Background. Patients on kidney replacement therapy comprise a vulnerable population and may be at increased risk of death from coronavirus disease 2019 (COVID-19). Currently, only limited data are available on outcomes in this patient population. Methods. We set up the ERACODA (European Renal Association COVID-19 Database) database, which is specifically designed to prospectively collect detailed data on kidney transplant and dialysis patients with COVID-19. For this analysis, patients were included who presented between 1 February and 1 May 2020 and had complete information available on the primary outcome parameter, 28-day mortality. Results. Of the 1073 patients enrolled, 305 (28%) were kidney transplant and 768 (72%) dialysis patients with a mean age of 60 ± 13 and 67 ± 14 years, respectively. The 28-day probability of death was 21.3% [95% confidence interval (95% CI) 14.3–30.2%] in kidney transplant and 25.0% (95% CI 20.2–30.0%) in dialysis patients. Mortality was primarily associated with advanced age in kidney transplant patients, and with age and frailty in dialysis patients. After adjusting for sex, age and frailty, in-hospital mortality did not significantly differ between transplant and dialysis patients [hazard ratio (HR) 0.81, 95% CI 0.59–1.10, P = 0.18]. In the subset of dialysis patients who were a candidate for transplantation (n = 148), 8 patients died within 28 days, as compared with 7 deaths in 23 patients who underwent a kidney transplantation <1 year before presentation (HR adjusted for sex, age and frailty 0.20, 95% CI 0.07–0.56, P < 0.01). Conclusions. The 28-day case-fatality rate is high in patients on kidney replacement therapy with COVID-19 and is primarily driven by the risk factors age and frailty. Furthermore, in the first year after kidney transplantation, patients may be at increased risk of COVID-19-related mortality as compared with dialysis patients on the waiting list for transplantation. This information is important in guiding clinical decision-making, and for informing the public and healthcare authorities on the COVID-19-related mortality risk in kidney transplant and dialysis patients.

Purpose: The success of cancer immunotherapy depends on the balance between effector T cells and suppressive immune regulatory mechanisms within the tumor microenvironment. In this study we investigated whether transient monoclonal antibody-mediated depletion of CD25 high regulatory T cells (Treg) is capable of enhancing the immunostimulatory efficacy of dendritic cell vaccines.Experimental Design: Thirty HLA-A2.1 + metastatic melanoma patients were vaccinated with mature dendritic cells pulsed with tumor peptide and keyhole limpet hemocyanin (KLH). Half of the patients were pretreated with daclizumab, a humanized antibody against the interleukin-2 (IL-2) receptor α-chain (CD25), either four or eight days before dendritic cell vaccinations. Clinical and immunologic parameters were determined.Results: Daclizumab efficiently depleted all CD25 high immune cells, including CD4 + FoxP3 + CD25 high cells, from the peripheral blood within four days of administration. Thirty days after administration, daclizumab was cleared from the circulation and all CD25 + cells reappeared. The presence of daclizumab during dendritic cell vaccinations prevented the induction of specific antibodies in vivo but not the presence of antigen-specific T cells. Daclizumab, however, did prevent these CD25 + T cells from acquiring effector functions. Consequently, significantly less patients pretreated with daclizumab developed functional, vaccine-specific effector T cells and antibodies compared with controls. Daclizumab pretreatment had no significant effect on progression-free survival compared with the control group.Conclusions: Although daclizumab depleted the CD4 + FoxP3 + CD25 high Tregs from the peripheral circulation, it did not enhance the efficacy of the dendritic cell vaccine. Residual daclizumab functionally suppressed de novo induced CD25 + effector cells during dendritic cell vaccinations. Our results indicate that for immunotherapeutic benefit of transient Treg depletion, timing and dosing as well as Treg specificity are extremely important. Clin Cancer Res; 16(20); 5067-78. ©2010 AACR.Melanoma is considered one of the most immunogenic types of cancers. This is based on the following arguments: (a) several melanoma-specific antigens have been identified (1, 2); (b) functional lymphocytes specific for melanoma antigens are increased in melanoma patients (3); (c) immune-stimulating agents can have a positive effect on disease outcome (4, 5); and (d) spontaneous melanoma regressions with simultaneous onset of vitiligo have been reported (6).Immunotherapeutic clinical trials have succeeded in expanding melanoma-specific effector T cells in vivo, but favorable outcomes are still limited because tumor-induced mechanisms of immune evasion may render the host tolerant for melanoma antigens (7,8). Immunosuppression at the tumor microenvironment mediated by regulatory T cells (Treg) is one of the most critical mechanisms of tumor-immune escape and a major hurdle for successful immunotherapy (9-11).In melanoma patients, selective...

The immunosuppressive drugs rapamycin and cyclosporin A (CsA) are widely used to prevent allograft rejection. Moreover, they were shown to be instrumental in experimental models of tolerance induction. However, it remains to be elucidated whether these drugs have an effect on the CD4 ؉ CD25 ؉ regulatory T-cell (T REG ) population, which plays an important role in allograft tolerance. Recently, we reported that alloantigen-driven expansion of human CD4 ؉ CD25 ؉ T REG s gives rise to a distinct highly suppressive CD27 ؉ T REG subset next to a moderately suppressive CD27 ؊ T REG subset. In the current study we found that rapamycin and CsA do not interfere with the suppressive activity of human naturally occurring CD4 ؉ CD25 ؉ T cells. However, in contrast to CsA, rapamycin preserved the dominance of the potent CD27 ؉ T REG subset over the CD27 ؊ T REG subset after alloantigen-driven expansion of CD4 ؉ CD25 ؉ T REG s in vitro. Accordingly, CD4 ؉ CD25 ؉ T REG s cultured in the presence of rapamycin displayed much stronger suppressive capacity than

To aid efforts to manage the coronavirus disease 2019 (COVID-19) pandemic, it is essential to understand the epidemiology of the disease. We need to know which individuals are at increased risk of SARS-CoV-2 infection as well as their risk of morbidity and mortality if they become infected. The number of articles describing these aspects is multiplying almost at the same pace as the pandemic, reflecting our uncertainty regarding this disease. The first publications described single-centre experiences in small numbers of patients in China where the pandemic was first reported 1. These reports were soon followed by multicentre experiences from China 2 , and shortly thereafter from Europe 3,4 and the USA 5 , mimicking the course of the epicentre of the pandemic as it moved across the globe. In general, these reports identify older age, male sex, obesity, hypertension, diabetes, cardiovascular disease and chronic lung disease as risk factors for COVID-19 mortality. Notably, few reports have mentioned the possible importance of chronic kidney disease (CKD). A new study by Williamson et al. recently published in Nature addresses this knowledge gap 6. Reported mortality rates and the risk confer red by individual risk factors differ considerably between COVID-19 studies. This variation can only partly be explained by differences in the age distributions of the study populations 7. At least two other methodo logical aspects should be taken into consi deration. First, it is important to note the study population. Some papers describe outcomes in the general population, whereas

Steroids have been included in most immunosuppressive regimens after renal transplantation, but are feared for their side-effects. We conducted a prospective multicenter study to investigate whether it is feasible to withdraw steroids early after transplantation with the use of anti-IL-2Ra induction, tacrolimus and mycophenolate mofetil (MMF). A total of 364 patients were randomized to receive either two doses of daclizumab (1 mg/kg) and, for the first 3 days, 100 mg of prednisolone (daclizumab group n = = 186), or steroids (tapered to 0 mg at week 16; controls n = = 178). All patients received tacrolimus and MMF. The incidence of biopsy-confirmed acute rejection at 12 months was not different between the daclizumab group (15%) and the controls (14%) (95% confidence interval of difference: −6 to + + 8%, NS). Graft survival at 12 months was comparable in the two groups (daclizumab group: 91%; controls: 90%). Mean arterial blood pressure, serum lipids, and incidence of patients with hyperglycemia were temporary lower in the daclizumab group compared with controls. The immunosuppressive regimen of the daclizumab group was associated with increased costs. In conclusion, with the use of anti-IL-2Ra induction and daily therapy with tacrolimus and MMF it is feasible to withdraw steroids at 3 days after renal transplantation.

Graft-versus-host-disease (GVHD) is the most common cause of poor outcome after allogeneic stem cell transplantation (SCT). Of late, exploitation of FOXP3 þ regulatory T-cell (T REG ) function is emerging as a promising strategy in suppression of GVHD, while preserving graft-versus-leukemia (GVL). Cyclosporine and rapamycin reduce the expansion of effector T cells by blocking interleukin (IL)-2, but signaling by IL-2 is pivotal for T REG homeostasis. The resolution of GVHD is critically dependent on thymus-dependent reconstitution of the immunoregulatory system. Thus, there has been concern about the impact of blocking IL-2 signaling by immunosuppressive agents on T REG homeostasis. Here we demonstrate in a mouse model that in contrast to rapamycin, cyclosporine compromises not only the thymic generation of CD4 þ CD25 þ FoxP3 þ T cells but also their homeostatic behavior in peripheral immune compartments. Treatment with cyclosporine resulted in a sharp reduction of peripheral CD25 þ FoxP3 þ T cells in all immune compartments studied. Prolonged rapamycin treatment allowed for thymic generation of CD4 þ FoxP3 þ T cells, whereas treatment with cyclosporine led to a reduced generation of these cells. In conclusion, cyclosporine and rapamycin differentially affect homeostasis of CD4 þ FoxP3 þ T REG in vivo. As peripheral tolerance induction is a prerequisite for successful treatment outcome after allogeneic SCT, these findings are of potential clinical relevance.

A single dose of the anti-CD20 monoclonal antibody rituximab induces a nearly complete B cell depletion in peripheral blood, but not in secondary lymphoid organs. Modulation of this remaining B cell population due to rituximab treatment may contribute to the therapeutic effects of rituximab. To assess the in vivo effects of rituximab we used lymph nodes (LNs) collected during renal transplant surgery in patients who had received rituximab 4 weeks earlier in preparation for an ABO-incompatible transplantation. Rituximab treatment resulted in a lower percentage of na € lve (IgD þ CD27 À ) and a higher percentage of switched memory (IgD À CD27 þ ) B cells. Remarkably, transitional (CD24 þþ CD38 þþ ) B cells were virtually lacking in the LNs of rituximab-treated patients. Moreover, LN-derived B cells from rituximab-treated patients produced different amounts of various Ig-subclasses after anti-CD40/IL-21 stimulation ex vivo. Finally, after stimulation of allogeneic T cells with LN-derived B cells from rituximab-treated patients, the proliferated T cells showed a decreased production of IL-17. In conclusion, after treatment with rituximab there remains a B cell population with different functional capacities. Consequently, the effect of rituximab on the immune response will not only be determined by the extent of B cell depletion, but also by the functional properties of the remaining B cells.

BackgroundTreg based immunotherapy is of great interest to facilitate tolerance in autoimmunity and transplantation. For clinical trials, it is essential to have a clinical grade Treg isolation protocol in accordance with Good Manufacturing Practice (GMP) guidelines. To obtain sufficient Treg for immunotherapy, subsequent ex vivo expansion might be needed.Methodology/Principal FindingsTreg were isolated from leukapheresis products by CliniMACS based GMP isolation strategies, using anti-CD25, anti-CD8 and anti-CD19 coated microbeads. CliniMACS isolation procedures led to 40–60% pure CD4posCD25highFoxP3pos Treg populations that were anergic and had moderate suppressive activity. Such CliniMACS isolated Treg populations could be expanded with maintenance of suppressive function. Alloantigen stimulated expansion caused an enrichment of alloantigen-specific Treg. Depletion of unwanted CD19pos cells during CliniMACS Treg isolation proved necessary to prevent B-cell outgrowth during expansion. CD4posCD127pos conventional T cells were the major contaminating cell type in CliniMACS isolated Treg populations. Depletion of CD127pos cells improved the purity of CD4posCD25highFoxP3pos Treg in CliniMACS isolated cell populations to approximately 90%. Expanded CD127neg CliniMACS isolated Treg populations showed very potent suppressive capacity and high FoxP3 expression. Furthermore, our data show that cryopreservation of CliniMACS isolated Treg is feasible, but that activation after thawing is necessary to restore suppressive potential.Conclusions/SignificanceThe feasibility of Treg based therapy is widely accepted, provided that tailor-made clinical grade procedures for isolation and ex vivo cell handling are available. We here provide further support for this approach by showing that a high Treg purity can be reached, and that isolated cells can be cryopreserved and expanded successfully.