Our data show that the posttransplant presence of persisting or de novo HLA antibodies, especially if C1q binding, is associated with graft loss, even if the antibodies are not specific for mismatched donor HLA.
SummaryVarious complement-mediated renal disorders are treated currently with the complement inhibitor eculizumab. By blocking the cleavage of C5, this monoclonal antibody prevents cell damage caused by complement-mediated inflammation. We included 23 patients with atypical haemolytic uraemic syndrome (aHUS, n 5 12), C3 glomerulopathies (C3G, n 5 9) and acute antibody-mediated renal graft rejection (AMR, n 5 2), treated with eculizumab in 12 hospitals in Germany. We explored the course of complement activation biomarkers and the benefit of therapeutic drug monitoring of eculizumab. Complement activation was assessed by analysing the haemolytic complement function of the classical (CH50) and the alternative pathway (APH50), C3 and the activation products C3d, C5a and sC5b-9 prior to, 3 and 6 months after eculizumab treatment. Eculizumab concentrations were determined by a newly established specific enzyme-linked immunosorbent assay (ELISA). Serum eculizumab concentrations up to 1082 lg/ml point to drug accumulation, especially in paediatric patients. Loss of the therapeutic antibody via urine with concentrations up to 56 lg/ml correlated with proteinuria. In aHUS patients, effective complement inhibition was demonstrated by significant reductions of CH50, APH50, C3d and sC5b-9 levels, whereas C5a levels were only reduced significantly after 6 months' treatment. C3G patients presented increased C3d and consistently low C3 levels, reflecting ongoing complement activation and consumption at the C3 level, despite eculizumab treatment. A comprehensive complement analysis together with drug monitoring is required to distinguish mode of complement activation and efficacy of eculizumab treatment in distinct renal disorders. Accumulation of the anti-C5 antibody points to the need for a patient-orientated tailored therapy.
Summary
There is evidence that interferon‐gamma (IFN‐γ)‐dependent interactions of dendritic cell (DC), T regulatory (Treg), and T suppressor (Ts) subpopulations contribute to allograft acceptance. We measured DC subsets, CD3+CD4+CD25+ (Treg phenotype) and CD3+CD8+CD28− (Ts phenotype) peripheral blood lymphocytes (PBL) expressing Foxp3, Th1 or Th2 cytokines, peripheral T‐ and B‐cell counts, and plasma cytokines in 33 kidney transplant recipients with a serum creatinine of ≤1.8 mg/dl and 32 recipients with a serum creatinine of ≥2.0 mg/dl more than 100 days post‐transplant. Cell subsets were measured in whole blood using four‐color flow cytometry. Patients with increased creatinine had less frequently detectable CD3+CD4+CD25+IFN‐γ+ PBL than patients with good graft function (P = 0.017). In patients with good graft function, CD3+CD4+CD25+IFN‐γ+ PBL were associated with high Foxp3+, IL‐2+, IL‐12+, IL‐4+, and IL‐10+ CD3+CD4+CD25+ T PBL (P < 0.001), low CD3+CD8+CD28−Foxp3+ (P = 0.002), CD3+CD4+DR+ (P = 0.002), CD3+CD8+DR+ T (P = 0.005) and CD19+ B PBL (P = 0.005), and low lineage−HLA‐DR+CD11c+CD123− DC1 (P = 0.006). Patients with impaired graft function did not show these associations. Additional flow cytometric analysis confirmed strong co‐expression of IFN‐γ and Foxp3 by CD4+CD25+ PBL particularly in patients with good graft function. Our data support an immunoregulatory role of CD3+CD4+CD25+Foxp3+IFN‐γ+ cells in a subgroup of transplant recipients with good graft acceptance.
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