Respiratory dysfunction and proinflammatory chemokines in the pneumonia virus of mice (PVM) model of viral bronchiolitis

We explore relationships linking clinical symptoms, respiratory dysfunction, and local production of proinflammatory chemokines in the pneumonia virus of mice (PVM) model of viral bronchiolitis. With a reduced inoculum of this natural rodent pathogen, we observe virus clearance by day 9, while clinical symptoms and respiratory dysfunction persist through days 14 and 17 postinoculation, respectively. Via microarray and ELISA, we identify expression profiles of proinflammatory mediators MIP-1alpha, MCP-1, and MIP-2 that correlate with persistent respiratory dysfunction. MIP-1alpha is localized in bronchial epithelium, which is also the major site of PVM replication. Interferon-gamma was detected in lung tissue, but at levels that do not correlate with respiratory dysfunction. Taken together, we present a modification of our pneumovirus infection model that results in improved survival and data that stand in support of a connection between local production of specific mediators and persistent respiratory dysfunction in the setting of acute viral bronchiolitis.     

Leukemia derived dendritic cell (DCleu) mediated immune response goes along with reduced (leukemia-specific) regulatory T-cells

The blastmodulatory Kit-M, composed of granulocyte-macrophage colony-stimulating-factor (GM-CSF) and Prostaglandin E1 (PGE₁), is known to convert myeloid leukaemic blasts (from AML patients) into leukaemia derived dendritic cells (DC_leu), which activate immunoreactive cells to gain antileukemic/leukaemia-specific activity. In this study we had a special focus on the influence of Kit-M treated, DC/DCleu containing patients’whole blood (WB, n = 16) on the provision of immunosuppressive regulatory T-cells.We could confirm that Kit-M significantly increased frequencies of (mature) dendritic cells (DC) and DC_leu from leukemic whole blood (WB) without induction of blast proliferation. After mixed lymphocyte culture (MLC) with patients’ T-cells we confirmed that DC_leu mediated leukemia-specific responses- going along with activated and leukemia-specific T- and NK-cells in an intracellular cytokine staining assay (ICS) and a degranulation assay (Deg)- resulted in an increased anti-leukemic cytotoxicity (Cytotoxicity Fluorolysis Assay = CTX). We could demonstrate that (leukemia-specific) CD4⁺ and CD8⁺ regulatory T-cell population (T_reg) decreased significantly after MLC compared to controls. We found significant positive correlations of leukemia-specific CD3⁺CD4⁺ cells with frequencies of (mature) DC_leu. Achieved anti-leukemic cytotoxicity correlated significantly positive with leukemia-specific CD3⁺CD8⁺ cells and significantly negatively with (leukemia-specific) T_reg.In summary we demonstrate that immunesuppressive (leukemia-specific) regulatory T-cells are significantly downregulated after Kit-M triggered MLC- going along with a (reinstalled) antileukemic reactivity of the immune system (as demonstrated with functional assays ICS, Deg, CTX).     

Insight into the role of TSLP in inflammatory bowel diseases

Proinflammatory cytokines are thought to modulate pathogeneses of various inflammatory bowel diseases (IBDs). Thymic stromal lymphopoietin (TSLP), which has been studied in various allergic diseases such as asthma, atopic dermatitis (AD) and eosinophilic esophagitis (EoE), has been less considered to be involved in IBDs. However, mucosal dendritic cells (DCs) induced by various cytokines including TSLP were reported to cause polarization of T cell toward Th2 response, the differentiation of regulatory T-cell (Treg), and secretion of IgA by B cells. In this review, we discuss the concept that decreased TSLP has the potential to accelerate the development of Th1 response dominant diseases such as the Crohn's disease (CD) while increased TSLP has the potential to lead to a development of Th2 cell dominant diseases such the ulcerative colitis (UC). To examine TSLP's role as a potential determining factor for differentiating UC and CD, we analyzed the effects of other genes regulated by TSLP in regards to the UC and CD pathogeneses using data from online open access resources such as NetPath, GeneMania, and the String database. Our findings indicate that TSLP is a key mediator in the pathogenesis of IBDs and that further studies are needed to evaluate its role.