EP-1179: What the gamma? The correlation between QA and clinical risk estimates for prostate RapidArc plans

Influenza virus infection can be accompanied by life-threatening immune pathology most likely due to excessive antiviral responses. Inhibitory immune receptors may restrain such overactive immune responses. To study the role of the inhibitory immune receptor CD200R and its ligand CD200 during influenza infection, we challenged wild-type and CD200(-/-) mice with influenza virus. We found that CD200(-/-) mice in comparison to wild-type controls when inoculated with influenza virus developed more severe disease, associated with increased lung infiltration and lung endothelium damage. CD200(-/-) mice did develop adequate adaptive immune responses and were able to control viral load, suggesting that the severe disease was caused by a lack of control of the immune response. Interestingly, development of disease was completely prevented by depletion of T cells before infection, despite dramatically increased viral load, indicating that T cells are essential for the development of disease symptoms. Our data show that lack of CD200-CD200R signaling increases immune pathology during influenza infection, which can be reduced by T cell depletion. The Journal of Immunology, 2009, 183: 1990-1996

The inhibitory CD200R is differentially expressed on human and mouse T and B lymphocytes

To ensure an adequate response against pathogens and prevent unwanted self-reactivity, immune cells need to functionally express both activating and inhibitory receptors. CD200R is an inhibitory receptor mainly expressed on myeloid cells that down-modulates cellular activation both in vivo and in vitro. Although previously mainly studied as a regulator of myeloid function, we now show that CD200R is differentially expressed on human and mouse T-cell subsets. In both species, CD4(+) T cells express higher amounts of CD200R than CD8(+) T cells, and memory cells express higher amounts of CD200R than naive or effector cells. CD200R expression is up-regulated on both CD4(+) and CD8(+) T cells after stimulation in vitro. Furthermore, we show CD200R expression on human and mouse B cells. In human tonsils, CD200R is differentially expressed on B cells, with high expression on memory cells and plasmablasts. Mice lacking the ligand for CD200R, CD200(-/-) mice, do not show abnormal composition of the lymphocyte compartment and have normal B cell responses to antigenic challenge. Although the functional implications remain to be elucidated, the expression of CD200R on lymphocytes suggests a much broader role for CD200R-mediated immune regulation than previously anticipated. (c) 2007 Elsevier Ltd. All rights reserved

Ligation of CD200R by CD200 is not required for normal murine myelopoiesis

CD200R is an inhibitory receptor involved in the regulation of myeloid cells. It recruits Dok-1 and Dok-2, which are potent inhibitors of the Ras signalling pathway used by colony-stimulating factor (CSF) receptors. Dok-1/Dok-2 double knockout (DKO) mice develop leukaemia at 10-12 months of age. We investigated whether disturbed CD200R signalling could be responsible for this phenotype. Therefore, we studied whether CD200(-/-) mice have altered myelopoiesis and develop leukaemia. We report that CD200R is expressed on haematopoietic progenitor cells. However, CD200(-/-) mice have normal numbers of myeloid progenitors in the bone marrow and these cells have normal proliferative capacity. These results indicate that the development of leukaemia in Dok-1/Dok-2 DKO mice is not solely due to an absence of CD200R signalling. In addition, we show that the previously reported enhanced numbers of myeloid cells do not occur in all CD200(-/-) mice. We determined whether variations in the numbers of peripheral myeloid cells were due to an enhanced response to granulocyte-CSF (G-CSF) or an inflammatory stimulus. Mobilisation of immature neutrophils via G-CSF and infiltration of mature neutrophils and macrophages upon thioglycolate injection were not altered in CD200(-/-) mice. We conclude that CD200(-/-) mice exhibit normal myelopoiesis and that development of leukaemia in Dok-1/Dok-2 DKO mice is not caused by a lack of CD200-mediated CD200R signallin