AUC-guided dosing of tacrolimus prevents progressive systemic overexposure in renal transplant recipients

AUC-guided dosing of tacrolimus prevents progressive systemic overexposure in renal transplant recipients.BackgroundTacrolimus has a narrow therapeutic window, and bioavailability is known to vary considerably between renal transplant recipients. Most centers still rely on measurement of trough levels, but there are conflicting reports on the correlation between tacrolimus trough levels and systemic exposure, as measured by the area-under-the-concentration-over-time curve (AUC(0-12h)).MethodsWe developed and validated a two-compartmental population-based pharmacokinetic model with Bayesian estimation of tacrolimus systemic exposure. Subsequently, we used this model to apply prospectively AUC-guided dosing of tacrolimus in 15 consecutive renal transplant recipients. The main objective was to study intrapatient variability in the course of time.ResultsBayesian forecasting with a two-point sampling strategy, a trough level, and a second sample obtained between two and four hours post-dose significantly improved the squared correlation with the AUC(0-12h) (r2= 0.94). Compared with trough level monitoring only, this approach reduced the 95%-prediction interval by 50%. The Bayesian approach proved to be feasible in clinical practice, and provided accurate information about systemic tacrolimus exposure in individual patients. In the AUC-guided dosing cohort the apparent clearance of tacrolimus decreased gradually over time, which was not reflected in corresponding trough levels.ConclusionThis simple, flexible method provides the opportunity to tailor immunosuppression, and should help minimize tacrolimus-related toxicity, such as nephrotoxicity and post-transplant diabetes mellitus

Non-Japanese Residents and the Earthquake : Reflections on our work thus far (Research Group on Non-Japanese Residents and the Earthquake)

BACKGROUND: Renal tubular epithelial cells (TECs) are one of the main targets of inflammatory insults during interstitial nephritis and kidney transplant rejection. While Th1 cells are know to be essential in the pathogenesis of rejection, the role of Th17 is still under debate. We hypothesize that TECs modulate the outcome of rejection process by production of distinct chemokines and cytokines that determine the attraction of different T-cell subsets. Therefore, we studied differential effects of activated human renal epithelial cells on T-cell migration. METHODS: Human primary TECs were stimulated by IFN-γ and TNF-α in vitro. Chemokines and cytokines produced by activated TECs were measured using Luminex or ELISA. Chemotaxis assay was performed using activated peripheral blood mononuclear cells composed of CD4+CXCR3+ and CD4+CCR6+ T cells migrating towards stimulated and unstimulated TECs. RESULTS: While activated TECs secreted abundant amounts of the pro-inflammatory cytokines IL-6 and IL-8, the T helper cell differentiation cytokines IL-1β, IL-12p70, IL-23 or TGF-β1 were not produced. The production of Th1 chemokines CXCL9, CXCL10 and CCL5 were significantly upregulated after TEC stimulation. In contrast, Th17 chemokine CCL20 could not be detected. Finally, activated TECs attracted significantly higher numbers of CD4+CXCR3+ T cells as compared to unstimulated TECs. No migration of CD4+CCR6+ T cells could be observed. CONCLUSION: Activated primary renal tubular epithelial cells do not attract Th17 cells nor produce cytokines promoting Th17 cell differentiation in our experimental system mimicking the proinflammatory microenvironment of rejection

Humoral immunity in renal transplantation: clinical significance and therapeutic approach

Donor-specific antibodies (DSA) form a significant barrier in solid organ transplantation of highly pre-sensitized candidates. Although avoiding transplantation over a positive cross-match test can largely prevent the occurrence of hyperacute antibody-mediated rejection, transplantation of highly pre-sensitized candidates is often complicated by the occurrence of acute and chronic antibody-mediated graft rejection leading to diminished graft function and survival. The pre-existent HLA and/or non-HLA-specific antibodies are without any doubt important contributing factors underlying humoral-mediated graft injury. Furthermore, increasing evidence underlines the association of newly formed de novo DSA after transplantation with poor graft function and survival. There is still a need to further develop desensitizing therapies not only to make transplantation of highly pre-sensitized candidates feasible, but also to reduce the new formation of allo-antibodies. Here, we summarize current views on desensitization therapies and the impact of the presence of DSA on the fate of the kidney graf

Serine proteases of the human immune system in health and disease

Serine proteases form a large family of protein-cleaving enzymes that play an essential role in processes like blood coagulation, apoptosis and inflammation. Immune cells express a wide variety of serine proteases such as granzymes in cytotoxic lymphocytes, neutrophil elastase, cathepsin G and proteinase 3 in neutrophils and chymase and tryptase in mast cells. Regulation of proteolysis induced by these serine proteases is essential to prevent self-induced damage Hence, there are specialized serine protease inhibitors, serpins, which are broadly distributed Here, we discuss the function of human serine proteases in inflammation, apoptosis and tissue remodeling. Furthermore, we address their Impact on development and progression of immune mediated-diseases Understanding the mode of action of senile proteases will help to unravel molecular processes involved in immunological disorders and will facilitate the identification of new therapeutic targets. (C) 2010 Elsevier Ltd All rights reserve

Hyperexpression of the granzyme B inhibitor PI-9 in human renal allografts: A potential mechanism for stable renal function in patients with subclinical rejection

Hyperexpression of the granzyme B inhibitor PI-9 in human renal allografts: A potential mechanism for stable renal function in patients with subclinical rejection.BackgroundGranzyme B–positive T lymphocytes infiltrate renal allografts during acute cellular rejection and cause graft injury by inducing apoptosis of tubular cells. Protease inhibitor 9 (PI-9), an intracellular serpin that inhibits granzyme B, is known to protect cells from the action of cytotoxic T lymphocytes.MethodsExpression of granzyme B and PI-9 in transplant biopsies from patients with acute cellular rejection (N = 18), subclinical rejection showing a mononuclear cell infiltrate without deterioration of renal function (N = 15), or stable transplant function (N = 13) were studied. Immunohistochemical stainings were analyzed and scored semiquantitatively by two independent observers who were not aware of clinical results.ResultsGranzyme B was expressed by mononuclear cells in all biopsies with cellular infiltrates. PI-9 was diffusely expressed by tubular cells in the allografts of all patients with subclinical rejection. In contrast, PI-9 expression was only focally in the patients with clinical rejection or without rejection. Although no difference was observed in granzyme B levels between acute and subclinical rejection, in subclinical rejection tubular epithelial cells showed significantly stronger expression of PI-9 than in acute rejection (P = 0.011).ConclusionThese data suggest that a high expression of PI-9 by tubular epithelial cells can serve as one of the factors protecting renal allografts from rejection in spite of the presence of inflammatory cell infiltrates

Hyperexpression of the granzyme B inhibitor PI-9 in human renal allografts: A potential mechanism for stable renal function in patients with subclinical rejection

Background. Granzyme B-positive T lymphocytes infiltrate renal allografts during acute cellular rejection and cause graft injury by inducing apoptosis of tubular cells. Protease inhibitor 9 (PI-9), an intracellular serpin that inhibits granzyme B, is known to protect cells from the action of cytotoxic T lymphocytes. Methods. Expression of granzyme B and PI-9 in transplant biopsies from patients with acute cellular rejection (N=18), subclinical rejection showing a mononuclear cell infiltrate without deterioration of renal function (N=15), or stable transplant function (N=13) were studied. Immunohistochemical stainings were analyzed and scored semiquantitatively by two independent observers who were not aware of clinical results. Results. Granzyme B was expressed by mononuclear cells in all biopsies with cellular infiltrates. PI-9 was diffusely expressed by tubular cells in the allografts of all patients with subclinical rejection. In contrast, PI-9 expression was only focally in the patients with clinical rejection or without rejection. Although no difference was observed in granzyme B levels between acute and subclinical rejection, in subclinical rejection tubular epithelial cells showed significantly stronger expression of PI-9 than in acute rejection (P=0.011). Conclusion. These data suggest that a high expression of PI-9 by tubular epithelial cells can serve as one of the factors protecting renal allografts from rejection in spite of the presence of inflammatory cell infiltrate

CD103 is a marker for alloantigen-induced regulatory CD8+ T cells

The alphaEbeta7 integrin CD103 may direct lymphocytes to its ligand E-cadherin. CD103 is expressed on T cells in lung and gut and on allograft-infiltrating T cells. Moreover, recent studies have documented expression of CD103 on CD4+ regulatory T cells. Approximately 4% of circulating CD8+ T cells bear the CD103 molecule. In this study, we show that the absence or presence of CD103 was a stable trait when purified CD103- and CD103+ CD8+ T cell subsets were stimulated with a combination of CD3 and CD28 mAbs. In contrast, allostimulation induced CD103 expression on approximately 25% of purified CD103- CD8+ T cells. Expression of CD103 on alloreactive cells was found to be augmented by IL-4, IL-10, or TGF-beta and decreased by addition of IL-12 to MLCs. The alloantigen-induced CD103+ CD8+ T cell population appeared to be polyclonal and retained CD103 expression after restimulation. Markedly, in vitro-expanded CD103+ CD8+ T cells had low proliferative and cytotoxic capacity, yet produced considerable amounts of IL-10. Strikingly, they potently suppressed T cell proliferation in MLC via a cell-cell contact-dependent mechanism. Thus, human alloantigen-induced CD103+ CD8+ T cells possess functional features of regulatory T cell

Clinical and immunologic aspects of cytomegalovirus infection in solid organ transplant recipients

Primary cytomegalovirus (CMV) infection is a major cause of morbidity and mortality in recipients after solid organ transplantation (SOT). Widespread and prolonged use of antiviral drugs has changed the natural course of CMV disease by delaying its onset and causing drug resistance. CMV induces a strong cellular immune response, even in immunosuppressed patients, and has developed strategies to evade this immune surveillance. This review summarizes challenges in managing CMV infection in transplant recipients and highlights current insights in the cellular immune response against CM