Hepatitis E virus (HEV) is a major cause of acute hepatitis globally. Chronic and fulminant courses are observed especially in immunocompromised transplant recipients since administration of ribavirin (RBV) does not always lead to a sustained virologic response. By in vitro stimulation of NK cells through hepatoma cell lines inoculated with a full-length HEV and treatment with RBV, we analyzed the viral replication and cell response to further elucidate the mechanism of action of RBV on immune cells, especially NK cells, in the context of HEV infection. Co-culture of HEV-infected hepatoma cells with PBMCs and treatment with RBV both resulted in a decrease in viral replication, which in combination showed an additive effect. An analysis of NK cell functions after stimulation revealed evidence of reduced cytotoxicity by decreased TRAIL and CD107a degranulation. Simultaneously, IFN-ɣ production was significantly increased through the IL-12R pathway. Although there was no direct effect on the IL-12R subunits, downstream events starting with TYK-2 and subsequently pSTAT4 were upregulated. In conclusion, we showed that RBV has an immunomodulatory effect on the IL-12R pathway of NK cells via TYK-2. This subsequently leads to an enhanced IFN-ɣ response and thus, to an additive antiviral effect in the context of an in vitro HEV infection.

Infection with the hepatitis E virus (HEV) is one of the main ubiquitous causes for developing an acute hepatitis. Moreover, chronification plays a predominant role in immunocompromised patients such as transplant recipients with more frequent severe courses. Unfortunately, besides reduction of immunosuppression and off-label use of ribavirin or pegylated interferon alfa, there is currently no specific anti-viral treatment to prevent disease progression. So far, research on involved immune mechanisms induced by HEV is limited. It is very difficult to collect clinical samples especially from the early phase of infection since this is often asymptomatic. Nevertheless, it is certain that the outcome of HEV-infected patients correlates with the strength of the proceeding immune response. Several lymphoid cells have been identified in contributing either to disease progression or achieving sustained virologic response. In particular, a sufficient immune control by both CD4+ and CD8+ T cells is necessary to prevent chronic viral replication. Especially the mechanisms underlying fulminant courses are poorly understood. However, liver biopsies indicate the involvement of cytotoxic T cells in liver damage. In this review, we aimed to highlight different parts of the lymphoid immune response against HEV and point out questions that remain unanswered regarding this underestimated global threat.

IntroductionProtective loop-ileostomy is one of the most common interventions in abdominal surgery to provide an alternative intestinal outlet until sufficient healing of a distal anastomosis has occurred. However, closure of a loop-ileostomy is also associated with complications. Thus, knowledge of the optimal time interval between primary and secondary surgery is crucial.MethodsData from 409 patients were retrospectively analyzed regarding complications and risk factors in closure-associated morbidity and mortality. A modified Clavien-Dindo classification of surgical complications was used to evaluate the severity of complications.ResultsA total of 96 (23.5%) patients suffered from postoperative complications after the closure of the loop-ileostomy. Early closure within 150 days from enterostomy (n = 229) was associated with less complications (p < 0.001**). Looking at the severity of complications, there were significantly more (p = 0.014*) mild postoperative complications in the late closure group (>150 days). Dysfunctional digestive problems—either (sub-) ileus (p = 0.004*), diarrhea or stool incontinence (p = 0.003*)—were the most frequent complications associated with late closure. Finally, we could validate in a multivariate analysis that “time to closure” (p = 0.002*) is independently associated with the development of complications after closure of a protective loop-ileostomy.ConclusionLate closure (>150 days) of a loop-ileostomy is an independent risk factor in post-closure complications in a multivariate analysis. Nevertheless, circumstances of disease and therapy need to be considered when scheduling the closure procedure.

This study was supported by grant We-4675/3-1 from the Deutsche Forschungsgemeinschaft (DFG),

Cytoreductive surgery (CRS) combined with hyperthermic intraperitoneal chemotherapy (HIPEC) is a treatment option for peritoneal carcinomatosis (PC) from colorectal cancer (CRC), which is otherwise a terminal stage of disease. Nevertheless, survival outcomes are only marginally superior to other treatments. This fact highlights the need for better strategies to control intra-abdominal disease recurrence after CRS-HIPEC, including the complementary use of immunotherapies. The aim of this study was therefore to investigate the immune phenotype of T cells in patients with PC. Fifty three patients with CRC (34 patients with PC and 19 patients without PC) were enrolled in a prospective study (clinicaltrials.gov: NCT04108936). Peripheral blood and omental fat were collected to isolate peripheral blood mononuclear cells (PBMCs) and adipose tissue mononuclear cells (ATMCs). These cells were analysed by flow cytometry using a panel focused upon T cell memory differentiation and exhaustion markers. We found a more naïve profile for CD8+T cells in peripheral blood and intra-abdominal fat of PC patients compared to comparator group (CG) patients. Furthermore, there was an over-representation of CD4+T cells expressing inhibitory receptors in adipose tissue of PC patients, but not in blood. Our description of intraperitoneal T cell subsets gives us a better understanding of how peritoneal carcinomatosis shapes local immune responses.