Recurrence of hepatitis C after liver transplantation is associated with increased systemic IL-10 levels.

BACKGROUND: Recurrence of hepatitis C after liver transplantation is an almost universal occurrence. T-cell derived cytokines have an important role in the development of liver damage associated with chronic hepatitis C, their post-transplant levels, however, have not been correlated with histologic recurrence of the disease. AIMS: We sought to analyze levels of TNF-alpha, soluble IL-2 receptor, IL-4 and IL-10 at 1 month, 6 months and 1 year after transplantation in 27 patients undergoing transplantation for hepatitis C related end-stage liver disease. METHODS: HCV RNA levels were monitored by a branched-chain DNA signal amplification assay. Diagnosis of recurrent hepatitis was based on 1-year protocol biopsies and on biopsies performed for liver enzyme elevations. RESULTS: Recurrent hepatitis C was detected in 52% (n=14) of the 27 patients. HCV RNA levels rose over time in all patients regardless of histologic recurrence. TNF-alpha, and IL-4 levels, although elevated, did not show specific patterns over time or in correlation with recurrence. Similarly, the early elevation followed by a gradual decrease over the first year in the amount of soluble IL-2 receptor was not related to histologic recurrence. We observed a significant increase in circulating IL-10 levels over the first year in patients with biopsy-proven recurrence, while patients with no signs of histologic recurrence displayed increased, but steady levels. CONCLUSIONS: These results suggest that while these cytokines are associated with post-transplant recurrence of hepatitis C, their production may be altered by additional factors

Th Subset Balance in Lupus Nephritis

Lupus nephritis, which has various histological patterns and variable clinical outcomes, is one of the most important complications of systemic lupus nephritis (SLE). This pathogenetic mechanism in each histologically different type of lupus nephritis (LN) remains unclear. Although SLE is suggested to be a Th2-driven disease, elevation of both Th1 and Th2 cytokines occurs in both humans and mice, suggesting that SLE is a complex disease driven by different lymphocyte subsets with high heterogeneity of clinical manifestations and organ involvement. Recent findings in LN elucidate an essential role for the Th1, IL-17 producing T cells and Th17 cells in the development of diffuse proliferative lupus nephritis (DPLN), and Th2 cytokine in that of membranous lupus nephritis (MLN). These data support the hypothesis that individual Th1/Th2 balance is one of the critical determinants for histopathology of LN

Newborn patients exhibit an unusual pattern of interleukin 10 and interferon γ serum levels in response to cardiac surgery

AbstractObjective: The aim of this study was to determine the clinical significance of serum levels of interleukin 10 and interferon γ in pediatric patients undergoing cardiopulmonary bypass. Methods: We divided the patients into 2 groups: 8 neonates and 19 nonnewborn children. Interleukin 10 and interferon γ serum levels were quantified before sternotomy, at admission to the pediatric intensive care unit (30 minutes postoperatively), 24 hours after the onset of the operation, and 3 days after the operation. Results: Newborn patients displayed significantly greater amounts of serum interleukin 10 than older children, not only in regard to the peak level achieved but also at every postoperative time point analyzed. In contrast, no significant changes in interferon γ serum levels were observed in neonates at any time point, whereas nonnewborn pediatric patients showed a significant increase in interferon γ serum concentrations immediately after the operation. This unusual pattern of cytokine response in newborn patients was not associated with modifications in cortisol serum levels. Furthermore, although neonates had significantly different surgical and clinical variables than did the nonnewborn pediatric patients, the variation in interleukin 10 production in neonates could not be accounted for by differences in the magnitude of surgical injury. In the group of neonates, there were significant positive correlations between peak interleukin 10 serum levels and both partial pressure of arterial oxygen/fraction of inspired oxygen ratio and postoperative body weight gain. Conclusions: Newborn patients undergoing cardiopulmonary bypass exhibit a distinctive biologic response pattern characterized by high levels of serum interleukin 10 without changes in serum interferon γ. This cytokine imbalance could have potential clinical implications.J Thorac Cardiovasc Surg 2002;123:451-

CD8α Coreceptor to Improve TCR Gene Transfer to Treat Melanome: Down-Regulation of Tumor-Specific Production of IL-4, IL-5 and IL-10

Therapeutic success of TCR gene transfer to treat tumors depends on the ability of redirected T cells to become activated upon tumor recognition in vivo. Help provided by tumor-specific Th1 cells is reported to relieve T cells from an anergized state and to induce tumor regression. We recently demonstrated the ability to generate melanoma-specific Th1 cells by genetic introduction of both a CD8-dependent TCR and the CD8α coreceptor into CD4⁺ T cells. In this study, we analyzed a TCR that binds Ag independently of CD8, a property generally preferred to induce tumor-specific T cell responses, and addressed the contribution of CD8α following introduction into TCR-transduced CD4⁺ T cells. To this end, primary human CD4⁺ T cells were gene transferred with a high-avidity TCR, and were shown not only to bind peptide/MHC class I, but also to effectively kill Ag-positive tumor cells in the absence of CD8α. The introduction of CD8α up-regulates the tumor-specific production of TNF-α and IL-2 to some extent, but significantly down-regulates production of IL-4, IL-5, and IL-10 in CD4⁺ T cells. The introduction of a mutated cysteine motif in CD8α, which prevents its binding to LCK and linker for activation of T cells, did not adversely affect expression and T cell cytotoxicity, but counteracted the CD8α-mediated down-regulation of IL-4 and IL-5, but not IL-10. In conclusion, CD8α down-regulates the production of major Th2-type cytokines, in part mediated by LCK and/or linker for activation of T cells, and may induce differentiation of tumor-specific Th1 cells, which makes this coreceptor an interesting candidate to improve the clinical potential of TCR gene transfer to treat cancer

Pathway-based analysis using reduced gene subsets in genome-wide association studies

<p>Abstract</p> <p>Background</p> <p>Single Nucleotide Polymorphism (SNP) analysis only captures a small proportion of associated genetic variants in Genome-Wide Association Studies (GWAS) partly due to small marginal effects. Pathway level analysis incorporating prior biological information offers another way to analyze GWAS's of complex diseases, and promises to reveal the mechanisms leading to complex diseases. Biologically defined pathways are typically comprised of numerous genes. If only a subset of genes in the pathways is associated with disease then a joint analysis including all individual genes would result in a loss of power. To address this issue, we propose a pathway-based method that allows us to test for joint effects by using a pre-selected gene subset. In the proposed approach, each gene is considered as the basic unit, which reduces the number of genetic variants considered and hence reduces the degrees of freedom in the joint analysis. The proposed approach also can be used to investigate the joint effect of several genes in a candidate gene study.</p> <p>Results</p> <p>We applied this new method to a published GWAS of psoriasis and identified 6 biologically plausible pathways, after adjustment for multiple testing. The pathways identified in our analysis overlap with those reported in previous studies. Further, using simulations across a range of gene numbers and effect sizes, we demonstrate that the proposed approach enjoys higher power than several other approaches to detect associated pathways.</p> <p>Conclusions</p> <p>The proposed method could increase the power to discover susceptibility pathways and to identify associated genes using GWAS. In our analysis of genome-wide psoriasis data, we have identified a number of relevant pathways for psoriasis.</p

Interleukin 18 Acts on Memory T Helper Cells Type 1 to Induce Airway Inflammation and Hyperresponsiveness in a Naive Host Mouse

Interleukin (IL)-18 was originally regarded to induce T helper cell (Th)1-related cytokines. In general, factors favoring interferon (IFN)-γ production are believed to abolish allergic diseases. Thus, we tested the role of IL-18 in regulation of bronchial asthma. To avoid a background response of host-derived T cells, we administered memory type Th1 or Th2 cells into unsensitized mice and examined their role in induction of bronchial asthma. Administration of antigen (Ag) induced both airway inflammation and airway hyperresponsiveness (AHR) in mice receiving memory Th2 cells. In contrast, the same treatment induced only airway inflammation but not AHR in mice receiving memory Th1 cells. However, these mice developed striking AHR when they were coadministered with IL-18. Furthermore, mice having received IFN-γ–expressing Th1 cells sorted from polarized Th1 cells developed severe airway inflammation and AHR after intranasal administration of Ag and IL-18. Thus, Th1 cells become harmful when they are stimulated with Ag and IL-18. Newly polarized Th1 cells and IFN-γ–expressing Th1 cells, both of which express IL-18 receptor α chain strongly, produce IFN-γ, IL-9, IL-13, granulocyte/macrophage colony-stimulating factor, tumor necrosis factor α, regulated on activation, normal T cell expressed and secreted, and macrophage inflammatory protein 1α upon stimulation with Ag, IL-2, and IL-18 in vitro. Thus, Ag and IL-18 stimulate memory Th1 cells to induce severe airway inflammation and AHR in the naive host