with systemic lupus erythematosus have an altered expression of CD107a which seems to be associated with disease activity. The proof of intrarenal CD107a(+)CD8(+) suggests a role in the pathogenesis of lupus nephritis

Increased expression of costimulatory markers CD134 and CD80 on interleukin-17 producing T cells in patients with systemic lupus erythematosus

Introduction: There is growing evidence that interleukin 17 (IL-17) producing T cells are involved in the pathogenesis of systemic lupus erythematosus (SLE). Previous studies showed that increased percentages of T-cell subsets expressing the costimulatory molecules CD80 and CD134 are associated with disease activity and renal involvement in SLE. The aim of this study was to investigate the distribution and phenotypical characteristics of IL-17 producing T-cells in SLE, in particular in patients with lupus nephritis, with emphasis on the expression of CD80 and CD134. Methods: Thirty-four patients (3 male, 31 female, mean age 41 +/- 15 years) fulfilling at least four of the American College of Rheumatology (ACR) revised criteria for the diagnosis of SLE and 24 healthy controls were enrolled. T-cells from the peripheral blood were analysed by fluorescence activated cell sorting (FACS) for their expression levels of CD80, CD134 and CCR6. In vitro stimulated CD3(+)IL17(+) cells were also investigated for the expression of these costimulatory markers. Finally, renal biopsies from SLE patients were evaluated for the presence of CD134 expressing T-cells. Results: Percentages of IL-17 expressing T-cells were significantly increased in patients with active disease as compared to healthy controls (1.46 +/- 0.58% versus 0.93 +/- 0.30%, P = 0.007). The percentage of IL-17 producing T-cells was correlated with disease activity as assessed by systemic lupus erythematosus disease activity index (SLEDAI) (r = 0.53, P = 0.003). In patients, most of the IL-17 producing T-cells were confined to the CCR6(+) T-cell subset (80 +/- 13%). Expression of CD80 and CD134 on the IL-17 producing T-cell subset was higher in SLE than in healthy controls (HC) (CD134: 71.78 +/- 14.51% versus 51.45 +/- 16.58%, P = 0.002; CD80: 25.5 +/- 14.99% versus 14.99 +/- 5.74%, P = 0.02). Also, patients with lupus nephritis expressed higher levels of CD134(+) on CD3(+)IL-17(+) cells as compared to HC (72.69 +/- 11.54% versus 51.45 +/- 16.58%, P = 0.006). Furthermore, renal biopsies of lupus nephritis patients showed infiltration of CD134(+) T cells. Conclusions: Percentages of IL-17 expressing T-cells correlate with disease activity. Further, these cells show increased expression of costimulatory markers such as CD134 and CD80. The presence of CD134(+) T-cells in renal biopsies of lupus nephritis patients suggest that these cells migrate to the kidney and might contribute to inflammatory processes through IL-17 secretion

Transplantation of Renal Allografts From Organ Donors Reactive for HCV Antibodies to HCV-Negative Recipients: Safety and Clinical Outcome

IntroductionBecause of the shortage of available organs for renal transplantation, strategies enabling the safe use of organs from donors with potential chronic infections such as hepatitis C are necessary. The aim of this study was to analyze the outcome of renal transplant donation from hepatitis C virus (HCV)-positive donors.MethodsBetween September 2002 and May 2007, 51 kidneys (34 donors) reactive for HCV antibodies were further evaluated. Six kidneys (5 donors) were transplanted to 6 recipients with known chronic HCV infection. The remaining 29 donors underwent extended virological testing. Nine donors were HCV RNA positive and thus not suitable for HCV-negative patients. Twenty donors (21 kidneys) did not have detectable HCV RNA copies and were transplanted into 21 HCV-negative recipients. Clinical outcomes focusing on safety, allograft function, and de novo HCV infection in the recipient were collected.ResultsThere were no de novo HCV infections detected in recipients who were HCV negative before transplantation. The extended virological donor screening did not have an impact on median cold ischemia time. Five-year graft survival was 75%.DiscussionOrgans from anti-HCV-reactive, nonviremic donors can be transplanted safely to HCV-negative recipients

Sex-Associated Differences in Cytomegalovirus Prevention: Prophylactic Strategy is Potentially Associated With a Strong Kidney Function Impairment in Female Renal Transplant Patients

Post-transplantation cytomegalovirus (CMV) syndrome can be prevented using the antiviral drug (val)ganciclovir. (Val)ganciclovir is typically administered following a prophylactic or a pre-emptive strategy. The prophylactic strategy entails early universal administration, the pre-emptive strategy, early treatment in case of infection. However, it is not clear which strategy is superior with respect to transplantation outcome; sex-specific effects of these prevention strategies are not known. We have retrospectively analyzed 540 patients from the multi-centre Harmony study along eight pre-defined visits: 308 were treated according to a prophylactic, 232 according to a pre-emptive strategy. As expected, we observed an association of prophylactic strategy with lower incidence of CMV syndrome, delayed onset and lower viral loads compared to the pre-emptive strategy. However, in female patients, the prophylactic strategy was associated with a strong impairment of glomerular filtration rate one year post-transplant (difference: -11.8 ± 4.3 ml min-1·1.73 m-2, p = 0.006). Additionally, we observed a tendency of higher incidence of acute rejection and severe BK virus reactivation in the prophylactic strategy group. While the prophylactic strategy was more effective for preventing CMV syndrome, our results suggest for the first time that the prophylactic strategy might lead to inferior transplantation outcomes in female patients, providing evidence for a strong association with sex. Further randomized controlled studies are necessary to confirm this potential negative effect

Effect of everolimus-based drug regimens on CMV-specific T-cell functionality after renal transplantation: 12-month ATHENA subcohort-study results

Post-transplant cytomegalovirus (CMV) infections and increased viral replication are associated with CMV-specific T-cell anergy. In the ATHENA-study, de-novo everolimus (EVR) with reduced-exposure tacrolimus (TAC) or cyclosporine (CyA) showed significant benefit in preventing CMV infections in renal transplant recipients as compared to standard TAC + mycophenolic acid (MPA). However, immunomodulatory mechanisms for this effect remain largely unknown. Ninety patients from the ATHENA-study completing the 12-month visit on-treatment (EVR + TAC n = 28; EVR + CyA n = 19; MPA + TAC n = 43) were included in a posthoc analysis. Total lymphocyte subpopulations were quantified. CMV-specific CD4 T cells were determined after stimulation with CMV-antigen, and cytokine-profiles and various T-cell anergy markers were analyzed using flow cytometry. While 25.6% of MPA + TAC-treated patients had CMV-infections, no such events were reported in EVR-treated patients. Absolute numbers of lymphocyte subpopulations were comparable between arms, whereas the percentage of regulatory T cells was significantly higher with EVR + CyA versus MPA + TAC (p = 0.019). Despite similar percentages of CMV-specific T cells, their median expression of CTLA-4 and PD-1 was lower with EVR + TAC (p < 0.05 for both) or EVR + CyA (p = 0.045 for CTLA-4) compared with MPA + TAC. Moreover, mean percentages of multifunctional CMV-specific T cells were higher with EVR + TAC (27.2%) and EVR + CyA (29.4%) than with MPA + TAC (19.0%). In conclusion, EVR-treated patients retained CMV-specific T-cell functionality, which may contribute to enhanced protection against CMV infections

Detection of pre-existing SARS-CoV-2-reactive T cells in unexposed renal transplant patients

Background: Recent data demonstrate potentially protective pre-existing T cells reactive against the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) in samples of healthy blood donors, collected before the SARS-CoV-2 pandemic. Whether pre-existing immunity is also detectable in immunosuppressed patients is currently not known. Methods: Fifty-seven patients were included in this case-control study. We compared the frequency of SARS-CoV-2-reactive T cells in the samples of 20 renal transplant (RTx) patients to 20 age/gender matched non-immunosuppressed/immune competent healthy individuals collected before the onset of the SARS-CoV-2 pandemic. Seventeen coronavirus disease 2019 (COVID-19) patients were used as positive controls. T cell reactivity against Spike-, Nucleocapsid-, and Membrane-SARS-CoV-2 proteins were analyzed by multi-parameter flow cytometry. Antibodies were analyzed by neutralization assay. Results: Pre-existing SARS-CoV-2-reactive T cells were detected in the majority of unexposed patients and healthy individuals. In RTx patients, 13/20 showed CD4(+) T cells reactive against at least one SARS-CoV-2 protein. CD8(+) T cells reactive against at least one SARS-CoV-2 protein were demonstrated in 12/20 of RTx patients. The frequency and Th1 cytokine expression pattern of pre-formed SARS-CoV-2 reactive T cells did not differ between RTx and non-immunosuppressed healthy individuals. Conclusions: This study shows that the magnitude and functionality of pre-existing SARS-CoV-2 reactive T cell in transplant patients is non-inferior compared to the immune competent cohort. Although several pro-inflammatory cytokines were produced by the detected T cells, further studies are required to prove their antiviral protection

Immune Response in Moderate to Critical Breakthrough COVID-19 Infection After mRNA Vaccination

SARS-CoV-2 variants of concern (VOCs) can trigger severe endemic waves and vaccine breakthrough infections (VBI). We analyzed the cellular and humoral immune response in 8 patients infected with the alpha variant, resulting in moderate to fatal COVID-19 disease manifestation, after double mRNA-based anti-SARS-CoV-2 vaccination. In contrast to the uninfected vaccinated control cohort, the diseased individuals had no detectable high-avidity spike (S)-reactive CD4+ and CD8+ T cells against the alpha variant and wild type (WT) at disease onset, whereas a robust CD4+ T-cell response against the N- and M-proteins was generated. Furthermore, a delayed alpha S-reactive high-avidity CD4+ T-cell response was mounted during disease progression. Compared to the vaccinated control donors, these patients also had lower neutralizing antibody titers against the alpha variant at disease onset. The delayed development of alpha S-specific cellular and humoral immunity upon VBI indicates reduced immunogenicity against the S-protein of the alpha VOC, while there was a higher and earlier N- and M-reactive T-cell response. Our findings do not undermine the current vaccination strategies but underline a potential need for the inclusion of VBI patients in alternative vaccination strategies and additional antigenic targets in next-generation SARS-CoV-2 vaccines