Specific serum antibodies mediating humoral immunity and autoimmunity are provided by mature plasma cells (PC) residing in the bone marrow (BM), yet their dynamics and composition are largely unclear. We here characterize distinct subsets of human PC differing by CD19 expression. Unlike CD19⁺ PC, CD19⁻ PC were restricted to BM, expressed predominantly IgG, and they carried a prosurvival, distinctly mature phenotype, that is, HLA-DR^lowKi-67⁻CD95^lowCD28⁺CD56^+/−, with increased BCL2 and they resisted their mobilization from the BM after systemic vaccination. Fewer mutations within immunoglobulin V_H rearrangements of CD19⁻ BMPC may indicate their differentiation in early life. Their resistance to in vivo B-cell depletion, that is, their independency from supply with new plasmablasts, is consistent with long-term stability of this PC subset in the BM. Moreover, CD19⁻ PC were detectable in chronically inflamed tissues and secreted autoantibodies. We propose a multilayer model of PC memory in which CD19⁺ and CD19⁻ PC represent dynamic and static components, respectively, permitting both adaptation and stability of humoral immune protection. Key Points Healthy human BM is enriched for PC lacking CD19 that express a prosurvival and distinctly mature phenotype. CD19⁻ PC resist mobilization into blood during immune responses after vaccination as well as B-cell depletion with rituximab.

Cytomegalovirus (CMV) infection remains a significant cause of morbidity and mortality in transplant recipients. Letermovir (AIC246), is a novel anti‐HCMV drug in development, acting via a novel mechanism of action. In this proof‐of‐concept trial with first administration of letermovir to patients, 27 transplant recipients with active CMV replication were randomly assigned to a 14‐day oral treatment regimen of either letermovir 40 mg twice a day, letermovir 80 mg once a day, or local standard of care (SOC) in a multicenter, open‐label trial. Efficacy, safety, and limited pharmacokinetic parameters were assessed. All groups had a statistically significant decrease in CMV‐DNA copy number from baseline (40 mg BID: P = 0.031; 80 mg QD: P = 0.018; SOC: P = 0.001), and comparison of viral load reduction between treatment groups showed no statistically significant differences. Viral clearance was achieved for 6 of 12 patients (50%) in the letermovir groups versus two of seven SOC patients (28.6%). Letermovir treatment was generally well tolerated, no patient developed CMV disease during the trial. Both letermovir treatment regimens resulted in equally high trough level plasma concentrations. The efficacy, safety, and pharmacokinetics observed in these viremic transplant recipients indicate that letermovir is a promising new anti‐CMV drug.

New immunosuppressants and the better use of immunosuppressant combination therapy have led to significant improvements in renal allograft outcomes over the last decades. Yet, despite dramatic reduction in rejection rates and improvement in 1‐year graft survival, long‐term graft attrition rates remained rather constant. Current immunosuppressant combinations are frequently leading to overimmunosuppression and are increasing cardiovascular risk. Importantly, calcineurin inhibitors are nephrotoxic, contribute to cardiovascular risk and chronic allograft dysfunction. Furthermore, immunosuppressant‐associated toxicities aggravate immune‐mediated nephron injury and side effects lead to nonadherence, an identified important reason for late acute and chronic antibody‐mediated rejections. The frequent development of a chronic humoral response indicates rather insufficient immunosuppression of current combinations than simple under‐immunosuppression. While there is no evidence that increasing immunosuppressive doses will improve outcomes or reduce de novo HLA‐antibody formation, there is clear evidence that adequate minimization strategies will reduce side effect burden. Because of low rejection risk, but frequent side effects, drug minimization is particularly relevant for the many maintenance patients. In summary, new therapeutic strategies need to be developed from adequately powered clinical trials for reduction of the many side effects of immunosuppressants. Such evidence‐based and time‐dependent immunosuppressive minimization strategies are needed to achieve better long‐term outcomes in the future.

Background and objective: The clinical manifestation of angioedema ranges from minor facial edema up to life-threatening swelling of mouth and throat. Hereditary defects, drugs, and food allergies may play a role in the development of angioedema. We systematically investigated the incidence of angioedema in renal allograft recipients treated with mTOR inhibitors (mTORis). Design, setting, participants, & measurements: All patients in the authors9 electronic database who had received mTORis (n = 309) between 2000 and 2008 were identified. Of these, 137 were additionally treated with angiotensin-converting enzyme inhibitors (ACEis). Results: Nine patients (6.6%, 3.8 per 100 treatment years) developed angioedema after a mean period of 123 days under combined therapy with mTORi and ACEi. Among the remaining 172 patients on mTORi, including 119 patients treated with angiotensin-receptor blockers, only two developed angioedema (1.2%, 0.5 per 100 treatment years, P = 0.01). In patients receiving mycophenolate and ACEi (n = 462), 10 instances of angioedema were found (2.1%, 0.8 per 100 treatment years, P = 0.004). Conclusions: This systematic investigation demonstrated a noticeable incidence of 6.6% angioedema under combined therapy with mTORi and ACEi in kidney transplant recipients. Treatment with either ACEi or mTORi alone resulted in a significantly lower incidence of angioedema, suggesting that this combination should be avoided.

The use of belatacept is not yet approved for maintenance kidney-transplant patients. This retrospective multicenter European study aimed to assess the efficacy and safety of conversion to belatacept in a large cohort of patients in a real-life setting, and to identify the predictive factors for improved kidney function after the switch. Two-hundred and nineteen maintenance kidney-transplant patients from 5 European kidney-transplant centers were converted to belatacept at 21.2 (0.1–337.1) months posttransplantation, mainly because of impaired kidney function. Thirty-two patients were converted to belatacept within the first 3 months posttransplantation. The mean duration of follow-up was 21.9±20.2 months. The actuarial rate of patients still on belatacept-based therapy was 77.6%. Mean estimated glomerular-filtration rate (eGFR) increased from 32±16.4 at baseline to 38±20 mL/min/1.73 m2 (p<0.0001) at last follow-up. Conversion to belatacept before 3 months posttransplantation was the main predictive factor for a significant increase in eGFR (of 5 and 10 mL/min/1.73 m2 at 3 and 12 months after the switch, respectively). Eighteen patients (8.2%) presented with an acute-rejection episode after conversion; 3 developed a donor-specific antibody (DSA). Overall efficacy and safety were good, including for the 35 patients that had a DSA at conversion. The conversion to belatacept was effective, especially when performed early after transplantation.

Late antibody-mediated rejection (ABMR) triggered by donor-specific antibodies (DSA) is a cardinal cause of kidney allograft dysfunction and loss. Diagnostic criteria for this rejection type are well established, but effective treatment remains a major challenge. Recent randomized controlled trials (RCT) have failed to demonstrate the efficacy of widely used therapies, such as rituximab plus intravenous immunoglobulin or proteasome inhibition (bortezomib), reinforcing a great need for new therapeutic concepts. One promising target in this context may be interleukin-6 (IL-6), a pleiotropic cytokine known to play an important role in inflammation and adaptive immunity. This investigator-driven RCT was designed to assess the safety and efficacy of clazakizumab, a genetically engineered humanized monoclonal antibody directed against IL-6. The study will include 20 DSA-positive kidney allograft recipients diagnosed with ABMR ≥ 365 days after transplantation. Participants will be recruited at two study sites in Austria and Germany (Medical University of Vienna; Charité University Medicine Berlin). First, patients will enter a three-month double-blind RCT (1,1 randomization, stratification according to ABMR phenotype and study site) and will receive either clazakizumab (subcutaneous administration of 25 mg in monthly intervals) or placebo. In a second open-label part of the trial (months 4–12), all patients will receive clazakizumab at 25 mg every month. The primary endpoint is safety and tolerability. Secondary endpoints are the pharmacokinetics and pharmacodynamics of clazakizumab, its effect on drug metabolism in the liver, DSA characteristics, morphological ABMR lesions and molecular gene expression patterns in three- and 12-month protocol biopsies, serum/urinary biomarkers of inflammation and endothelial activation/injury, Torque Teno viral load as a measure of overall immunosuppression, kidney function, urinary protein excretion, as well as transplant and patient survival. Currently, there is no treatment proven to be effective in halting the progression of late ABMR. Based on the hypothesis that antagonizing the effects of IL-6 improves the outcome of DSA-positive late ABMR by counteracting DSA-triggered inflammation and B cell/plasma cell-driven alloimmunity, we suggest that our trial has the potential to provide proof of concept of a novel treatment of this type of rejection. ClinicalTrials.gov, NCT03444103 . Registered on 23 February 2018 (retrospective registration).