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Introduction: In autoimmune diseases, IL-17 producing T-cells (Th17), a pro-inflammatory subset of T-cells, are pathophysiologically involved. There is little knowledge on the role of Th17 cells in granulomatosis with polyangiitis (GPA). In the present study, we investigated Th17 cells, Tregs and subsets of circulating Th17 cells in GPA and related results to disease activity.Methods: 42 GPA patients in remission, 18 with active disease and 14 healthy controls (HC) were enrolled. Th17 cells, their subsets and regulatory T-cells were determined by intracellular fluorescence activated cell sorter (FACS). Data are given as mean percentage ±SD of total T-helper-cells.Results: Th17 cells are expanded in active and quiescent GPA as compared to HC (1.7±1.4% vs. 0.7 ±0.3%, P = 0.006 and 1.9 ±1.5% vs. 0.7 ±0.3%, P

IL-17 producing T-cells (Th17) were recently defined as a new, pro-inflammatory T-cell subset and are considered to have a key role in autoimmune diseases. Importantly, it was recently described that anti-inflammatory regulatory T-cells (Treg) are able to convert to pro-inflammatory Th17 cells (“Plasticity”) and vice versa. Little is known about the Th17 response or plasticity in ANCA-associated vasculitis (AAV). Therefore, we investigated Th17 responses in AAV.

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.

Background: Atypical hemolytic uremic syndrome (aHUS) is a rare microangiopathic hemolytic anemia characterized by the uncontrolled progression of the alternative complement pathway due to genetic or acquired dysregulation of steady state alternative pathway activity leading to a proinflammatory and prothrombotic condition. Atypical HUS is characterized by intravascular hemolysis, consumptive thrombocytopenia, and microvascular glomerular thrombosis with the formation of thrombi in glomerular capillaries. As the thrombotic microangiopathy is particularly severe in the renal microvasculature, the disease inevitably leads to acute kidney injury with most cases progressing to end-stage-renal-disease. Eculizumab is a complement inhibitor that has been shown to completely and consistently block the activation of the terminal complement cascade thereby preventing the generation of the proinflammatory and prothrombotic molecules C5a and C5b-9. In recent phase 3 clinical studies in patients with the rare hemolytic disease paroxysmal nocturnal hemoglobinuria, chronic eculizumab treatment was shown to be safe, and demonstrated an effective reduction in intravascular hemolysis and a 85% reduction in thrombotic events. Aim: The safety and efficacy of eculizumab in the management of aHUS. We sought to investigate the potential benefit of the complement inhibitor eculizumab in aHUS, a disease characterized by uncontrolled progression of the alternative complement pathway. Methods: Two aHUS patients that were unresponsive to plasmapheresis were dosed with 600 mg of eculizumab to inhibit the terminal complement cascade. The patients were monitored closely for adverse events and platelet counts, creatinine and haptoglobin were assessed. PK/PD analyses were performed on one of the two patients. Results: We report aHUS in two patients successfully treated with the complement inhibitor eculizumab. The first was a 37-year old female with recurrence of aHUS after renal transplantation. At the age of 25 years, the patient developed aHUS with end-stage-renal- disease and stayed on dialysis until she received a first cadaveric kidney transplant 5 years later. This first transplant was lost 5 weeks after transplantation due to chronic aHUS. A second attempt of kidney transplantation was undertaken using a calcineurin-inhibitor free immunosuppressive protocol and despite immediate plasmapheresis (4 times), aHUS worsened (platelet count dropping, haptoglobin decreasing, creatinine increasing) indicating a high probability of repeated renal transplant loss. The patient was characterized as having a missense mutation in the gene encoding the complement regulatory protein factor H. The current literature indicates that patients with such mutations have a high incidence of graft rejection (7 of 8 grafts rejected). Eculizumab was therefore administered and resulted in immediate and complete inhibition of terminal complement activation for at least 5 days. During the week following treatment, platelet count increased, hemolysis normalized (as assessed by haptoglobin levels), and transplant function recovered (as assessed by creatinine levels) indicating successful reversal of aHUS (see Figure A). The second patient was an 18-year old female with first the initial manifestation of aHUS. After a total of 18 plasmaphereses, the young patient was referred to our hospital with aHUS. When symptoms persisted despite another three plasmaphereses in our University hospital, we decided to administer eculizumab. Over the following week, platelet count normalized, hemolysis was reversed, and renal function partially recovered (see Figure B). Summary: This is the first report evaluating the use of a complement inhibitor as a potential therapy for the treatment of aHUS. These data suggest that eculizumab therapy results in a reduction in thrombotic microangiopathy and hemolysis as evidenced by a reversal of thrombocytopenia, the normalization of hemolytic parameters, and the recovery of kidney transplant function. These data suggest the eculizumab modifies the course of aHUS and warrant further clinical investigation to confirm whether complement inhibition with eculizumab is an effective treatment of this devastating and life-threatening disease. Figure Figure

OBJECTIVE In young spontaneously hypertensive rats (SHR), transient angiotensin II type 1 receptor (AT1R) blockade decreases blood pressure for a prolonged period. We tested the hypothesis that transient AT1R blockade in SHR leads to cardiac protection until advanced age. METHOD Wistar-Kyoto rats, SHR and transiently losartan-treated SHR (SHR-Los) (20 mg/kg per day; weeks 4-8 of age) were followed up until week 72 (n=9 each group), including repeated echocardiography, radiotelemetric investigations and 24-h urine collection. End-point measurements comprised left ventricular function parameters, left ventricular histomorphology and molecular biology (types I and III collagen, brain natriuretic peptide, AT1R mRNA) as well as renal morphology. RESULTS Prehypertensive treatment with losartan, but not with the general vasodilator hydralazine, reduced blood pressure until age 48 weeks. In untreated SHR, the end-diastolic volume increased from week 36 and the left ventricular ejection fraction fell from week 48. In contrast, age-related changes in end-diastolic volume and ejection fraction were comparable in SHR-Los and Wistar-Kyoto rats up to age 60 weeks. At age 72 weeks, the ejection fraction was reduced in SHR-Los but higher than that in untreated SHR (ejection fraction: Wistar-Kyoto rats, 58 +/- 3%; SHR, 39 +/- 3%; SHR-Los, 46 +/- 3%; P < 0.01 and P < 0.05, respectively). The heart weight/body weight ratio (SHR-Los, 4.7 +/- 0.1 g/kg; SHR, 5.2 +/- 0.2 g/kg) and cardiac brain natriuretic peptide mRNA levels were improved by treatment. Left ventricular histomorphology and 24-h albuminuria were significantly improved in SHR-Los (41 +/- 5 mg/day; SHR, 80 +/- 22 mg/day; P < 0.05). CONCLUSION In young SHR, transient AT1R blockade, not blood pressure lowering, attenuates the development of hypertension and exerts cardioprotective effects up to age 72 weeks.

Background1-year data from this trial showed the noninferiority of a novel once-daily extended-release tacrolimus (LCPT; Envarsus XR) to immediate-release tacrolimus (IR-Tac) twice daily after kidney transplantation.Study DesignFinal 24-month analysis of a 2-armed, parallel-group, randomized, double-blind, double-dummy, multicenter, phase 3 trial.Setting & Participants543 de novo kidney recipients randomly assigned to LCPT (n=268) or IR-Tac (n=275); 507 (93.4%) completed the 24-month study.InterventionLCPT tablets once daily at 0.17mg/kg/d or IR-Tac twice daily at 0.1mg/kg/d; subsequent doses were adjusted to maintain target trough ranges (first 30 days, 6-11ng/mL; thereafter, 4-11ng/mL). The intervention was 24 months; the study was double blinded for the entirety.Outcomes & MeasurementsTreatment failure (death, transplant failure, biopsy-proven acute rejection, or loss to follow up) within 24 months. Safety end points included adverse events, serious adverse events, new-onset diabetes, kidney function, opportunistic infections, and malignancies. Pharmacokinetic measures included total daily dose (TDD) of study drugs and tacrolimus trough levels.Results24-month treatment failure was LCPT, 23.1%; IR-Tac, 27.3% (treatment difference, −4.14% [95% CI, −11.38% to +3.17%], well below the +10% noninferiority criterion defined for the primary 12-month end point). Subgroup analyses showed fewer treatment failures for LCPT versus IR-Tac among black, older, and female recipients. Safety was similar between groups. From month 1, TDD was lower for LCPT; the difference increased over time. At month 24, mean TDD for LCPT was 24% lower than for the IR-Tac group (P

Summary This report describes the case of patient FR, a 31-year-old recipient of a living-related kidney transplant from a donor against whom he was presensitized. Seventeen days prior to transplantation, a central venous infusion of transplant acceptance-inducing cells (TAICs) was administered to the patient. During the 27-month follow up, the patient experienced no acute rejection episodes under an immunosuppressive regime comprising anti-thymocyte globulin (ATG) induction, corticosteroids and tacrolimus. In a similar manner to the kidney transplant recipients treated preoperatively with TAICs in a previous study, patient FR achieved a state of donor-specific hypo-responsiveness. Most remarkably, the deliberate preoperative exposure of a sensitized patient to the sensitizing alloantigen did not heighten his response; on the contrary, after TAIC treatment and transplantation, HLA-specific antibodies were no longer detectable. The case of patient FR provides further evidence of the safety of pre-transplantation treatment with TAICs.