The Danger Model 2: how tissues control Immunity

National Institute Of Allergy And Infectious Diseases

Investigators

Linked publications & trials

Abstract

Because our lab was shut down by the NIAID administration on April 1st, 2013, we focused on three projects that had some possibility of completion. We managed to finish one of these projects, but will continue the others through collaborations with other scientists on and off campus. We also started a new project on the immuno-inhibitory effect of P falciparum. Ongoing projects from the Ghost Lab 1) (completed) analysis of the stimulatory effect of P gingivalis (PG) on dendritic cells: we compared the stimulatory capacity of PG with that of E coli and F nucleatum, and found that PG are almost entirely non-stimulatory. For example, it takes 1000 times more PG LPS than E coli LPS to stimulate dendritic cells. Further, PG has the capacity to degrade several key immune cyctokines made by dendritic cells and/or T cells. 2) (not completed) analysis of the effect of GATA4: GATA 4 is a transcription factor highly expressed by the epithelial cells of the jejunum. In mice carrying a targeted deletion in jejunal GATA4, the jejunal epithelial cells upregulate a network of immune genes. To determine whether the immune upregulation is a direct effect of the loss of GATA4, or an indirect effect because of GATA4-induced changes in the intestinal flora, we took two approaches. First we generated germ-free GATA4KO mice. Second we used siRNA to downregulate GATA4 in the intestinal cell line, MODE-K. The germ free mice are now sitting, waiting for a collaborator to collect their tissues, as we are not being allowed to spend our budget to do this. The cell line revealed that at least three immune genes are upregulated, in the absence of bacteria, when GATA4 is downregulated by siRNA. We are now continuing this project as a collaboration with Bana Jabri at the University of Chicago 3) (Collaboration with Bana Jabri). IgA and B cell deficient mice show changes in intestinal epithelium indicating that these cells take up several aspects of immunity. Most of these changes only occur when the intestines harbor commensal organisms. we are now ascertaining which of the these commensals are responsible for stimulating the innate immune genes in the intestinal epithelium. 4) Having shown in previous years that newborns are not immunologically incompetent, we wondered why children that are less than a year of age do not respond well to measles vaccine. we found that the problem lies neither with the child's ability to respond, nor to the passage of maternal antibodies, but rather with the vaccine itself. Newborns express a variant of the cell receptor that is longer than that of adults, and this variant slowly changes into adult form over the first year or so of life. the virus has been shown in other studies to be incapable of using this long form for successful entry into cells. we suggest that this may be the reason that newborns respond poorly to measles vaccination.