Lrg1 as a therapeutic target in Graft-versus-Host Disease

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Graft-versus-host disease (GVHD) is the main complication of allogeneic hematopoietic stem cell transplantation (allo-HSCT) causing considerable mortality. There is a medical need for novel therapies because standard GVHD treatments with immunosuppressive drugs have severe unwanted effects including fatal infection and tumor relapse. In our previous work, we found that angiogenesis initiates organ inflammation during GVHD, making therapeutic inhibition of angiogenesis an attractive novel approach to reduce inflammation during GVHD without severely impairing immunity. The main obstacle to this approach, however, has been the lack of suitable molecular targets, which are differentially upregulated during pathological angiogenesis and physiological angiogenesis. Leucine-rich alpha-2-glycoprotein 1 (Lrg1) could be such a suitable target, as it has been demonstrated to be involved in pathological angiogenesis, whereas it appears to be dispensable for physiological angiogenesis. Mice lacking Lrg1 develop normally, but exhibit a significant reduction in pathological angiogenesis. Lrg1 binds to transforming growth factor-β1 (TGF-β1) accessory receptor endoglin and promotes the pro-angiogenic Smad1/5/8 signaling pathway in endothelial cells. Lrg1 antibody blockade inhibits this pro-angiogenic switch and attenuates angiogenesis. Results from our preliminary studies suggest that:1) Lrg1 is upregulated in target organs during GVHD. 2) Experimental GVHD and colitis are attenuated in Lrg1-deficient mice.We therefore hypothesize that Lrg1 can be used as a therapeutic target in GVHD.We propose studies in murine allo-HSCT models and in clinical samples with the following specific aims:Aim 1. Genetic as well as pharmacologic Lrg1 depletion in experimental GVHD and mechanisms of Lrg1 production Aim 2. Functional and mechanistic analyses of Lrg1 depletion in different in vitro studiesAim 3. Lrg1 expression in human GVHD and analyses of cellular, molecular and clinical alterationsThe results from the planned experiments will contribute to: - A better understanding of the role of pathological angiogenesis during GVHD and its regulation by Lrg1. - The translational development of therapeutic strategies targeting Lrg1 in GVHD and possibly in other inflammatory diseases.