Grant: Foundation Grant

The interplay between subtypes of neutrophils, monocytes, macrophage, iNKT cells and platelets in infection, sterile injury and metastasis in the liver and other organs

<html> <body> <p>For the last 25 years I have been studying how the innate immune system functions in vivo using imaging approaches complemented by knockout technology, with particular interest in leukocyte subsets. We have examined leukocyte recruitment into sites of infection, sterile injury and more recently in cancer and we were intrigued to see similar players involved, namely: platelets, neutrophils, monocytes/macrophages and iNKT cells.</p> <p> <strong>Our overarching hypothesis is that through evolutionary pressure we have evolved a very effective way of dealing with infections and trauma.</strong> <strong>However, inappropriate immunity and disrepair can result from conditions such as ischemia/reperfusion caused by surgical intervention (transplant or bypass), new world diseases referred to as non-evolutionary insults due to diet and lifestyle (stroke, heart attacks, drug-induced liver toxicity) and cancer.</strong> Understanding the fundamental mechanisms by which we effectively respond to infection and trauma will inform us as to how tumor cells and certain pathogens are able to subvert the immune response.</p> <p>The direction of the program will rely on our expertise in imaging the innate immune system to begin to understand the role of leukocyte subtypes including subsets of neutrophils (newly identified), subsets of monocytes and macrophage and iNKT cells in aforementioned diseases. We propose to examine infection, sterile inflammation and tumorogenesis in the liver where we have done most of our imaging and then compare specific models across tissues including skin, brain, joints and lung. Our work indicates that platelets arrive very rapidly in all insults. There are two populations of neutrophils for which we now have reporter mice (new unpublished discovery), one of which seems to carve out new conduits that will ultimately be the structures necessary for revascularization.</p> <p>Two populations of monocytes M1 (inflammatory)&nbsp;which can switch to an&nbsp;M2 (reparative&nbsp;- we have reporters for both in the same mouse)&nbsp;are seen in sterile injury and infections but they may have a single origin and there are two types of iNKT cells as master regulators of individual immune responses. All of these cells are co-localized in the vasculature and we will examine how they interact. We predict that during infection N1 (inflammatory) and M1 (inflammatory) dominate and during tumor development more anti-inflammatory cells dominate. During normal sterile injury and repair a balance of each occurs while fibrosis causes dysregulated recruitment of cells. The iNKT cells push the immunity towards the inflammatory or anti-inflammatory direction depending on stimulus.</p> <p>We will use what we learn in appropriate responses to study non-evolutionary insults as well as tumorogenesis. Immunotherapy targeting iNKT cells, N1, N2, M1 and M2 cells will be tested to improve outcomes in cancer, infections&nbsp;and sterile inflammation. The fundamental information derived can translate&nbsp;in a meaningful way&nbsp;to patients with&nbsp;inflammatory liver diseases. The work is done with a group of experts including a cell biologist with optogenetic approaches to alter cell behaviour (Klaus Hahn North Carolina), two cancer biologists (Marjolein van Egmond and Steve Robbins) and a clinical specialist (Mark Swain) and Physicians from the ICU. Trainees will formally learn imaging, immunology and have co-supervision from an MD and myself.</p> </body> </html>