Exclusion of these data points from their respective analyses did not alter our findings (data not shown), and results of other assays for this neonate were at or near the median

Exclusion of these data points from their respective analyses did not alter our findings (data not shown), and results of other assays for this neonate were at or near the median. DISCUSSION Our results show that HCV-exposed neonates had a relative suppression of T cell activation and pro-inflammatory markers compared with controls, which was offset by a higher production capacity for IFN-. plasma levels of Rimeporide pro-inflammatory markers than did controls. However, CD4+ and CD8+ T cells from HCV-exposed neonates had higher IFN- production in response to polyclonal stimulation than did T cells from controls. IDO activity was comparable between groups. No HCV-specific T cell responses or anti-HCV IgM were detected in any neonates. HCV-exposed neonates showed a relative suppression of immune activation and pro-inflammatory markers, which was counterbalanced by an increased production capacity for IFN-. These results suggest that HCV encounters the fetal immune system in utero, and alters the balance between suppressive and pro-inflammatory responses. Hepatitis C virus (HCV) is a major cause of chronic liver disease in both children and adults worldwide [1]. Since the advent of universal screening of blood products, mother-to-child transmission (MTCT) has become the major route Rimeporide of HCV contamination in children [2]. It is estimated that 10,000C60,000 newborns worldwide are infected with HCV by MTCT each year [3]. The rate of MTCT from HCV-seropositive, HCV RNA-positive women is usually 4%C6% and transmission occurs almost exclusively from women who are viremic [2]. Although the timing of transmission is not well defined, it appears that approximately one-third of transmission events occur in utero [4], with the rest occurring peripartum. Risk factors for HCV MTCT include HIV coinfection and intrapartum exposure to maternal blood [2]. Breastfeeding, HCV genotype, and mode of delivery are not associated with MTCT. There are very Rimeporide few studies investigating the biology of HCV MTCT, and the reason for the low rate of transmission remains unexplained. The findings that female sex [5] and the absence of HLA-DR13 in the infant [6] might be risk factors for transmission suggest that the fetal immune system may play a role in protection against and/or facilitation of MTCT. Fetal exposure to HCV likely occurs more frequently than in utero transmission. Bidirectional trafficking of maternal and fetal cells across the placenta occurs routinely [7, 8], and it is therefore difficult to imagine a scenario whereby viral particles would not also cross the placenta with some regularity. Based on an HCV load of 105C106 copies/mL and 600 mL/min placental blood flow at term [9], an estimated 1013C1014 HCV virions access the placental bed during gestation, making it highly probable that some particles would cross the placenta even if transfer was inefficient. This led us to inquire: if HCV exposure in utero is usually common, what is the effect of such exposure around the fetal immune system? The fetal immune environment is usually skewed toward tolerance and Th2 immune responses to avoid Th1 and pro-inflammatory responses that are toxic to the placental/fetal unit [10C12]. There are multiple mechanisms of maternal-fetal tolerance, including regulatory T cells (Tregs) and the suppressive enzyme indoleamine 2,3-dioxygenase (IDO) [11, 13]. Indeed, recent work from our laboratory has shown that Rabbit Polyclonal to RPL26L this fetus mounts a Treg response to noninherited maternal antigens on cells that cross into the fetal circulation [7]. We hypothesized that exposure to HCV antigens in utero might elicit a similar suppressive immune response. In this study, we aimed to determine if in utero exposure to HCV altered the fetal immune environment, with particular attention to Tregs, T cell activation and pro-inflammatory markers, IDO activity, and antigen-specific immune responses. METHODS Patients and blood samples Umbilical cord blood (UCB) was obtained from 7 neonates born to HCV-seropositive, HCV RNA-positive women (HCV-exposed group) and 8 neonates born to HCV-seronegative women (control group). All deliveries occurred at San Francisco General Hospital. Basic clinical and demographic data were collected at the time of delivery (Table 1). All maternal laboratory values were obtained from the medical record and were performed as part of routine clinical care. HCV antibody status was determined by immunoassay (Siemens Healthcare Diagnostics), HCV RNA by the VERSANT HCV RNA 3.0 Assay (Siemens Healthcare Diagnostics), and HCV genotype by sequencing of the 5 UTR (ARUP Laboratories). All subjects were hepatitis B surface antigen unfavorable. At delivery, UCB was collected from the umbilical vein using sterile cordocentesis to minimize the possibility of maternal blood contamination. Serum was immediately isolated and tested for the level of alanine aminotransferase and HCV RNA (as above). Blood samples from HCV-positive adults were used as positive controls in some assays and were obtained from the Liver Studies Group at the San Francisco Veterans Rimeporide Affairs Medical Center. All samples were collected under protocols approved by the Institutional Review Board at the University of California, San Francisco, that were in accordance with the guidelines of the US Rimeporide Department of Health and Human Services. Table 1. Clinical and Demographic Characteristics of Study Groups = 8)HCV-exposed neonates (= 7)avalues were calculated for all those test statistics and .05 was considered significant. Statistical analyses were performed using GraphPad Prism software, version 5.01 (GraphPad). RESULTS Study group.

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