טכניון מכון טכנולוגי לישראל
הטכניון מכון טכנולוגי לישראל - בית הספר ללימודי מוסמכים  
Ph.D Thesis
Ph.D StudentAnunu Rachel
SubjectThe Involvment of Scavenger Receptor Class B Type I in the
Directional Polarization of Activated Macrophages
DepartmentDepartment of Medicine
Supervisors Professor Nathan Karin
Professor Eyal Bengal


Abstract

In my study we have shown that during experimental autoimmune encephalomyelitis (EAE), an autoimmune disease of the central nervous system, serving as an experimental model for Multiple Sclerosis, mice mount a selective autoantibody response to the macrophage scavenger molecule SR-BI, which is a natural receptor for HDL. Targeted DNA vaccine encoding the extracellular part of this receptor could amplify this response and suppress an ongoing disease. The beneficial effect of the vaccine could be transferred by SR-BI specific autoantibodies. To investigate the underlying mechanism these antibodies were added to LPS activated peritoneal macrophages, as well as to monocyte cell lines. The interaction of these antibodies with their target receptor elicited IL-10 production while suppressing inflammatory mediator and iNOS production by these cells. Our working hypothesis is that these antibodies participate in the natural regulation of disease, in part, by activating anti-inflammatory SR-BI+ macrophages (M2 macrophages). This has motivated us to develop a highly specific mAb to rodent SR-BI, with cross reactivity to its human counter molecule (CLA-I). This particular monoclonal antibody could well preserve all the characteristics of the polyclonal antibodies including suppression of ongoing EAE. Our results also show that it activates macrophages by phosphorilating Akt in a similar manner, but higher efficiency, than HDL. Finally, primary cultured T cells from protected mice treated with the above mAb produced increased levels of IL-10 and low levels of inflammatory mediators. One possibility is that high levels of IL-10 produced by the anti inflammatory macrophages affect the polarization of CD4+ T cells into high IL-10 producing T cells. Alternatively, it could well be that they directly activate potential, yet to be identified, SR-BI+ regulatory T cells.  Based on these findings our laboratory now continues to identify these SR-BI+ regulatory cells and explore their properties.