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Aim: To investigate the effect of latent cytomegalovirus (CMV) infection on experimental anti-myeloperoxidase (MPO) autoimmunity and glomerulonephritis (GN). Background(s): Autoimmunity to MPO results in anti-neutrophil cytoplasmic antibody (ANCA)-associated vasculitis (AAV) and GN. CMV is present, lifelong, in a latent state after primary infection. Latent CMV infection causes increased peripheral blood CD28- T cells that contribute to mortality in AAV, but this is mechanistically unclear. Method(s): Mice were infected with mouse CMV (K181delm157). Seven weeks later, when viral latency was established (by organ CMV plaque assay, including kidneys), mice were immunised with MPO and autoimmunity assessed 10- and 28-days after immunization. Anti-MPO GN was induced by immunising mice with MPO, GN was triggered by low dose anti-mouse basement membrane globulin, and disease assessed 4 days post trigger (day 21). Result(s): Latent CMV infection induced heightened anti-MPO autoimmunity with increased lymph node MPO-stimulated IL-17A and IFNgamma production (ELISPOT day 10, sustained at day 21 in anti-MPO GN). Latent CMV infection did not significantly increase MPO-ANCA titres, but autoreactive B cell numbers were increased. In mice with GN, latent infection resulted in increased intrarenal macrophages, CD4 + and CD8+ T cells. Intrarenal CMVspecific CD8+ T cells were detected in CMV infected mice with GN by MHCIpeptide tetramer staining. CD28-CD4 + and CD8 + populations were expanded, while intrarenal CD4+ and CD8+ T cells in CMV infected mice with GN exhibited heightened TNF and IFNgamma production as well as increased cytotoxic potential, measured by surface CD107a expression. CMV infected mice with GN developed increased proteinuria, though short-term histological glomerular injury was similar. Conclusion(s): Experimentally, latent CMV infection results in heightened anti-MPO autoimmunity and renal inflammation; and may directly influence the course of MPO-AAV in humans.

Aim: To investigate IL-7Ralpha signalling in experimental anti-myeloperoxidase (MPO) glomerulonephritis (GN) by inhibiting IL-7Ralpha using a neutralising, non-depleting monoclonal antibody. Background(s): Microarray profiling of T cells from patients with anti-neutrophil cytoplasmic antibody (ANCA)-associated vasculitis (AAV) has demonstrated that signalling through the memory T cell receptor IL-7Ralpha predicts relapse and overall severity, but whether IL-7Ralpha has any direct functional role is unknown. Method(s): Anti-MPO GN was induced by immunising mice with MPO, then GN triggered with low dose anti-mouse basement membrane globulin 4 days before the end of experiments. Autoimmunity was either acute (immunizations days 0, 7; ending day 21) or chronic (immunizations days 0, 7, 42; ending day 56). Anti-IL-7Ralpha (or control) antibodies were administered (ip) after the onset of autoimmunity, one day before GN was triggered. In a further experiment in the chronic model, anti-IL7Ralpha treatment commenced on day 35. Treatment was administered every second day. Result(s): Control ovalbumin-immunized mice given anti-basement membrane globulin developed minimal injury. Compared with mice with anti- MPO GN given control antibodies, anti-IL-7Ralpha antibodies administered after the induction of anti-MPO autoimmunity (day 17) attenuated GN at day 21 with reduced albuminuria, glomerular segmental necrosis, tubulointerstitial injury, glomerular and interstitial leukocytes and intrarenal chemokines, with no corresponding increase in intrarenal PD-1 expression. Anti-IL-7Ralpha therapy in the 56-day model dampened systemic proinflammatory immune responses and renal leukocyte infiltration, without affecting albuminuria or glomerular histology. Prophylactic therapy prior to the induction of disease in the chronic model resulted in a similar outcome. Conclusion(s): These findings mechanistically validate a role for the IL-7Ralpha in AAV and suggest that neutralizing anti-IL-7Ra

Anti-neutrophil cytoplasmic antibody (ANCA) associated vasculitis (AAV) is a rare and severe autoimmune multisystemic disease. Its pathogenesis involves multiple arms of the immune system, as well as complex interactions between immune cells and target organs. Experimental animal models of disease can provide the crucial link from human disease to translational research into new therapies. This is particularly true in AAV, due to low disease incidence and substantial disease heterogeneity. Animal models allow for controlled environments in which disease mechanisms can be defined, without the clinical confounders of environmental and lifestyle factors. To date, multiple animal models have been developed, each of which shed light on different disease pathways. Results from animal studies of AAV have played a crucial role in enhancing our understanding of disease mechanisms, and have provided direction toward newer targeted therapies. This review will summarize our understanding of AAV pathogenesis as has been gleaned from currently available animal models, as well as address their strengths and limitations. We will also discuss the potential for current and new animal models to further our understanding of this important condition.© Copyright © 2020 Shochet, Holdsworth and Kitching.

Despite improvements in graft survival, solid organ transplantation is still associated with considerable infection induced morbidity and mortality. If we were able to show that serious infection risk was associated with excessive suppression of immune capacity, we would be justified in "personalizing" the extent of immunosuppression by carefully monitored reduction to see if we can improve immune compromize without increasing the risk of rejection. Reliable biomarkers are needed to identify this patients at an increased risk of infection. This review focuses on the currently available evidence in solid organ transplant recipients for immune non-pathogen specific biomarkers to predict severe infections with the susceptibility to particular pathogens according to the component of the immune system that is suppressed. This review is categorized into immune biomarkers representative of the humoral, cellular, phagocytic, natural killer cell and complement system. Biomarkers humoral and cellular systems of the that have demonstrated an association with infections include immunoglobulins, lymphocyte number, lymphocyte subsets, intracellular concentrations of adenosine triphosphate in stimulated CD4+ cells and soluble CD30. Biomarkers of the innate immune system that have demonstrated an association with infections include natural killer cell numbers, complement and mannose binding lectin. Emerging evidence shows that quantification of viral nucleic acid (such as Epstein Barr Virus) can act as a biomarker to predict all-cause infections. Studies that show the most promise are those in which several immune biomarkers are assessed in combination. Ongoing research is required to validate non-pathogen specific immune biomarkers in multi-centre studies using standardized study designs.Copyright © 2018 Elsevier Inc.

The aim of this study was to determine if natural killer cell number (CD3-/CD16+/-/CD56+/-) and cytotoxic killing function predicts severity and frequency of infection in kidney transplant recipients. A cohort of 168 kidney transplant recipients with stable graft function underwent assessment of natural killer cell number and functional killing capacity immediately prior to entry into this prospective study. Participants were followed for 2 years for development of severe infection, defined as hospitalization for infection. Area under receiver operating characteristic (AUROC) curves were used to evaluate the accuracy of natural killer cell number and function for predicting severe infection. Adjusted odds ratios were determined by logistic regression. Fifty-nine kidney transplant recipients (35%) developed severe infection and 7 (4%) died. Natural killer cell function was a better predictor of severe infection than natural killer cell number: AUROC 0.84 and 0.75, respectively (P =.018). Logistic regression demonstrated that after adjustment for age, transplant function, transplant duration, mycophenolate use, and increasing natural killer function (odds ratio [OR] 0.82, 95% confidence interval [CI] 0.74-0.90; P <.0001) but not natural killer number (OR 0.96, 95% CI 0.93-1.00; P =.051) remained significantly associated with a reduced likelihood of severe infection. Natural killer cell function predicts severe infection in kidney transplant recipients.Copyright © 2018 The American Society of Transplantation and the American Society of Transplant Surgeons

The aim of this study was to determine if natural killer cell number (CD3- /CD16± /CD56± ) and cytotoxic killing function predicts severity and frequency of infection in kidney transplant recipients. A cohort of 168 kidney transplant recipients with stable graft function underwent assessment of natural killer cell number and functional killing capacity immediately prior to entry into this prospective study. Participants were followed for 2 years for development of severe infection, defined as hospitalization for infection. Area under receiver operating characteristic (AUROC) curves were used to evaluate the accuracy of natural killer cell number and function for predicting severe infection. Adjusted odds ratios were determined by logistic regression. Fifty-nine kidney transplant recipients (35%) developed severe infection and 7 (4%) died. Natural killer cell function was a better predictor of severe infection than natural killer cell number: AUROC 0.84 and 0.75, respectively (P = .018). Logistic regression demonstrated that after adjustment for age, transplant function, transplant duration, mycophenolate use, and increasing natural killer function (odds ratio [OR] 0.82, 95% confidence interval [CI] 0.74-0.90; P < .0001) but not natural killer number (OR 0.96, 95% CI 0.93-1.00; P = .051) remained significantly associated with a reduced likelihood of severe infection. Natural killer cell function predicts severe infection in kidney transplant recipients.