Anti-TNF monoclonal antibody [PerCP/Cy5.5®]

Background: Pregnancy-specific beta 1-glycoproteins are capable of regulating innate and adaptive immunity, exerting predominantly suppressive effects. In this regard, they are of interest in terms of their pharmacological potential for the treatment of autoimmune diseases and post-transplant complications. The effect of these proteins on the main pro-inflammatory subpopulation of T lymphocytes, IL-17-producing helper T cells (Th17), has not been comprehensively studied. Therefore, the effects of the native pregnancy-specific beta 1-glycoprotein on the proliferation, Th17 polarization and cytokine profile of human CD4(+) cells were assessed. Results: Native human pregnancy-specific beta 1-glycoprotein (PSG) at a concentration of 100 mu g/mL was shown to decrease the frequency of Th17 (ROR gamma tau(+)) in CD4(+) cell culture and to suppress the proliferation of these cells (ROR gamma tau(+)Ki-67(+)), along with the proliferation of other cells (Ki-67(+)) (n = 11). A PSG concentration of 10 mu g/mL showed similar effect, decreasing the frequency of Ki-67(+) and ROR gamma tau(+)Ki67(+) cells. Using Luminex xMAP technology, it was shown that PSG decreased IL-4, IL-5, IL-8, IL-12, IL-13, IL-17, MIP-1 beta, IL-10, IFN-gamma, TNF-alpha, G-CSF, and GM-CSF concentrations in Th17-polarized CD4(+) cell cultures but did not affect IL-2, IL-7, and MCP-1 output. Conclusions: In the experimental model used, PSG had a mainly suppressive effect on the Th17 polarization and cytokine profile of Th17-polarized CD4(+) cell cultures. As Th17 activity and a pro-inflammatory cytokine background are unfavorable during pregnancy, the observed PSG effects may play a fetoprotective role in vivo.

Interferon (IFN) family cytokines stimulate genes (interferon-stimulated genes [ISGs]) that are integral to antiviral host defense. Type I IFNs act systemically, whereas type III IFNs act preferentially at epithelial barriers. Among barrier cells, intestinal epithelial cells (IECs) are particularly dependent on type III IFN for the control and clearance of virus infection, but the physiological basis of this selective IFN response is not well understood. Here, we confirm that type III IFN treatment elicits robust and uniform ISG expression in neonatal mouse IECs and inhibits the replication of IEC-tropic rotavirus. In contrast, type I IFN elicits a marginal ISG response in neonatal mouse IECs and does not inhibit rotavirus replication. In vitro treatment of IEC organoids with type III IFN results in ISG expression that mirrors the in vivo type III IFN response. However, IEC organoids have increased expression of the type I IFN receptor relative to neonate IECs, and the response of IEC organoids to type I IFN is strikingly increased in magnitude and scope relative to type III IFN. The expanded type I IFN-specific response includes proapoptotic genes and potentiates toxicity triggered by tumor necrosis factor alpha (TNF-alpha). The ISGs stimulated in common by type I and III IFNs have strong interferon-stimulated response element (ISRE) promoter motifs, whereas the expanded set of type I IFN-specific ISGs, including proapoptotic genes, have weak ISRE motifs. Thus, the preferential responsiveness of IECs to type III IFN in vivo enables selective ISG expression during infection that confers antiviral protection but minimizes disruption of intestinal homeostasis. IMPORTANCE Enteric viral infections are a major cause of gastroenteritis worldwide and have the potential to trigger or exacerbate intestinal inflammatory diseases. Prior studies have identified specialized innate immune responses that are active in the intestinal epithelium following viral infection, but our understanding of the benefits of such an epithelium-specific response is incomplete. Here, we show that the intestinal epithelial antiviral response is programmed to enable protection while minimizing epithelial cytotoxicity that can often accompany an inflammatory response. Our findings offer new insight into the benefits of a tailored innate immune response at the intestinal barrier and suggest how dysregulation of this response could promote inflammatory disease.